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Structural and conformational study of 3,7-disubstituted 3,7-diazabicyclo[3.3.1]nonan-9-ones
Journal of Molecular Structure, 156 (1987) 239-246 Elsevier Science Publishers B.V., Amsterdam -Printed
in The Netherlands
STRUCTURAL AND CONFORMATIONAL STUDY OF 3,7-DISUBSTITUTED 3,7-DIAZABICYCL0[3.3.1]NONAN-g-ONES
M. S. ARIAS, E. GALVEZ*, J. CHICHARRO Departamento
J. C. DEL CASTILLO, J. J. VAQUERO and
de Quimica Orgirnica, Universidad de Alcalh de Henares, Madrid (Spain)
(Received 13 June 1986)
ABSTRACT 3-Alkyl-7-methyl-3,7-diazabicyclo[3,3.1]nonan-9-ones have been studied by ‘H- and ‘%-NMR spectroscopy. In CDCl, solutions, these ketones adopt a flattened chair-chair conformation with the N-substituents in the equatorial position. From the smallest (R = CH,) to the largest (R = CH(CH,),) substituent, an increase of the distortion for the N-alkylated piperidone ring is observed. INTRODUCTION
The 3,7-diazabicyclo [ 3.3.llnonane derivatives are compounds of great importance not only because of the presence of the 3,7-diazabicyclo[3.3.1]nonane (bispidine) moiety in a wide range of alkaloids, the best known of which is sparteine [l], but also because of the increasing pharmacological interest of bispidine derivatives themselves [ 21. These factors have stimulated several conformational studies on bicyclo[3.3.l]nonane derivatives as well as on the structurally related aza analogues [3--141. From the reviewed literature, it seems clearly established that the so-called chair-chair conformation is preferred to either the chair-boat or boat-boat forms (Scheme 1). However,
chair-chair
chair-
boat
boat-boat
some authors [7, 8, 12, 131 have suggested a conformational equilibrium chair-chair and chair-boat in which the stability of the less stable chairboat form increases with the size of the groups located at positions 3 and 7 and, eventually, can be the preferred conformation. Other authors [3--G, 10, 11, 141 have proposed a flattened chair-chair conformation whose conversion into the chair-boat form would not be possible unless a very bulky substituent and/or intramolecular hydrogen bonding were present. 002272860/87/$03.50
o 1987 Elsevier Science Publishers B.V.
240
In connection with our interest in the preparation and pharmacological screening of monaza- and diazabicyclo derivatives [14,15] we wish to report here the conformational and structural analysis by ‘H- and 13C-NMR spectroscopy of a series of 3-alkyl-7-methyl-3,7-diazabicyclo[3.3.l]nonan-9-ones (I-IV) (Scheme 2). The preferred conformation in CDCl, solution of the
II, III,
IV,
CH -CH3 1’ * 2’ CHr;,H2-;,H3 1’ Ekq’H3 $H3
titled compounds was established models for the structural analysis.
by using the latter of the above indicated
EXPERIMENTAL
Compounds (I-IV) were prepared following the method reported by Douglass and Ratliff [4]. The samples used for spectroscopy were distilled twice under vacuum through a 12-in. Vigreux column. ‘H-NMR spectra were recorded at 500 MHz with a Bruker AM-500 spectrometer at a spectral width of 5000 Hz. 13C-NMR spectra were obtained at 20 MHz on a Varian FT-80 A (PFT) spectrometer. Three types of spectra were recorded: proton noise-decoupled spectra (to determine the chemical shifts), off-resonance decoupled spectra (to help assign the signals) and proton-coupled spectra (to estimate the coupling constants) at a spectral width of 5000 Hz using an acquisition time of 1.64 s, a delay time of 1.64 s and a pulse width of 5 ~.ls.For proton-coupled spectra, gated decoupling with the decoupler on during delay, was employed. Solutions (13% w/v for ‘H-NMR and 25% w/v for 13C-NMR spectra) in CDC13 at 303 K with TMS as internal reference were used. RESULTS
AND DISCUSSION
Spectral analysis lH- (500 MHz) &id 13C-NMR (20 MHz) spectroscopy was used to provide the required information. The assignment for proton and carbon resonances has been made on the basis of literature data for related systems [3-141.
241
‘H-NMR spectra
The bridge protons Hl( 5) appear in all cases as a wide singlet ( W1,z = ll13 Hz). The long-range couplings between protons in a “W” orientation, HZ,--H8, or H4,,-H6,, were not observed. The signals of all the protons appear well differentiated in the spectra and the assignment of those corresponding to bicyclic system protons was made on the basis of their shape and chemical shifts. H2(4), and H6(8), signals correspond to protons gauche to the nitrogen electron pairs [8b, c, 141. H2(4), and H6(8), signals appear at higher field due to the u-electron delocalization of the nitrogen lone pair in trans-coplanar C-H bonds [Sb, c, 141. Hl, H2,, H2, (or H5, H4,, H4,) and Hl, H8,, H8, (or H5, H6,, H6,) form a three spin AMX system whose first order analysis lead to establish the protonic parameters given in Tables 1 and 2. The vicinal coupling constants 3JI-12(4),q-H1(5) and 3JH6(8)-H1(5) present low values, that could only be unambiguously measured in the cases given in Table 2; for the remaining cases, a maximum value of 2 Hz was estimated on the basis of W1,2 of the doublet peaks corresponding to H2(4), and/or H6(8),. In the spectrum of 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.l]nonan-9-one (II) all the signals appear duplicated due to the overlap of two signals of similar intensity with only a very small difference in their chemical shifts (about 2.2 Hz), except for H2( 4), and H6(8), where a slight widening of the signals was observed. The Hl( 5) signal does not change appreciably. The chemical shifts and coupling constants measured are listed in two different groups (Tables 1 and 2) and the values indicated for each parameter can be interchanged without affecting the spectrum. 13C-NMR spectra
13C-NMR chemical shifts of 3,7-diazabicyclo[3.3.1]nonan-g-ones (I-IV) are tabulated with the signal assignments in Table 3. Substituent steric and electronic effects on 13C chemical shifts [ 16,171, signal multiplicity obtained from off-resonance decoupled spectra and our previous studies of related compounds [ 141 were taken into consideration. The proton-coupled spectra of compounds I-IV show a very complex system of signals. From the first-order analysis [16,18] the one-bond, ‘Jc__n coupling constant can be calculated for all the carbon atoms as well as some of the ‘Jc-n and 3Jc_n coupling constants (Table 3). The values obtained for the coupling constants of the carbon atoms on the bicyclic system are nearly the same in the disubstituted 9-bispidinone series under investigation. The mean values, lJC1cS,-HlcS, = 138.2; 1JC2e,j-H2(4j = 135.5; 1JC,+j-H6(8j = 136.5 Hz can be proposed. Conformational
study
Among the more significant data, the range of values of 11-13 Hz observed for Wl12 of Hl(5) in the ‘H-NMR spectra of the titled compounds is in good
2.465(brs), 3.013( dd) 3.013(dd) 2.699(dd) 2.699(dd) 2.220(s) 2.220(s) -
H-1(5) H-2(4),, H-6(8),, H-2(4), H-6(8 ), N-CH, H-l’ H-2’ H-3‘ W,,, 11.0 Hz
II b
(ppm)
2.402(brs), W,,, 11.5 Hz 2.838(d) 2818(d) 2.553(dd) 2.620(dd) i.625(dd) 2.548(dd) 2.080(s) 2.085(s) 2.266(q) 2.261(q) 0.861(t) 0.856(t) -
a
I-IV
2.480(brs), 2.939(d) 2.939(d) 2.795( dd) 2.620(dd) 2.199(s) 2.266(t) 1.398(m)b 0.838(t)
III
W,,,11.0 Hz
2.459(brs), 2.892(d) 2.855(dd) 2.814(dd) 2.648(dd) 2.152(s) 2.738(m)b 0.909(d) 0.909(d)
IV
W,,Z 13.0 Hz
aDirectly measured on the spectra with an error of to.001 ppm. The abbreviations br (broad), d (doublet), dd (doublet of doublets), m (multiplet), q (quartet), s (singlet) and t (triplet) are used. bTabulated chemical shift corresponds to the centre of the multiplet.
I
Chemical shiftsa 6 (ppm)
‘H Chemical shifts of 3,7-diazabicyclo[3.3.l]nonan-g-ones
TABLE 1
243 TABLE 2 Coupling constants (Hz) deduced from the first-order analysis of the ‘H-NMR spectra of 3,7 diazabicyclo[ 3.3.1 ]nonan-g-ones I-IV I
Coupling constantsa J t-1 H2(4),-H2(4 H2(4),-Hl(5)
-11.1 5.7 2.3 -11.1 5.1 2.3 -
H2(4),,-Hl(5) H6(8),-H6(8),, H6( 8),-Hl( 5) H6(8),,-Hl(5) Hl’-H2’ H2’-H3’
IV
-10.7 7.1 <2 -11 .o 5.1 <2 1.4 7.4
-10.6 7.5 <2 -10.8 4.5 3.2 6.6 -
b
a
)es
III
II
-10.3 6.8
5.5 <2 -10.8
5.5
6.8 <2 1.2 -
aError to.2 Hz. TABLE 3 13C Chemical shifts (ppm) and ‘“C--‘H nonan-g-ones I-IV I Chemical shift.+ 6 (ppm) 46.81 C-l(5) (d) 61.05 C-2(4) (t) 61.05 C-6(8) (t) c-9 (s) 214.27 45.05 N--CH, (q) C-l ’ 45.05(q) C-2’ C-3’ Coupling constant& Cl(5 jHl(5) C2(4)-H2(4) C6(8 jH6(8) C(CH,)_H Cl’-Hl’ C2’-H2’ C3’-H3’
‘JC-H (Hz) 138.0 136.0 136.0 133.0 133.0 -
coupling constants (Hz) of 3,7-diazabicyclo[3.3.1]-
II
III
IV
46.66 58.17 60.76 213.93 44.86 50.69(t) 12.35(q) -
46.73 58.62c 60.63 213.84 44.88 58.75(t)C 20.44(t) 11.85(q)
46.84 54.04 60.33 214.62 44.91 53.41(d) 18.40(q) 18.40(q)
138.2 135.4 136.6 133.0 133.1 125.5 -
138.8 135.0 137.5 133.0
138.0 136.4 135.6 133.0 133.0 125.0 125.0
-d
125.0 121.5
aDirectly measured on the spectra. Error kO.05 ppm. Signal multiplicity obtained from off-resonance decoupled spectra: s (singlet), d (doublet), t (triplet), q (quartet). b Deduced from the proton coupled spectra. Error +l Hz. The following coupling constants were also established: ZJC2’-H1’, 12.81 Hz (II) and 13.31Hz (IV); ‘JC(CH,)-H2(4), 1.7 Hz for II, III and IV; ‘JC2’-H3’, 4.8 Hz for IV. CValues may be interchanged. dThis coupling constant could not be established.
244
agreement with previously reported values for a flattened chair--chair conformation in related bicyclic systems with the N-substituents in the equatorial position [3-6, 10, 11, 141. Furthermore, Ah Hz(4JaX-Hs(sjax slightly increases from I (R = CH3) to IV (R = CH(CH,),) because the decrease of the truns-coplanarity of the nitrogen lone pair with HZtajax is higher than with H 6(8jax and in consequence the chair form of the N-alkylated piperidone ring must be slightly more flat than the N-methylpiperidone ring. It was found that, in all cases, the following relations are present: 3JH~(4~ax-H~~s~> 3JH~(+p-H~(~j; 3JH~(sjax-H~(~j > 3JHs(sjeg-H1( 5); 3JH~(4ja~H l(5) > 3JHs~qax-H~w. Hence the dihedral angle H2~4~ax-C-C-H1~5~ (and H 6(8)ax-C-C-H& is smaller than H2~l~es-C-C-H10~ (and H,,,,,,--C-CHlcsj) which is in keeping with the Karplus relationship [19]. Furthermore, the dihedral angle HZtJjax-C-C-H,,,, is smaller than H6(8jaX-C+-H1(5j, except for I (R = CHB) where both angles have the same value and no change of the latter was observed (3JHs(s)aX-H1(sj = 5 Hz) whereas the former decreases from I to III [3JH2(,+jaX-H 1(5J takes value from 5.7 (R = CH3) to 7.1 (R = CH(CH3),]. Th ese facts are also more consistent with a chair-chair flattened conformation than with a chair-boat conformation since the latter form should not only give a value of ca. 10 Hz for 3JH2(4jaX-H1(5j but also the signal corresponding to Hl(5) should appear as an apparent doublet, a common feature in previously reported systems that adopt the chair-boat conformation [ 141. Qualitatively, the forementioned conclusions can also be applied to the 9-bispidinone (IV) [R = CH(CH,),] even though the smaller difference found . . in this compound between 3m6(8)aX-HltSj and 3JH6(8)esH1(5j (Table 2) can be explained if the N-methyl piperidone ring adopts a less distorted form than in the rest of the cases as result of a higher distortion of the N-isopropyl piperidone ring. The peaks duplicity observed in the spectrum of the compound II (R = CH2-CH3) suggests a conformational equilibrium between two flattened chair-chair conformations [6a]. -The most likely cause for this behaviour seems to be the similar effect on the molecular geometry provoked by the great similarity of methyl and ethyl substituents. In fact, the values of the coupling constants (3JH~(4jaX-H1(5) = 6.8 Hz and 3JH6(8jaX-H1(5j = 5.5 Hz for one conformer and 3JH2(4jaX-H1(sj = 5.5 Hz and 3JHs(sjaX-H1(5j = 6.8 Hz for the other one) predict a similar distortion in each conformer. 13C-NMR spectra of the 3-alkyl-7-methyl-3,7The proton noise-decoupled diazabicyclo[3.3.l]nonan-g-ones (I-IV) are very simple, with a lone signal for each kind of carbon atom (Table 3). The chemical shifts of C1(5), C6(8), C9(CO) and A%-CH3 are very similar in this series of bispidinones. The most significant change was observed for C2( 4). The chemical shifts of the carbon atoms of CH2 alpha to nitrogen, C2(4) and C6(8), are in good agreement with previously reported values for CH2 of related systems [ll, 141 in which the piperidine ring adopts a flattened chair-chair conformation. A6 C6(8j-C2(4j from I to IV is due to the increased
245
ring. The eclipsing between H2(4jBx-H1(5) in the more flattened chair-chair = 0 for compound I suggests the same degree of disvalue of A6C6(s) --G(4) tortion in each piperidone ring whereas the rest of the values (2.59 (II), 2.01 (III) and 6.29 ppm (IV)) are in accord with a more flattened conformation for the N-alkylated piperidone ring. The unusually high value found for compound IV can be explained by an additional shielding due to the y effect of the isopropyl group [16,17]. The possibility that in this case the iv-isopropyl piperidone ring must adopt a boat conformation was also explored but discarded on the basis of ‘H-NMR I-IV (ca. 45 ppm, data. The N--CH3 13C chemical shifts of compounds Table 3) are consistent with the N-CH3 group occupying the equatorial position of a flattened chair piperidone ring. The last statement can also be applied to the other substituents even though their different nature makes it impossible to carry out a comparative study. In summary, several points of evidence lead to establish that the 3-alkyl7-methyl-3,7diazabicyclo[3.3.l]nonan-9-ones under investigation adopt, in CDC13 solution, a flattened chair--chair conformation with the N-substituents in equatorial positions. Furthermore, from the smallest (R = CH3) to the largest (R = CH(CH,),) N-substituent, an increase in distortion of the Nalkylated piperidone ring is observed. Finally, the presence of an sp2-hybridized carbonyl carbon facilitates [6a] the flattening of the six-membered ring and diminishes the severity of the steric interactions. This fact is an additional support for the aforementioned conclusions. ACKNOWLEDGEMENTS
We thank the Comision Asesora de Investigacibn 1750/82) for support of this research.
Ciencia y Tecnica (Grant
REFERENCES 1 N. Reuter, E. Heeg and II. Hailer, Arch. Pharmacol., 268 (1971) 323. 2 R. Jerayaman and S. Avila, Chem. Rev., 81 (1981) 149. 3 (a) R. Haller, Arzneitmittelforsch., 15 (1965) 1327. (b) R. Haller, Arch. Pharmaz., 302 (1969) 113. (c) R. Haller and H. Hunholzer, Arch. Pharmaz., 304 (1971) 654. (d) R. Haller and H. Hunholzer, Arch. Pharmaz., 304 (1971) 866. (e) R. Haller and H. Hunholzer, Arch. Pharmaz., 305 (1972) 855. 4 J. E. Douglass and T. B. Ratliff, J. Org. Chem., 33 (1968) 355. 5 N. S. Zefirov and S. V. Rogozina, Tetrahedron, 30 (1974) 2345. 6 (a) J. R. Wiseman and H. 0. Krabbenhoft, J. Org. Chem., 40 (1975) 3222. (b) J. R. Wiseman and H. 0. Krabbenhoft, J. Org. Chem., 42 (1977) 2240. 7 (a) P. Scheiber and K. Nador, Acta Chim. Acad. Sci. Hung., 84 (1975) 193. (b) P. Scheiber and K. Nador, Acta Chim. Acad. Sci. Hung., 102 (1979) 297. 8 (a) E. E. Smissman and P. C. Ruenitz, J. Med. Chem., 19 (1976) 184. (b) P. C. Ruenitz and E. E. Smissman, J. Org. Chem., 42 (1977) 937. (c) P. C. Ruenitz, J. Org. Chem., 43 (1978) 2910 and references therein. 9V. Baliah and R. Jerayaman, Ind. J. Chem., 16B (1978) 597,1197.
246 10s. K. Bhattacharjee and K. K. Chacko, Tetrahedron, 35 (1979) 1999. 11 P. Livant, K. A. Roberts, M. D. Eggers and S. D. Worley, Tetrahedron, 37 (1981) 1853. 12 R. Caujolle, P. Castera and A, Lattes, Bull. Sot. Chim. Fr., (9-10, Pt II) (1984) 413. 13L. M. Jackman, T. S. Dunne, J. L. Roberts, B. Miiller and H. Quast, J. Mol. Struct., 126 (1985) 433. 14 E. Gdlvez, M. S. Arias, J. Bellanato, J. V. Garcia-Ramos, F. Florencio, P. Smith Verdier and S. Garcia-Blanco, J. Mol. Struct., 127 (1985) 185. 15 M. S. Arias, E. Gblvez, M. L. Izquierdo and C. Burgos, J. Mol. Struct., 147 (1986) 381. 16 F. W. Werhii and T. Wirthlin, Interpretation of Carbon-13 NMR Spectra, Heyden, London, 1980. 17 E. Breitmaier and W. Voelter, I%-NMR Spectroscopy Methods and Applications in Organic Chemistry, 2nd edn., Verlag Chemie, Weinheim, 1978. 18 J. L. Marshall, Carbon-Carbon and Carbon-Proton NMR Couplings: Applications to Organic Stereochemistry and Conformational Analysis, Verlag Chemie International, Deerfield Beach, FL, 1983. 19 C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona, Tetrahedron, 36 (1980) 2783.
in The Netherlands
STRUCTURAL AND CONFORMATIONAL STUDY OF 3,7-DISUBSTITUTED 3,7-DIAZABICYCL0[3.3.1]NONAN-g-ONES
M. S. ARIAS, E. GALVEZ*, J. CHICHARRO Departamento
J. C. DEL CASTILLO, J. J. VAQUERO and
de Quimica Orgirnica, Universidad de Alcalh de Henares, Madrid (Spain)
(Received 13 June 1986)
ABSTRACT 3-Alkyl-7-methyl-3,7-diazabicyclo[3,3.1]nonan-9-ones have been studied by ‘H- and ‘%-NMR spectroscopy. In CDCl, solutions, these ketones adopt a flattened chair-chair conformation with the N-substituents in the equatorial position. From the smallest (R = CH,) to the largest (R = CH(CH,),) substituent, an increase of the distortion for the N-alkylated piperidone ring is observed. INTRODUCTION
The 3,7-diazabicyclo [ 3.3.llnonane derivatives are compounds of great importance not only because of the presence of the 3,7-diazabicyclo[3.3.1]nonane (bispidine) moiety in a wide range of alkaloids, the best known of which is sparteine [l], but also because of the increasing pharmacological interest of bispidine derivatives themselves [ 21. These factors have stimulated several conformational studies on bicyclo[3.3.l]nonane derivatives as well as on the structurally related aza analogues [3--141. From the reviewed literature, it seems clearly established that the so-called chair-chair conformation is preferred to either the chair-boat or boat-boat forms (Scheme 1). However,
chair-chair
chair-
boat
boat-boat
some authors [7, 8, 12, 131 have suggested a conformational equilibrium chair-chair and chair-boat in which the stability of the less stable chairboat form increases with the size of the groups located at positions 3 and 7 and, eventually, can be the preferred conformation. Other authors [3--G, 10, 11, 141 have proposed a flattened chair-chair conformation whose conversion into the chair-boat form would not be possible unless a very bulky substituent and/or intramolecular hydrogen bonding were present. 002272860/87/$03.50
o 1987 Elsevier Science Publishers B.V.
240
In connection with our interest in the preparation and pharmacological screening of monaza- and diazabicyclo derivatives [14,15] we wish to report here the conformational and structural analysis by ‘H- and 13C-NMR spectroscopy of a series of 3-alkyl-7-methyl-3,7-diazabicyclo[3.3.l]nonan-9-ones (I-IV) (Scheme 2). The preferred conformation in CDCl, solution of the
II, III,
IV,
CH -CH3 1’ * 2’ CHr;,H2-;,H3 1’ Ekq’H3 $H3
titled compounds was established models for the structural analysis.
by using the latter of the above indicated
EXPERIMENTAL
Compounds (I-IV) were prepared following the method reported by Douglass and Ratliff [4]. The samples used for spectroscopy were distilled twice under vacuum through a 12-in. Vigreux column. ‘H-NMR spectra were recorded at 500 MHz with a Bruker AM-500 spectrometer at a spectral width of 5000 Hz. 13C-NMR spectra were obtained at 20 MHz on a Varian FT-80 A (PFT) spectrometer. Three types of spectra were recorded: proton noise-decoupled spectra (to determine the chemical shifts), off-resonance decoupled spectra (to help assign the signals) and proton-coupled spectra (to estimate the coupling constants) at a spectral width of 5000 Hz using an acquisition time of 1.64 s, a delay time of 1.64 s and a pulse width of 5 ~.ls.For proton-coupled spectra, gated decoupling with the decoupler on during delay, was employed. Solutions (13% w/v for ‘H-NMR and 25% w/v for 13C-NMR spectra) in CDC13 at 303 K with TMS as internal reference were used. RESULTS
AND DISCUSSION
Spectral analysis lH- (500 MHz) &id 13C-NMR (20 MHz) spectroscopy was used to provide the required information. The assignment for proton and carbon resonances has been made on the basis of literature data for related systems [3-141.
241
‘H-NMR spectra
The bridge protons Hl( 5) appear in all cases as a wide singlet ( W1,z = ll13 Hz). The long-range couplings between protons in a “W” orientation, HZ,--H8, or H4,,-H6,, were not observed. The signals of all the protons appear well differentiated in the spectra and the assignment of those corresponding to bicyclic system protons was made on the basis of their shape and chemical shifts. H2(4), and H6(8), signals correspond to protons gauche to the nitrogen electron pairs [8b, c, 141. H2(4), and H6(8), signals appear at higher field due to the u-electron delocalization of the nitrogen lone pair in trans-coplanar C-H bonds [Sb, c, 141. Hl, H2,, H2, (or H5, H4,, H4,) and Hl, H8,, H8, (or H5, H6,, H6,) form a three spin AMX system whose first order analysis lead to establish the protonic parameters given in Tables 1 and 2. The vicinal coupling constants 3JI-12(4),q-H1(5) and 3JH6(8)-H1(5) present low values, that could only be unambiguously measured in the cases given in Table 2; for the remaining cases, a maximum value of 2 Hz was estimated on the basis of W1,2 of the doublet peaks corresponding to H2(4), and/or H6(8),. In the spectrum of 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.l]nonan-9-one (II) all the signals appear duplicated due to the overlap of two signals of similar intensity with only a very small difference in their chemical shifts (about 2.2 Hz), except for H2( 4), and H6(8), where a slight widening of the signals was observed. The Hl( 5) signal does not change appreciably. The chemical shifts and coupling constants measured are listed in two different groups (Tables 1 and 2) and the values indicated for each parameter can be interchanged without affecting the spectrum. 13C-NMR spectra
13C-NMR chemical shifts of 3,7-diazabicyclo[3.3.1]nonan-g-ones (I-IV) are tabulated with the signal assignments in Table 3. Substituent steric and electronic effects on 13C chemical shifts [ 16,171, signal multiplicity obtained from off-resonance decoupled spectra and our previous studies of related compounds [ 141 were taken into consideration. The proton-coupled spectra of compounds I-IV show a very complex system of signals. From the first-order analysis [16,18] the one-bond, ‘Jc__n coupling constant can be calculated for all the carbon atoms as well as some of the ‘Jc-n and 3Jc_n coupling constants (Table 3). The values obtained for the coupling constants of the carbon atoms on the bicyclic system are nearly the same in the disubstituted 9-bispidinone series under investigation. The mean values, lJC1cS,-HlcS, = 138.2; 1JC2e,j-H2(4j = 135.5; 1JC,+j-H6(8j = 136.5 Hz can be proposed. Conformational
study
Among the more significant data, the range of values of 11-13 Hz observed for Wl12 of Hl(5) in the ‘H-NMR spectra of the titled compounds is in good
2.465(brs), 3.013( dd) 3.013(dd) 2.699(dd) 2.699(dd) 2.220(s) 2.220(s) -
H-1(5) H-2(4),, H-6(8),, H-2(4), H-6(8 ), N-CH, H-l’ H-2’ H-3‘ W,,, 11.0 Hz
II b
(ppm)
2.402(brs), W,,, 11.5 Hz 2.838(d) 2818(d) 2.553(dd) 2.620(dd) i.625(dd) 2.548(dd) 2.080(s) 2.085(s) 2.266(q) 2.261(q) 0.861(t) 0.856(t) -
a
I-IV
2.480(brs), 2.939(d) 2.939(d) 2.795( dd) 2.620(dd) 2.199(s) 2.266(t) 1.398(m)b 0.838(t)
III
W,,,11.0 Hz
2.459(brs), 2.892(d) 2.855(dd) 2.814(dd) 2.648(dd) 2.152(s) 2.738(m)b 0.909(d) 0.909(d)
IV
W,,Z 13.0 Hz
aDirectly measured on the spectra with an error of to.001 ppm. The abbreviations br (broad), d (doublet), dd (doublet of doublets), m (multiplet), q (quartet), s (singlet) and t (triplet) are used. bTabulated chemical shift corresponds to the centre of the multiplet.
I
Chemical shiftsa 6 (ppm)
‘H Chemical shifts of 3,7-diazabicyclo[3.3.l]nonan-g-ones
TABLE 1
243 TABLE 2 Coupling constants (Hz) deduced from the first-order analysis of the ‘H-NMR spectra of 3,7 diazabicyclo[ 3.3.1 ]nonan-g-ones I-IV I
Coupling constantsa J t-1 H2(4),-H2(4 H2(4),-Hl(5)
-11.1 5.7 2.3 -11.1 5.1 2.3 -
H2(4),,-Hl(5) H6(8),-H6(8),, H6( 8),-Hl( 5) H6(8),,-Hl(5) Hl’-H2’ H2’-H3’
IV
-10.7 7.1 <2 -11 .o 5.1 <2 1.4 7.4
-10.6 7.5 <2 -10.8 4.5 3.2 6.6 -
b
a
)es
III
II
-10.3 6.8
5.5 <2 -10.8
5.5
6.8 <2 1.2 -
aError to.2 Hz. TABLE 3 13C Chemical shifts (ppm) and ‘“C--‘H nonan-g-ones I-IV I Chemical shift.+ 6 (ppm) 46.81 C-l(5) (d) 61.05 C-2(4) (t) 61.05 C-6(8) (t) c-9 (s) 214.27 45.05 N--CH, (q) C-l ’ 45.05(q) C-2’ C-3’ Coupling constant& Cl(5 jHl(5) C2(4)-H2(4) C6(8 jH6(8) C(CH,)_H Cl’-Hl’ C2’-H2’ C3’-H3’
‘JC-H (Hz) 138.0 136.0 136.0 133.0 133.0 -
coupling constants (Hz) of 3,7-diazabicyclo[3.3.1]-
II
III
IV
46.66 58.17 60.76 213.93 44.86 50.69(t) 12.35(q) -
46.73 58.62c 60.63 213.84 44.88 58.75(t)C 20.44(t) 11.85(q)
46.84 54.04 60.33 214.62 44.91 53.41(d) 18.40(q) 18.40(q)
138.2 135.4 136.6 133.0 133.1 125.5 -
138.8 135.0 137.5 133.0
138.0 136.4 135.6 133.0 133.0 125.0 125.0
-d
125.0 121.5
aDirectly measured on the spectra. Error kO.05 ppm. Signal multiplicity obtained from off-resonance decoupled spectra: s (singlet), d (doublet), t (triplet), q (quartet). b Deduced from the proton coupled spectra. Error +l Hz. The following coupling constants were also established: ZJC2’-H1’, 12.81 Hz (II) and 13.31Hz (IV); ‘JC(CH,)-H2(4), 1.7 Hz for II, III and IV; ‘JC2’-H3’, 4.8 Hz for IV. CValues may be interchanged. dThis coupling constant could not be established.
244
agreement with previously reported values for a flattened chair--chair conformation in related bicyclic systems with the N-substituents in the equatorial position [3-6, 10, 11, 141. Furthermore, Ah Hz(4JaX-Hs(sjax slightly increases from I (R = CH3) to IV (R = CH(CH,),) because the decrease of the truns-coplanarity of the nitrogen lone pair with HZtajax is higher than with H 6(8jax and in consequence the chair form of the N-alkylated piperidone ring must be slightly more flat than the N-methylpiperidone ring. It was found that, in all cases, the following relations are present: 3JH~(4~ax-H~~s~> 3JH~(+p-H~(~j; 3JH~(sjax-H~(~j > 3JHs(sjeg-H1( 5); 3JH~(4ja~H l(5) > 3JHs~qax-H~w. Hence the dihedral angle H2~4~ax-C-C-H1~5~ (and H 6(8)ax-C-C-H& is smaller than H2~l~es-C-C-H10~ (and H,,,,,,--C-CHlcsj) which is in keeping with the Karplus relationship [19]. Furthermore, the dihedral angle HZtJjax-C-C-H,,,, is smaller than H6(8jaX-C+-H1(5j, except for I (R = CHB) where both angles have the same value and no change of the latter was observed (3JHs(s)aX-H1(sj = 5 Hz) whereas the former decreases from I to III [3JH2(,+jaX-H 1(5J takes value from 5.7 (R = CH3) to 7.1 (R = CH(CH3),]. Th ese facts are also more consistent with a chair-chair flattened conformation than with a chair-boat conformation since the latter form should not only give a value of ca. 10 Hz for 3JH2(4jaX-H1(5j but also the signal corresponding to Hl(5) should appear as an apparent doublet, a common feature in previously reported systems that adopt the chair-boat conformation [ 141. Qualitatively, the forementioned conclusions can also be applied to the 9-bispidinone (IV) [R = CH(CH,),] even though the smaller difference found . . in this compound between 3m6(8)aX-HltSj and 3JH6(8)esH1(5j (Table 2) can be explained if the N-methyl piperidone ring adopts a less distorted form than in the rest of the cases as result of a higher distortion of the N-isopropyl piperidone ring. The peaks duplicity observed in the spectrum of the compound II (R = CH2-CH3) suggests a conformational equilibrium between two flattened chair-chair conformations [6a]. -The most likely cause for this behaviour seems to be the similar effect on the molecular geometry provoked by the great similarity of methyl and ethyl substituents. In fact, the values of the coupling constants (3JH~(4jaX-H1(5) = 6.8 Hz and 3JH6(8jaX-H1(5j = 5.5 Hz for one conformer and 3JH2(4jaX-H1(sj = 5.5 Hz and 3JHs(sjaX-H1(5j = 6.8 Hz for the other one) predict a similar distortion in each conformer. 13C-NMR spectra of the 3-alkyl-7-methyl-3,7The proton noise-decoupled diazabicyclo[3.3.l]nonan-g-ones (I-IV) are very simple, with a lone signal for each kind of carbon atom (Table 3). The chemical shifts of C1(5), C6(8), C9(CO) and A%-CH3 are very similar in this series of bispidinones. The most significant change was observed for C2( 4). The chemical shifts of the carbon atoms of CH2 alpha to nitrogen, C2(4) and C6(8), are in good agreement with previously reported values for CH2 of related systems [ll, 141 in which the piperidine ring adopts a flattened chair-chair conformation. A6 C6(8j-C2(4j from I to IV is due to the increased
245
ring. The eclipsing between H2(4jBx-H1(5) in the more flattened chair-chair = 0 for compound I suggests the same degree of disvalue of A6C6(s) --G(4) tortion in each piperidone ring whereas the rest of the values (2.59 (II), 2.01 (III) and 6.29 ppm (IV)) are in accord with a more flattened conformation for the N-alkylated piperidone ring. The unusually high value found for compound IV can be explained by an additional shielding due to the y effect of the isopropyl group [16,17]. The possibility that in this case the iv-isopropyl piperidone ring must adopt a boat conformation was also explored but discarded on the basis of ‘H-NMR I-IV (ca. 45 ppm, data. The N--CH3 13C chemical shifts of compounds Table 3) are consistent with the N-CH3 group occupying the equatorial position of a flattened chair piperidone ring. The last statement can also be applied to the other substituents even though their different nature makes it impossible to carry out a comparative study. In summary, several points of evidence lead to establish that the 3-alkyl7-methyl-3,7diazabicyclo[3.3.l]nonan-9-ones under investigation adopt, in CDC13 solution, a flattened chair--chair conformation with the N-substituents in equatorial positions. Furthermore, from the smallest (R = CH3) to the largest (R = CH(CH,),) N-substituent, an increase in distortion of the Nalkylated piperidone ring is observed. Finally, the presence of an sp2-hybridized carbonyl carbon facilitates [6a] the flattening of the six-membered ring and diminishes the severity of the steric interactions. This fact is an additional support for the aforementioned conclusions. ACKNOWLEDGEMENTS
We thank the Comision Asesora de Investigacibn 1750/82) for support of this research.
Ciencia y Tecnica (Grant
REFERENCES 1 N. Reuter, E. Heeg and II. Hailer, Arch. Pharmacol., 268 (1971) 323. 2 R. Jerayaman and S. Avila, Chem. Rev., 81 (1981) 149. 3 (a) R. Haller, Arzneitmittelforsch., 15 (1965) 1327. (b) R. Haller, Arch. Pharmaz., 302 (1969) 113. (c) R. Haller and H. Hunholzer, Arch. Pharmaz., 304 (1971) 654. (d) R. Haller and H. Hunholzer, Arch. Pharmaz., 304 (1971) 866. (e) R. Haller and H. Hunholzer, Arch. Pharmaz., 305 (1972) 855. 4 J. E. Douglass and T. B. Ratliff, J. Org. Chem., 33 (1968) 355. 5 N. S. Zefirov and S. V. Rogozina, Tetrahedron, 30 (1974) 2345. 6 (a) J. R. Wiseman and H. 0. Krabbenhoft, J. Org. Chem., 40 (1975) 3222. (b) J. R. Wiseman and H. 0. Krabbenhoft, J. Org. Chem., 42 (1977) 2240. 7 (a) P. Scheiber and K. Nador, Acta Chim. Acad. Sci. Hung., 84 (1975) 193. (b) P. Scheiber and K. Nador, Acta Chim. Acad. Sci. Hung., 102 (1979) 297. 8 (a) E. E. Smissman and P. C. Ruenitz, J. Med. Chem., 19 (1976) 184. (b) P. C. Ruenitz and E. E. Smissman, J. Org. Chem., 42 (1977) 937. (c) P. C. Ruenitz, J. Org. Chem., 43 (1978) 2910 and references therein. 9V. Baliah and R. Jerayaman, Ind. J. Chem., 16B (1978) 597,1197.
246 10s. K. Bhattacharjee and K. K. Chacko, Tetrahedron, 35 (1979) 1999. 11 P. Livant, K. A. Roberts, M. D. Eggers and S. D. Worley, Tetrahedron, 37 (1981) 1853. 12 R. Caujolle, P. Castera and A, Lattes, Bull. Sot. Chim. Fr., (9-10, Pt II) (1984) 413. 13L. M. Jackman, T. S. Dunne, J. L. Roberts, B. Miiller and H. Quast, J. Mol. Struct., 126 (1985) 433. 14 E. Gdlvez, M. S. Arias, J. Bellanato, J. V. Garcia-Ramos, F. Florencio, P. Smith Verdier and S. Garcia-Blanco, J. Mol. Struct., 127 (1985) 185. 15 M. S. Arias, E. Gblvez, M. L. Izquierdo and C. Burgos, J. Mol. Struct., 147 (1986) 381. 16 F. W. Werhii and T. Wirthlin, Interpretation of Carbon-13 NMR Spectra, Heyden, London, 1980. 17 E. Breitmaier and W. Voelter, I%-NMR Spectroscopy Methods and Applications in Organic Chemistry, 2nd edn., Verlag Chemie, Weinheim, 1978. 18 J. L. Marshall, Carbon-Carbon and Carbon-Proton NMR Couplings: Applications to Organic Stereochemistry and Conformational Analysis, Verlag Chemie International, Deerfield Beach, FL, 1983. 19 C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona, Tetrahedron, 36 (1980) 2783.