Novel stereoselective synthesis of chiral nonracemic cis- and trans-3-alkyl-4-aminopiperidines

Full text of DOI:10.1023/B:COHC.0000033553.66254.0d

Chemistry of Heterocyclic Compounds, Vol. 40, No. 4, 2004
NOVEL STEREOSELECTIVE SYNTHESIS
OF CHIRAL NONRACEMIC cis- AND
trans-3-ALKYL-4-AMINOPIPERIDINES
E. R. Lukyanenko, A. A. Borisenko, and G. V. Grishina
Keywords: 4-aminopiperidines, cis and trans isomers, stereoselective synthesis.
We have shown that previously unknown optically pure trans-(3R,4R) isomers 4a-d with diastereomeric
excess de > 99% and the diastereomeric pair of cis-(3S,4R),-(3R,4S) isomers 3a-d with de < 71% of
N-[(1S)-1-phenylethyl]-4-amino-1,3-dialkylpiperidine are formed in 46%-90% yield by sequential lithiation and
alkylation by alkyl halides of the chiral imines 1a,b, with formation of Z-(3S)-3-alkyl- and Z-(3R)-3-alkylimines
2a-d followed by their reduction by sodium borohydride in ethanol. The entire reaction sequence is carried out
with no isolation of intermediates.
The cis isomers 3a-d and the trans isomers 4a-d were separated by column chromatography on
aluminum oxide; their structure and diastereomeric purity were established from elemental analysis, chromato-
1
mass spectrometry, and H, 13C NMR spectra. The cis and trans structure of isomers 3a-d and 4a-d was
established by analysis of the vicinal spin–spin coupling constants for the 3-H and 4-H protons of the piperidine
ring, using high-resolution one-dimensional and two-dimensional 1H NMR spectroscopy. Formation of only the
Me
N
N
Ph
O
(S)-PhCH(Me)NH2
1. LiNEt2
2. R1Hal
N
R
R
1a,b
Me
Me
Me
Me
Ph
R1
HN
N
Ph
R1
N
Ph
R1
Ph
R1
HN
3. NaBH4
+
+
N
R
N
R
N
R
N
R
Z-2a–d
3a–d
4a–d
1а R = Bn, b R = Me; 2–4 a R = Bn, R1 = Me; b R = Me, R1 = Me; c R = Me, R1 = Allyl;
d R = Me, R1 = CH2OMe
__________________________________________________________________________________________
M. V. Lomonosov Moscow State University, Moscow 119899, Russia; e-mail:
grishina@org.chem.msu.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 622-624,
April, 2004. Submitted February 4, 2004.
0009-3122/04/4004-0525©2004 Plenum Publishing Corporation
525

Z-form of the diastereomeric imines 2a-d is supported by the presence in the 13C NMR spectra of reaction
samples (after completion of the alkylation process) of signals from the C(4) atoms of only the Z-form of the (3S)-
and (3R)-isomers of imine 2b; signals from the E-form of these isomers appear after these samples have been
held for 10 h at room temperature, which is quite consistent with the data in [1-3]. Key factors determining the
diastereoselectivity of the process are the ratio of the Z-(3S)- and Z-(3R)-imines 2a-d formed and the subsequent
preference for hydride attack on one side of the prochiral C=N bond. The absolute configuration of the target
1,3-dialkyl-4-aminopiperidines was determined by the stereochemical correlation method, in line with the
configuration of (3R,4S)-cis-N-[(1S)-1-phenylethyl]-4-amino-1-methyl-3-(4-methylbenzyl)piperidine, as
established by X-ray diffraction.
The stereoselective synthesis we developed is the first general approach to optically pure trans isomers
and enriched cis isomers of 3-alkyl-4-aminopiperidines, which are chiral synthons for obtaining next-generation
analgesics.
Synthesis of the Compounds 3a-d and 4a-d, Using as an Example the cis and trans Isomers of
N-[(1S)-1-phenylethyl]-4-amino-1,3-dimethylpiperidine (3b, 4b) (General Procedure). The reaction was
carried out under an argon atmosphere using a septum and a syringe procedure. (1S)-N-(1-Methylpiperidin-4-
ylidene)-1-phenylethylamine (3 g, 13.9 mmol) in absolute THF (5 ml) was added to a solution of lithium
diethylamide, obtained at -10°C by stirring for 10 min a mixture of solutions of HNEt2 (1.32 g, 18 mmol) in
absolute THF (20 ml) and a 1.6 N BuLi solution in hexane (11.3 ml, 18 mmol). The reaction mixture was stirred
for 30 min at -10°C, then cooled down to -80°C; then MeI (2.56 g, 18 mmol) was added and the mixture was
stirred for 1 h at -80°C. Then in sequence we added absolute ethanol (2 ml) and NaBH4 (0.68 g, 18 mmol) and
then stirred this mixture for another hour at -80°C. Then the reaction mixture was allowed to stand with vigorous
stirring in order to warm up to room temperature. The solvents were evaporated off, the residue was decomposed
by careful addition of 6 N HCl until evolution of hydrogen stopped; then water (10 ml) was added, and a 20%
NaOH solution was added up to pH 12-13 and it was extracted with CH2Cl2 (2 × 30 ml). The organic extracts
were combined and dried with anhydrous Na2SO4, and then the solvent was evaporated off. The residue was
chromatographed on a column with Al2O3 in the hexane–EtOAc system with a gradient from 30:1 to 1:1. We
obtained 1.42 g (44%) of the cis-(3S,4R) and (3R,4S) diastereomeric pair 3b and 1.45 g (45%) of the
trans-(3R,4R) diastereomer 4b of N-[(1S)-1-phenylethyl]-4-amino-1,3-dimethylpiperidine. (3S,4R),(3R,4S)-3b:
20
de 29%, Rf 0.6 (Alufol, hexane–acetone 1:1), [α]D -59° (c 2.0, benzene). Chromato-mass spectrum (retention
time), m/z (Irel, %): (3R,4S)-3b: (12.08 min) 232 [M]+ (1); 127 [M - CH(CH3)C6H5]+ (100); 105 [CH(CH3)C6H5]+
(49); 96 (64); (3S, 4R)-3b: (12.20 min) 232 [M]+ (1); 127 [M - CH(CH3)C6H5]+ (100); 105 [CH(CH3)C6H5]+
20
(61); 96 (88); (3R,4R)-4b: de > 99%, Rf 0.2 (Alufol, hexane–acetone 1:1), [α]D -108° (c 2.0, benzene).
1H NMR spectrum (400 MHz, CDCl3, TMS), δ, ppm (J, Hz): 0.89 (3H, d, J = 6.2, 3-CH3); 1.04 (1H, br. s, NH);
1.26 (1H, m, J = 4.0, J = 11.0, J = 12.4, J = 12.6, 5a-H); 1.31 (3H, d, J = 6.4, CH(CH3)C6H5); 1.49 (1H, t,
J = 10.8, J = 10.8, 2a-H); 1.53 (1H, m, J = 2.1, J = 10.8, J = 6.2, J = 12.0, 3a-H); 1.71-1.78 (2H, m, J = 11.8,
J = 12.4, J = 3.0, J = 11.0, J = 4.1, J = 11.1, 4a-,6a-H); 2.04 (1H, d of pseudo q, J = 3.0, J = 12.7, J = 4.1,
J = 2.9, 5e-H); 2.17 (3H, s, 1-CH3); 2.69 (1H, dd, J = 7.3, J = 2.1, 2e-H); 2.78 (1H, m, J = 4.0, J = 4.1, J = 11.1,
J = 1.0, 6e-H); 3.95 (1H, q, J = 6.4, CH(CH3)C6H5); 7.19-7.33 (5H, m, CH(CH3)C6H5). 13C spectrum (CDCl3,
100 MHz, TMS), δ, ppm: 16.3; 25.7; 31.9; 37.2; 46.1; 54.1; 55.1; 57.3; 63.0; 126.6, 126.6, 128.2, 146.0.
Chromato-mass spectrum (retention time), m/z (Irel, %): (12.09 min) 232 [M]+ (1); 127 [M-CH(CH3)C6H5]+ (44);
105 [CH(CH3)C6H5]+ (48), 96 (100). Found, %: C 47.10; H 4.37; N 16.06. C15H24N2·2C6H3N3O7 (dipicrate).
Calculated, %: C 46.96; H 4.38; N 16.23.
This work was carried out with the financial support of the Russian Foundation for Basic Research, grant
No. 01-03-32781a.
526

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