Crowded Piperidines
3016 3026
À1
oriented to place the N atom and the two ring Ca atoms in the xy plane; the
z coordinate of the third Ca atom was changed to zero. Block diagonal
minimization of this structure with restricted motion along the z coordinate
for the N atom and three Ca atoms was performed; the final step was full-
matrix minimization (option 3) for the resulting structures. In both cases
a) and b) the NIR transition states were distinguished from the ISR
transition states by normal mode vibrational analysis.
7.0 7.7 (m, 10H; Ph); IR (CCl4): nÄ 1710 (C O), 3392 cm (OH);
elemental analysis calcd (%) for C19H21NO2 (295): C 77.3, H 8.6, N 4.7;
found: C 77.0, H 8.9, N, 5.1.
1-(2-Hydroxy-2,2-diphenylethyl)-2,2,3,5,6,6-heptamethyl-4-piperidone (a
1:1 mixture of cis- and trans- isomers) (19): M.p. 127 1298C; 1H NMR
(CDCl3, the signals of the trans-isomer are marked by asterisk): d 0.57*
(s, 3H; a-Meeq), 0.71 (s, 3H; a-Meeq), 0.71* (s, 3H; a-Meeq), 0.78 (s, 3H; a-
Meax), 0.83* (s, 3H; a-Meax), 0.96* (s, 3H; a-Meax), 0.84 0.88 (m, 9H; b-
Me), 1.24* (d, 3J(H,H) 7.2 Hz, 3H; b-Me), 2.14* (q, 3J(H,H) 7.2 Hz,
A stochastic search followed by full-matrix minimization (option 9) was
used for the generation of an entire set of transition states and stable
conformations for piperidine 4. This search (200 pushes) was performed six
times, starting from different ring conformations until no new conforma-
tions were generated in the last search. Coordinates derived from the
eigenvectors (produced by option 5 and Vibplot) of vibrational modes with
imaginary frequency were employed as starting coordinates for minimiza-
tion in the establishment of the formal relationship between conformers
and transition states.
MM3*, Amber and OPLS force fields (Macromodel6.5 package[22a c]) were
used for conformation analysis of the piperidine compounds as well as
amine 25. The ™no solvent∫ and ™distance-dependent dielectric electro-
statics∫ options were employed for the energy minimization. Full-matrix
minimization (FMNR) and vibrational analysis (VIBR) options were used
in the case of the NIR transition state for piperidine 5. The ™Monte-Carlo∫
option was used for conformation search (generation of 5 Â 105 structures
for each compound with the energy upper limit 3 kcalmolÀ1 from the
lowest energy conformer found).
The Gaussian98 package[31] was used for ab initio calculations (gas phase)
of the transition state of a concerted NIR/hydrogen-bond dissociation
process in 5 by employing the Berny optimization algorithm and the
Newton Raphson optimization procedure at each level of ab initio
calculations. MM3-derived geometry for TS2 served as the starting
structure. Initial ab initio geometry optimization was performed at the
restricted Hartree Fock level with the 3-21G basis set. The resulting
geometry was optimized at the RHF/6-31G* level. For the location of the
first-order NIR transition states the ™NoEigenTest∫ option was employed
at the initial calculation step at the RHF/3-21G level, followed by the use of
the ™CalcAll∫ option in the next calculation step (at the same level of
theory). Further calculations with the ™CalcAll∫ option were carried out at
the RHF/6-31G* level.
3
2H; b-H), 2.76 (q, J 6.6 Hz, 2H; b-H), 3.54* (brs, 2H; N-CH2), 3.62 (s,
2H; N-CH2), 5.4 (brs, 1H; OH), 6.9 8.1 (m, 10H; Ph); IR (CCl4): nÄ 1716
(C O), 3400 cmÀ1 (OH); MS: m/z (%): 361 [M À H2O]; elemental analysis
calcd (%) for C25H33NO2 (379): C 79.1, H 8.7, N 3.7; found: C 78.8, H 8.9, N
3.3.
Piperidine 4: A mixture of amine 8 (10 mmol) and iodide 9 (80 mmol) was
heated for 4 5 h at 1558C in a sealed tube. After addition of hexane and
filtration the solution was treated with 1m HCl to pH ꢀ 1 and extracted
with CH2Cl2. The aqueous phase was altered to pH ꢀ 11 by using NaOH
and extracted with CHCl3. The organic phase was concentrated at 258C
and loaded on to a 4 cm layer of silica gel. Elution with CH2Cl2/diethyl
ether (4:1) afforded compound 4.
1-(2-Acetoxy-2-methylpropyl)-2,2,6,6-tetramethylpiperidine 7: A solution
of amine 6 (21 mg, 0.1 mmol), acetyl chloride (24 mg, 0.3 mmol), triethyl-
amine (30 mg, 0.3 mmol), and DMAP (5 mg) in MeCN (2 mL) was stirred
for 3 days at 258C. Water and CH2Cl2 were added, the organic layer
evaporated, and gradient chromatography on C18 reversed phase silica
(from MeCN/water (80:20) to MeCN/water (95:5); eluent volume 200 mL)
led to compound 5 (16 mg, 56%).
N-Demethylation (general procedure): A solution of amine 11, 12, or 22
(10 mmol) in a water/ketone 10a mixture (4:1, 100 mL) was irradiated
(quartz) for 8 10 h under reflux and under bubbling argon. H2SO4
(0.5 mL), K2SO4 (5 g), and CHCl3 (80 mL) were added, the aqueous phase
was treated at 08C with NaOH to pH ꢀ11 and extracted with CHCl3 (3 Â
80 mL), and the organic phase (dried over K2CO3) was concentrated.
Chromatography on silica led to compounds 20, 21, or 23, respectively.
General procedure for preparation of piperidines 5, 6, 15 19: A solution of
amine 2 (10 mmol) in a benzene/ketone 10a mixture (7:3, 100 mL) or a
solution of amines 2 or 12 (10 mmol) and ketone 10b (15 mmol) in benzene
or a solution of amines 11 14 (10 mmol) and ketone 10c (15 mmol) in
benzene (80 100 mL) in a quartz flask were irradiated under reflux with
bubbling argon for 10 15 h. A solution of H2SO4 (10 mmol) in water
(50 mL) was added, the aqueous phase treated with NaOH to pH ꢀ 12 and
extracted with CHCl3, and the organic layer evaporated and purifies by
chromatography on a silica column. Gradient elution (from CCl4 to CHCl3)
afforded compounds 5, 6, 15 19.
Acknowledgemments
We are very grateful to a group of professors from the Israeli universities,
initiators of the governmental KAMEA support program (Profs. Benjamin
Fein, Eliezer Giladi, Dan Amir, Daniel Hupert, Elisha Haas, and others),
for their insistent and generous efforts in the ratification and continuation
of the program. A Bar-Ilan University grant to A.M.B. is also acknowl-
edged.
1-(2-Hydroxy-2-phenylpropyl)-2,2,6,6-pentamethyl-4-piperidone
(15):
À1
[1] a) R. F. Francis, E. L. Colling, J. Org. Chem. 1986, 51, 1889 1891;
b) A. M. Belostotskii, A. B. Shapiro, Bull. Acad. Sci. USSR Div.
Chem. Sci. 1991, 40, 486 495; c) K. Ogawa, J. Harada, M. Endo, Y.
Takeuchi, H. Kagawa, Tetrahedron Lett. 1997, 38, 563 566; d) P.
Geneste, J. M. Kamenka, R. Rogues, J. P. DeClercq, G. Germain,
Tetrahedron Lett. 1981, 22, 949 950; e) M. Cygler, M. Markowicz, J.
Skolimowski, R. Skowronski, J. Mol. Struct. 1980, 68, 161 171.
[2] a) T. A. Crabb, A. R. Katritzky, Adv. Heterocycl. Chem. 1984, 36, 3
176; b) J.-J. Delpuech in Cyclic Organonitrogen Stereodynamics (Eds.:
J. B. Lambert, Y. Takeuchi), VCH, Weinheim, 1992, 169 250; c) S.
Profeta, Jr., R. J. Unwalla, D. J. Russell, Int. J. Supercomput. Appl.
High Perform. Comput. 1994, 8, 35 46; d) N. S. Prostakov, A. A.
Fomichev, N. I. Golovtsov, V. A. Resakov, A. V. Varlamov, Russ. J.
Org. Chem. 1986, 21, 2113 2119; e) F. A. L. Anet, I. Yavari, I. J.
Ferguson, A. R. Katritzky, M. Moreno-Manas, M. J. T. Robinson, J.
Chem. Soc. Chem. Commun. 1976, 399 400; f) A. M. Belostotskii,
A. B. Shapiro, T. V. Timofeeva, Yu. T. Struchkov, Bull. Acad. Sci.
USSR Div. Chem. Science 1991, 40, 77 82.
M.p. 83 848C; IR (CCl4): nÄ 1720 (C O), 3260 cm (OH); elemental
analysis calcd (%) for C18H27NO2 (289): C 74.7, H 9.3, N 4.8; found: C 74.4,
H 9.3, N 5.0.
8-(2-Hydroxy-2,2-diphenylethyl)-8-azabicyclo[3.2.1]octane-3-one
(16):
1
M.p. 106 1088C; H NMR (CDCl3): d 1,49 (m, 2H; H-6, H-7), 1.88 (m,
2H; H-6, H-7), 2.04 (dd, 2J(H,H) 16.5 Hz, 3J(H,H) 1.5 Hz, 2H; Hax-2,
Hax-4), 2.50 (dd, 2J(H,H) 16.5 Hz, 3J(H,H) 4.5 Hz, 2H; Heq-2, Heq-4),
3.40 (s, 2H; N-CH2), 5.4 (brs, 1H; OH), 7.2 7.8 (m, 10H; Ph); IR (CCl4):
nÄ 1710 (C O), 3372 cmÀ1 (OH); MS: m/z (%): 303 [M À H2O];
elemental analysis calcd (%) for C21H23NO2 (321): C 78.5, H 7.2, N 4.5;
found: C 78.3, H 7.4, N 4.5.
1-(2-Hydroxy-2,2-diphenylethyl)-2,2,6,6-pentamethyl-4-piperidone (17):
1
M.p. 216 2188C; H NMR (CDCl3): d 0.7 (s, 6H; a-Meeq), 1.01 (s, 6H;
2
a-Meax), 2.00 (d, J(H,H) 11.5 Hz, 2H; Hax-3, Hax-5), 2.48 (d, 2J(H,H)
11.5 Hz, 2H; Heq-3, Heq-5), 3.54 (s, 2H; N-CH2), 5.5 (brs, 1H; OH), 6.9 7.6
À1
(m, 10H; Ph); IR (CCl4): nÄ 1725 (C O), 3360 cm (OH); elemental
analysis calcd (%) for C23H29NO2 (351): C 78.6, H 8.3, N 4.0; found: C 78.6,
H 8.1, N 3.1.
[3] A. M. Belostotskii, P. Aped, A. Hassner, J. Mol. Struct. (THEO-
CHEM) 1998, 429, 265 273.
[4] A. M. Belostotskii, H. E. Gottlieb, P. Aped, A. Hassner, Chem. Eur. J.
1999, 5, 449 455.
1-(2-Hydroxy-2,2-diphenylethyl)-4-piperidone (18): M.p. 62 648C;
1H NMR (CDCl3): d 2.28 (t, 3J(H,H) 6.0 Hz, 4H; b-H), 2.67 (t,
3J(H,H) 6.0 Hz, 4H; a-H), 3.38 (s, 2H; N-CH2), 5.2 (brs, 1H; OH),
Chem. Eur. J. 2002, 8, No. 13
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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3025