Asymmetric synthesis and stereochemistry of chiral cis-and trans-3-alkyl-4-aminopiperidines

Article abstract of DOI:10.1007/s10593-012-1052-9

Chiral nonracemic 3-substituted cis-and trans-4-aminopiperidines, which are precursors of anilidopiperidine analgesics, were obtained by diastereoselective synthesis from 1-methyl-and 1-benzyl-4-[(S)-1-phenylethyl]iminopiperidines, using the following rea

Full text of DOI:10.1007/s10593-012-1052-9

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
ASYMMETRIC SYNTHESIS AND STEREOCHEMISTRY OF
CHIRAL cis- AND trans-3-ALKYL-4-AMINOPIPERIDINES
G. V. Grishina1*, E. R. Luk'yanenko1, A. A. Borisenko1, and M. Yu. Antipin1
Chiral nonracemic 3-substituted cis- and trans-4-aminopiperidines, which are precursors of
anilidopiperidine analgesics, were obtained by diastereoselective synthesis from 1-methyl- and
1-benzyl-4-[(S)-1-phenylethyl]iminopiperidines, using the following reaction sequence: metalation with
lithium diethylamide, alkylation with alkyl halides, and hydride reduction or hydrogenation over Raney
nickel. The steric direction of the reaction, three-dimensional structure, preferred conformation, and
absolute configuration of the resultant aminopiperidines were determined.
Keywords: 3-alkyl-4-aminopiperidines, cis and trans isomers, conformational analysis, diastereomeric
excess, diastereoselective synthesis, Z-E isomerism of imines.
Functional derivatives of piperidine, in particular, 4-aminopiperidines, occupy a special place among
natural products and synthetic compounds with a broad spectrum of biological activity [1]. Despite the
extensive information on the biological activity of 4-aminopiperidine derivatives, on which anilidopiperidine
analgesics are based, there have been very few reports concerning the synthesis of chiral nonracemic
3-substituted 4-aminopiperidines. We should note that there is a strong relationship between analgesic activity
and the absolute configuration of the stereogenic sites of 2- and 3-substituted 4-aminopiperidine derivatives. For
example, the in vivo analgesic activity of the (+)-enantiomer of cis-3-methylfentanyl (+)-1 is almost 120 times
greater than that of the (-)-enantiomer, and 6846 times greater than the activity of morphine [1], while the in
vitro activity of the strong selective neurokinin NK1 receptor antagonist CGP 49823 (+)-2 is 12 times greater
than the activity of its (-)-enantiomer [2].
O
NH
N
N
N
N
Et
Me
Me
O
(+)-1
Me
(+)-2
[[______
*To whom correspondence should be addressed, e-mail: grishina@org.chem.msu.ru.
1M. V. Lomonosov Moscow State University, 1 Build. 3 Leninskie Gory, Moscow 119991, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 789-804, May, 2012. Original
article submitted April 12, 2012.
0009-3122/12/4805-0733©2012 Springer Science+Business Media, Inc.
733

The lack of simple and efficient methods for obtaining optically pure 3-substituted 4-aminopiperidines
is a serious obstacle to the study of the relationship between chirality and biological activity. The few reported
optically active compounds of this class have been obtained by traditional separation of racemates. Only one
example has been described in the literature for the efficient stereoselective synthesis of cis-(3S,4R)-4-amino-
3-phenylpiperidine from the imine formed from 3-phenylpiperidin-4-one and (R)-1-phenylethylamine by
hydrogenation of the imine over Raney nickel [3]. Thus, the development of a new diastereoselective synthetic
pathway is extremely important for obtaining optically pure cis and trans isomers of 3-substituted
4-aminopiperidines.
In the present article, an effective strategy is presented for the preparation of chiral nonracemic cis and
trans isomers of 3-substituted 4-aminopiperidines. A key point in this synthesis is the different steric direction
of the reduction of Z- and E-forms of 3-alkylpiperidine imines. A preliminary brief communication on the
reduction of the Z-form of 3-alkylpiperidine imines has already been published [4].
Imine 5 [5] was obtained for comparative experiments from 1,3-dimethylpiperidin-4-one (3) and
(1S)-1-phenylethylamine (4). The formation of two cis- and trans-diastereomeric pairs of 1,3-dimethyl-4-[(S)-
1-phe-nylethyl]aminopiperidine 6'a,b and 6'c,d in a 3:1 ratio has already been found in the asymmetric
reduction of the 3-methylimine 5 with NaBH4 in methanol. The diastereomeric excess (de) of the major isomers
(6'b and 6'd) in the cis and trans pairs was 62% and 74%, respectively [5].
Ph
Ph
Me
Me
Me
Me
N
N
O
NaBH4
–80°C
Me
Ph
+
+
Me
H2N
Ph
N
N
N
4
Me
(3R)-5
Me
(3S)-5
Me
3
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
HN
N
HN
N
HN
N
HN
+
+
+
N
Me
(3R,4S)-6'a
Me
(3S,4R)-6'b
Me
(3R,4R)-6'c
Me
(3S,4S)-6'd
trans
cis
The moderate stereoselectivity in the reduction of the 3-methylimine 5 is a consequence of its complex
1
isomeric and conformational composition. H NMR spectroscopy indicates that the imine 5 is formed as a 1:1
mixture of (3S)- and (3R)-epimers, and there is a 22:75 Z-E equilibrium for each of the (3S)- and (3R)-epimers;
the isomerization of these forms proceeds through an enamine [6].
Ph
Ph
Ph
N
NH
Me
Me
Me
Me
N
Me
Me
N
N
N
Me
E-5 (75%)
Me
3%
Me
Z-5 (22%)
734

Thus, a reduction of the individual Z- and E-forms of the 3-alkylimine 5 should improve the
stereoselectivity of this reaction.
A reaction sequence without separation of intermediates was also carried out, involving lithiation of a
3-unsubstituted imine, alkylation of the azaenolate by an alkyl halide, and reduction of the 3-alkylated imine by
NaBH4 [4]. Optically active imines 9 and 10, that were obtained from the reaction of (1S)-1-phenylethylamine
(4) with 1-methyl- (7) and 1-benzylpiperidin-4-one (8), respectively, were selected as the starting compounds.
As a result, a series of 1,3-disubstituted analogs 14-16 was obtained besides the amine 6.
Ph
Ph
Ph
O
Me
Me
R1
Me
R1
N
N
N
NaBH4
–80°C
1) LiNEt2
–10°C
2) R1Hal
–80°C
4
+
+
N
N
R
N
R
N
R
R
7, 8
(3R)-5
9, 10
(3S)-5
(3R)-11–13
(3R)-11–13
Ph
Ph
Ph
Ph
Me
R1
Me
R1
Me
R1
Me
R1
HN
HN
HN
HN
+
+
+
N
R
N
R
N
R
N
R
cis
trans
(3R,4S)-6a
(3S,4R)-6b
(3R,4R)-6c
(3S,4S)-6d
(3R,4S)-14–16 a
(3S,4R)-14–16 b
(3R,4R)-14–16 c
(3S,4S)-14–16 d
5, 6, 7, 9, 12, 13, 15, 16 R = Me, 8, 10, 11, 14 R = Bn;
5, 6, 11, 14 R1 = Me, 12, 15 R1 = allyl, 13, 16 R1 = CH2OMe
A
13C NMR spectral study of the stereochemistry of the key intermediate – the alkylated imine, in
which a new stereogenic site arises at C-3 with the formation of two Z-(3S)- and Z-(3R)-diastereomers, was
carried out for the already reported imine 5. Analysis of a reaction mixture sample 2 h after completion of the
methylation reaction at 20°C indeed confirmed the formation of only the Z-(3S)- and Z-(3R)-forms of the
3-methylimine 5, since two CH(Me)Ph carbon signals were observed at 65.6 and 65.7 ppm, respectively. Two
new low-intensity 13C NMR signals for the 1-phenylethyl substituent of the E-(3S)- and E-(3R)-forms were
found at 64.9 and 65.0 ppm, respectively, after maintenance of the reaction mixture for 7 h at room temperature.
Leveling out of the carbon signal intensities from 1-phenylethyl substituents of the Z- and E-forms
was observed only after 14 days, indicating a considerable kinetic stability of the Z-form of the
3-methylimine. The rate of the Z → E isomerization increases upon heating the reaction mixture to 50°C or
1
upon removal of the solvent from the reaction mixture. The H NMR spectrum indicates a ~3.5:1.0
equilibrium mixture of the E- and Z-isomers. Thus, the intermediate Z-form of the 3-substituted imine 5 has
an entirely sufficient lifetime for completion of the reaction.
The predominant formation of the Z-imines is a consequence of the syn effect, which is due to the
thermodynamic preference for formation of lithium azaenolate with syn orientation of the carbanion site and
N-substituent, and the kinetic preference for retention of syn orientation of the alkylated '-carbon atom and
N-substituent in the alkylation reaction [7]. These conclusions are based on a 13C NMR spectral study of the
stereochemistry of cyclic ketone lithioimines and the products of their alkylation [8-11].
Thus, we have found that only the Z-(3S,R)-form of the 3-methylimine 5 undergoes hydride reduction.
1H NMR signals at 0.85-1.05 ppm indicating three stereoisomers were found in the reaction mixture of the
desired product, 1,3-dimethyl-4-aminopiperidine 6. These signals were assigned to the 3-CH3 groups of the cis
735

pair 6a,b (0.94 ppm and 1.03 ppm, respectively) and to the 3-CH3 group of the trans isomer 6c (0.89 ppm),
which is in good accord with our previous results [5]. We should also note the absence of the trans isomer 6d in
the reaction mixture, which will be discussed later in greater detail. Chromatography on an alumina column
provided for separation of two individual compounds with Rf 0.2 and 0.6 (1:1 hexane–acetone), identified as the
trans-6c and cis-6a,b isomers of the desired amine 6, in accord with the chromatographic mobility of the trans
and cis diastereomeric pairs of the amine 6' [5]. The mass ratio of these two products was 1:1, and the total yield
was 90%. The mass ratio of the pure isomers of amine 6a-c was 0.64:0.36:1.00, which was virtually identical to
their composition in the reaction mixture as indicated by 1H NMR spectroscopy. The GC/MS of amine 6c with
Rf 0.2 also shows a single peak, while the nature of the decomposition of this compound upon electron impact is
in accord with the structure of amine 6.
1
The H NMR spectrum of isomer 6c corresponds to a single diastereomer (de > 98%), which was
assigned as trans configuration in light of the vicinal J3,4 coupling constant (12.0 Hz), indicating a diaxial
arrangement of H-3 and H-4 protons and, thus, a diequatorial orientation of the 4-amino and 3-methyl groups.
The trans orientation of the 4-amino and 3-methyl groups in the isomer 6c was also indicated by the large coupling
constants J2,3 = 10.8 Hz and J4,5 = 12.4 Hz. We should note that the chemical shift of the 3-CH3 group protons in
the isomer 6c (0.89 ppm) is identical to the chemical shift given earlier for the minor trans amine 6'c [4].
Two GC/MS peaks in a 1.76:1.00 ratio were found in the second product cis-6a,b with Rf 0.6. The
mass-spectral decomposition of these peaks was virtually identical and corresponded to the structure of amine 6.
The cis pair 6a,b and the trans amine 6c have identical mass spectral fragmentation, differing only in the
relative intensities of the characteristic ions with m/z 127, 111, 105, 96 and 84. The 1H NMR spectrum of the cis
pair 6a,b has two sets of signals in a 1.80:1.00 ratio, which agrees with the GC/MS data. The low values of the
vicinal coupling constants J3,4 = 4.2 Hz and J3,4 = 4.3 Hz, characteristic for an axial-equatorial interaction,
correspond to a cis orientation of the H-3 and H-4 protons, and therefore a cis arrangement of the 4-amino and
3-methyl groups, that is, the pair of diastereomers 6a,b has a cis structure.
A series of new 3-substituted 4-aminopiperidines 14-16 was synthesized under analogous conditions.
The stereoisomers were isolated by column chromatography and their composition was supported by elemental
1
analysis results, while their structure was established by H NMR spectroscopy (Tables 1 and 2). Similar
relations in isomeric composition, chromatographic mobility and three-dimensional structure were found among
the isomers of the target amines 14-16, as there were for the isomers of compound 6.
1H NMR spectroscopy indicated that all the isomers of 6c and 14-16 c have trans structure with equatorial
orientation of the 3-alkyl and 4-N-(1-phenylethyl)amine groups in accord with the large vicinal coupling constants,
J3a,4a, J2a,3a and the small vicinal coupling constant, J2e,3a. Furthermore, the chemical shift and multiplicity of the axial
proton H-4 signal at 1.8 ppm (a triplet of doublets) proved to be a general criterion for assigning trans structures to
all the isomers of 6c and 14-16. Individual trans amines 6c and 14-16 c were isolated with de > 98%.
1
The H and 13C NMR spectra of cis-6a,b and 14-16 a,b are complicated by the existence of a
conformational equilibrium, leading to broadening of the spectral lines. The cis orientation of the 4-N-substi-
tuent and the 3-alkyl group was established according to the vicinal coupling constants given in Table 2.
We should note that the 13C NMR spectrum of the trans isomer 6c indicates that this compound is
conformationally homogeneous, while the low-temperature 13C NMR spectrum of cis isomer 6a shows that this
compound exists as a conformational equilibrium (3a,4e)↔(3e,4a). A quantitative evaluation of this equilibrium
is given in Table 3.
1
TABLE 1. Vicinal Coupling Constants (J, Hz) in the H NMR Spectra of
trans- Amines 6c and 14-16 c
Amine
J3,4
J4, 5
Amine
J3,4
J4,5
12.0
10.2
12.4
10.2
11.9
10.2
11.9
10.2
6с
15с
16с
14с
736

1
TABLE 2. Vicinal Coupling Constants (J, Hz) in the H NMR Spectra of
cis Isomers 6a,b and 14-16 a,b*
Amine
T, °C
J3,4
J2,3
J4,5
Amine
T, °C
J3,4
J2,3
J4,5
20
40
20
20
4.2
—
5.0
—
—
7.1
9.1
6.7
8.7
60
60
20
20
4.0
4.2
3.9
4.0
7.3
—
—
—
6.7
6.7
7.0
8.1
6а
6b
15a
15b
16a
16b
4.3
4.2
4.1
14а
14b
_______
*The spectra of compounds 15a,b were recorded in DMSO-d6, while the
spectra of the other compounds were recorded in CDCl3.
TABLE 3. Chemical Shifts (, ppm) in the 13C NMR Spectra of
compounds cis-6a (Conformational Equilibrium (3a,4e)↔(3e,4a) at -65°C
in CD2Cl2) and trans-6c (27°C)
Conformer (%)
C-2 C-3 C-4 C-5 C-6 1-CH3 3-CH3 CН(Me)Ph CH(CH3)Ph
59.2 32.6 50.6 26.8 54.0 62.7
55.3 34.6 53.6 27.7 47.6 63.4
61.1 37.8 57.9 32.3 53.3 63.3
11.8
16.2
16.7
53.7
54.1
54.4
24.2
25.9
26.1
3a,4e-6а (62)
3e,4a-6а (38)
3e,4e-6с (100)
TABLE 4. Ratio and Diastereomeric Purity of cis and trans Isomers of the
Amines 6 and 14-16
de*3, %
Amine
Yield*, %
Ratio*2 cis (а + b) / trans (с)
cis-а
trans-с
90
54
81
63
1.0:1.0
1.1:1.0
1.9:1.0
2.0:1.0
28
36
38
70
>98
>98
>98
>98
6
14
15
16
_______
*The total yield of cis and trans isomers after chromatographic separation.
*2Mass ratio after chromatographic isolation.
*3The de value for the cis-a isomers of amines 6, 14, and 15 was
determined by GC/MS. The de for the cis-a isomer of amine 16 was
1
determined by H NMR spectroscopy. The de for the trans-c isomers of
amines 6, 14, and 15 was determined by GC/MS and 1H NMR
spectroscopy. The de for the trans-c isomer of amine 16 was determined
1
by H NMR spectroscopy. The individual isomers 15a and 15b were
isolated in a 2:1 ratio with de 98% and 90%, respectively.
Isomers 14-16 a,b were assigned to the cis series from an analysis of the multiplicity and chemical shift
of the axial proton H-4. The ratio of the cis and trans isomers and the diastereomeric purity of isomers in the cis
pairs of a,b are given in Table 4.
Antibatic steric direction of hydride reduction in the discussed reactions is noted from a comparison of
the spectral data for the cis and trans isomer pairs of amine 6 and the previously described amine 6'. Thus, for
the major cis amine 6a, the 3-CH3 group proton doublet at 0.94 ppm coincides with the chemical shift of the
3-CH3 protons of the minor component of the cis pair of the amine 6'a, while the minor cis amine 6b (1.03 ppm)
corresponds to major cis isomer 6'b.
737

Thus, the proposed variant of the hydride reduction of the stereochemically pure Z-form of the
3-substituted imines gave diastereomerically pure trans amines 6, 14-16 c with de > 98%, as well as
diastereomerically enriched cis pairs of 6, 14-16 a,b (with de up to 70%) of 3-substituted 4-aminopiperidines.
Separation of the cis pairs of 15, 16 a,b was additionally carried out by crystallization of the hydrochlorides
with subsequent 1H NMR analysis of the free bases.
13
An axial orientation of the 3-methyl group was established in a C NMR study of the stereochemistry
of the (3S)- and (3R)-forms of intermediate Z-5 by a double resonance technique. The 13C NMR spectrum of the
intermediate Z-5 in THF at -78°C shows two C-4 signals at 170.5 and 170.9 ppm, corresponding to the Z-(3S)-
and Z-(3R)-forms of intermediate Z-5 in 2.3:1.0 ratio. A cis pair arises from an axial hydride attack on the
prochiral C=N bond of each Z-form: the major isomer cis-6a and the minor isomer cis-6b. In this case, the
major cis isomer of 6a is formed from the more reactive Z-form of intermediate 5. In the case of an equatorial
hydride attack of the C=N bond, one trans isomer of 6c is formed. The second trans isomer of 6d, which should
also arise upon equatorial hydride attack, is not formed due to the different reactivity of the Z-(3S)- and Z-(3R)-
forms of the intermediate 5. Analogous behavior is seen in the entire series of trans isomers of 14-16 c.
The synthetic potential of the Z-form of the 3-substituted imines was expanded due to the "switch" of
the -alkylated Z-imines to α'-alkylated E-imines, which occurs upon repeated lithiation of the Z-form of the
imine at the '-position.
Relithiation of the 3-methylimine Z-5 was carried out by the action of three equivalents of lithium
diethylamide at 20°C for 2 h. Hydrolysis of the obtained lithioimine and reduction of the resulting imine E-5
were carried out by a consecutive addition of a solution of three equivalents of triethylammonium hydrochloride
in 20 equivalents absolute ethanol and one equivalent of NaBH4 at -80°C.
Ph
Ph
N
N
Me
Me
Me
Me
NaBH4
LiNEt2
Z-(3S,R)-5
+
6a + 6b
dr 75%
+
6c + 6d
dr 85%
EtOH
–80 °C
N
N
cis 2.3:1.0 trans
Me
Me
E-(3R)-5
E-(3S)-5
Indeed, the 13C NMR spectrum of intermediate 5 sample after relithiation showed four species: E-(3S,R)
(C-4, 169.8, 170.0 ppm) and Z-(3S,R) (C-4, 170.5, 170.9 ppm) in a ~3.5:1.0 ratio. The significant changes in the
stereochemical composition are a consequence of the transformation of the Z-imine to the E-imine.
Hydride reduction and chromatographic separation gave cis pair 6a,b and trans pair 6c,d in 95% total
1
yield. From H NMR spectrum data, the major form in the cis pair 6a,b proved to be the isomer 6b with de
75%, which was established from the integral intensity ratio of the doublets of the 3-CH3 group protons in
isomers 6a (0.94 ppm) and 6b (1.03 ppm). Analogously, the integral intensity ratio of the doublets of the 3-CH3
groups in trans isomers 6c (0.89 ppm) and 6d (0.99 ppm) gave de for the major isomer 6d, equal to 85%. The
large vicinal coupling constants (J3,4 = J4,5 = 11.7 Hz, J2a,3a = 11.3 Hz) confirm the trans structure of amine 6d,
whose conformational equilibrium is completely shifted toward the 3e,4e-conformer.
738

Thus, a difference is noted in the steric direction of the hydride reduction of imine E-5 compared to the
stereochemistry of the reduction of imine Z-5. The isomers cis-6b and trans-6d proved predominant in the
amine 6. These results indicate that Z → E isomerization of 3-methylimine 5 upon relithiation proceeds with a
high degree of conversion.
Dynamic kinetic resolution with predominant formation of the cis amine 6a with de > 98% occurs upon
hydrogenation of the equilibrium relithiated mixture of E- and Z-(3S,R)-3-methylimines 5 over 120 h in the
presence of freshly-prepared Raney nickel (W4 activity) in ethanol at a 20 atm hydrogen pressure and 20°C.
1
The reaction end-point was determined by H NMR spectra of reaction mixture samples, by disappearance of
the 3-methyl group signals from the imine 5.
At the end of the hydrogenation reaction, the 1H NMR spectrum of the reaction mixture showed 88% cis
isomer 6a, 6% cis isomer 6b, and 6% trans isomer 6d. Pure cis amine 6a was isolated from the reaction mixture
1
as dihydrobromide in a 55% yield. H NMR spectroscopy indicated that the de value for amine 6a after
crystallization from a mixture of absolute ethanol and ether was >98%. Alkylation of the imine 9 with
4-methylbenzyl chloride and subsequent relithiation gave also the Z- and E-forms of 4-imino-3-(4-methyl-
benzyl)piperidine 17. The hydrogenation of these compounds was carried out over seven days at 40°C with a
1
smaller amount of catalyst (0.5 g Raney nickel per 10 mmol of imine) and 5 atm pressure. H NMR
spectroscopy of the reaction mixture indicated that the de value for the desired product, cis-3-(4-methyl-
1
benzyl)piperidine-4-amine 18a was 97% (~3% of the cis isomer 18b). Similarly, H NMR spectra of the cis
amine 18a dihydrobromide indicated that this product was obtained with de > 98% and 47% yield.
Ph
Ph
1) LiNEt2
2) R1Hal
3) 3 equiv. LiNEt3
Me
R1
N
N
Me
R1
H2, Ni (Raney)
+
9
N
N
Me
Me
E-
5, 17
Ph
5, 17
Z-
Ph
Ph
Ph
Me
HN
Me
R1
Me
R1
Me
R1
HN
N
HN
HN
N
R1
+
+
+
N
N
Me
a
Me
b
Me
c
Me
d
6:
18: 97%
88%
6%
3%
–
–
6%
0%
17, 18 R1 = 4-MeC6H4CH2
Thus, all four imine forms (Z-(3S,3R) and E-(3S,3R)) in a dynamic equilibrium due to interconversion
through an enamine species are present in the reaction mixture during the optically pure 3-substituted 4-amino-
piperidine preparation sequence entailing lithiation, alkylation, and hydrogenation over Raney nickel [6]. Under
the catalysis conditions, the most reactive intermediate, Z-(3R)-5, is reduced significantly faster than the other
forms, which accelerates the conversion of the other intermediates into this more reactive species, as the
hydrogenation progresses, i.e., dynamic kinetic separation occurs in this process. Such an approach has been
used by Frahm et al. in the preparation of various cis-1-amino-2-substituted cycloalkanes with high
diastereomeric purity [12-16].
739

The absolute configuration of the cis amine 18a dihydrobromide was established as (αS,3R,4S) by X-ray
structural analysis (Fig. 1) using a 1-phenylethyl substituent with (S)-configuration as a chiral label. The
piperidine ring is in virtually ideal "chair" conformation with axial arrangement of the substituent at the C(3)
atom and equatorial orientation of the substituent at the C(4) atom.
Thus, the Z-(3R)-form proved the most reactive of the four forms of diastereomeric intermediates 17,
which also leads exclusively to the optically pure cis-(3R,4S)-amine 18a. This result helps to clarify the hydride
reduction stereochemistry of intermediate Z-(3R)-5. As shown above, the major cis amine 6a with (3R,4S)-
configuration is formed from the intermediate Z-(3R)-5 upon axial hydride attack (ax) on the prochiral C=N
bond, while the cis-(3R,4S)-amine 6b is formed from intermediate Z-(3S)-5. In the case of equatorial hydride
attack (eq) of the C=N bond, the trans isomer 6c, whose absolute configuration should be (3R,4R), would be
formed from intermediate Z-(3R)-5.
Fig. 1. General view of cis-(3R,4S)-1-methyl-3-(4-methylbenzyl)-N-[(1S)-phenylethyl]piperidin-4-amine (18a).
The atoms are shown as 50%-probability thermal vibration ellipsoids.
Me
H–
Me
H–
NHR*
N
Z-(3R)-5
Me
NHR*
N
(eq)
(ax)
Me
cis-(3R,4S)-6a
trans-(3R,4R)-6c
Thus, the entire series of cis amines 14-16 a also has (3R,4S)-configuration. The major isomer cis-
(3S,4R)-6b and minor isomer cis-(3R,4S)-6a are formed from intermediate E-(3R,S)-5 upon axial hydride attack
on the prochiral imine C=N bond, while equatorial hydride attack on the C=N bond leads to the major isomer trans-
(3S,4S)-6d and minor isomer trans-(3R,4R)-6c.
740

When the chiral (S)-1-phenylethyl group is removed by hydrogenolysis in the presence of Pd/C, the
optically pure cis isomer 6a and trans isomer 6c also give optically pure isomers of 1,3-dimethylpiperidin-
4-amine, cis-(3R,4S)-(19a) and trans-(3R,4R)-(19c), which were isolated as dihydrochloride salts in 73% and
56% yields, respectively.
NH2
NH2
HCO2NH4
Pd/C
Me
Me
H2, Pd/C
6c
6a
N
N
Me
Me
19c
19a
The composition of the obtained isomeric amines 19a,c was confirmed by elemental analysis. The
configuration of the stereogenic sites at C-3 and C-4 in isomers 19a and 19c was not altered during the
hydrogenolysis. The trans structure of isomer 19c, which exists exclusively as the 3e,4e-conformer, was indicated by
1
the large values of the vicinal coupling constants in the H NMR spectra (J3,4 = 11.9 Hz, J2,3 = 11.1 Hz and
J4,5 = 11.9 Hz). The cis structure of isomer 19a, which exists in a conformational equilibrium 3a,4e
3e,4a,
follows from the values of the vicinal coupling constants (J3,4 = 7.6 Hz and J4,5 = 6.5 Hz).
NH2
Me
N
Me
NH2
N
NH2
Me
Me
Me
Me
trans-19c
N
cis-19a
The absolute configuration of (+)-cis-(3R,4S)-1,3-dimethylpiperidin-4-amine (19a) was additionally
confirmed by comparison of the signs of specific rotation for this isomer and its stereochemical analog
(-)-cis-(3S,4R)-3-methyl-4-phenylpiperidinamine with a known absolute configuration [1]. The opposite signs
of their specific rotation indicate opposite configurations of the compounds compared.
Thus, a simple, highly-stereoselective sequence entailing metalation, alkylation, and hydride reduction
of imines obtained from piperidin-4-ones and the (S)- or (R)-enantiomers of 1-phenylethylamine leads to the
formation of various optically pure trans-3-substituted 4-aminopiperidines. An asymmetrical synthesis was
developed for optically pure 3-substitited cis-4-aminopiperidines by a reaction sequence involving metalation,
alkylation, and Raney nickel hydrogenation of 3-substituted 4-iminopiperidines. The steric direction of these
reactions and the absolute configuration were determined for the whole series of optically pure cis and trans
isomers of 3-substituted 4-aminopiperidines.
EXPERIMENTAL
1
The IR spectra were recorded neat on a UR-20 spectrometer. The H and 13C NMR spectra were
recorded on a Varian XL-400 spectrometer at 400 MHz and 100 MHz, respectively. The conformational
analysis of compounds cis-6a and trans-6c was carried out on a Bruker DRX-500 spectrometer at 500 MHz for
the 1H NMR spectra and at 125 MHz for the 13C NMR spectra with TMS as internal standard. The GC/MS data
were obtained on an HP-5890 Series II instrument with direct sample inlet using a 30 m0.25 mm HP-5MS
column packed with SPB-5 reverse phase. The high-resolution mass spectrum was recorded on
741

TABLE 5. Major Bond Lengths (l) in Compound 18a Molecule
Bond
N(1)–C(4)
l, Å
Bond
C(2)–C(3)
l, Å
1.488(13)
1.513(14)
1.520(14)
1.0877
1.515(14)
1.410(2)
1.390(2)
1.370(3)
1.380(2)
1.369(18)
1.538(13)
1.377(14)
1.396(18)
1.383(16)
1.409(13)
0.9600
N(1)–C(6)
N(1)–C(3)
N(1)–H(1N1)
N(2)–C(1)
N(2)–C(7)
N(2)–H(1N2)
N(2)–H(2N2)
C(1)–C(5)
C(1)–C(2)
C(2)–C(15)
C(5)–C(1)
C(1)–O(1)
C(4)–C(5)
C(7)–C(9)
C(7)–C(8)
C(2S)–H(2SC)
C(9)–C(10)
C(10)–C(11)
C(11)–C(12)
C(12)–C(13)
C(13)–C(14)
C(15)–C(16)
C(16)–C(21)
C(17)–C(18)
C(19)–C(20)
C(20)–C(21)
C(22)–H(22)
C(1S)–C(2S)
C(1S)–H(1SA)
C(2S)–H(2SA)
C(2S)–H(2SB)
O(1W)–H(1W)
1.496(12)
1.552(11)
0.8437
0.9601
1.541(15)
1.548(13)
1.535(14)
1.493(3)
1.197(2)
1.511(16)
1.499(18)
1.513(14)
0.9600
1.27(3)
0.9700
0.9600
0.9600
0.0802
TABLE 6. Major Valence Angles () in Compound 18a Molecule
Angle
ω, deg.
Angle
ω, deg.
C(4)–N(1)–С(6)
111.3(9)
109.7(8)
111.8(9)
114.4(15)
106.3
C(1)–N(2)–H(1N2)
C(7)–N(2)–H(1N2)
C(1)–N(2)–H(1N2)
C(7)–N(2)–H(2N2)
C(4)–N(1)–H(2N2)
N(2)–C(1)–C(5)
116.6 (7)
113.9
C(4)–N(1)–C(3)
С(6)–N(1)–C(3)
96.2
C(4)–N(1)–H(1N1)
C(6)–N(1)–H(1N1)
C(3)–N(1)–H(1N1)
C(1)–N(2)–C(7)
109.8
109.4
103.2
113.1(8)
110.4(8)
110.7(8)
107.5
116.9
N(2)–C(1)–C(2)
C(5)–C(1)–H(1)
107.2
C(8)–C(7)–N(2)
C(2)–C(2)–H(1)
107.2
C(9)–C(7)–H(7)
C(3)–C(2)–C(15)
C(3)–C(2)–C(1)
114.6(9)
106.8(8)
111.1(8)
109.5
H(SA)–C(1S)–H(1SB)
C(1S)–C(2S)–H(2SA)
C(1S)–C(2S)–H(2SC)
H(2SA)–C(2S)–H(2SC)
H(2SB)–C(2S)–H(2SC)
O(1S)–C(1S)–H(1SB)
110.4
109.5
C(9)–C(7)–N(2)
109.5
H(2SA)–C(S)–H(2SB)
C(1S)–C(2S)–H(2SB)
H(1W)–O(1W)–H(2W)
109.5
109.5
109.5
106.4
113.0
20
a JEOL AccuTOF instrument. The specific rotation []D was determined on a Perkin Elmer 241 polarimeter
with a 0.25-dm cell. The concentration is indicated in g/100 cm3. Thin layer chromatographic analysis was
carried out on Merck Silufol plates for compounds 19a,c and Alufol plates for the other compounds. The
elemental analysis was carried out on a Vario MICRO cube CPNS analyzer. Column chromatography was
carried out on neutral Merck alumina. The metalation reaction and subsequent alkylation of the imines were
carried out in an argon atmosphere. Imine 5 for the comparative experiments was obtained according to our
previous procedure [5], the physicochemical and spectral data corresponded to the literature values [5].
(1S)-N-(1-Methylpiperidin-4-ylidene)-1-phenylethylamine (9) and (1S)-N-(1-benzylpiperidin-
4-ylidene)-1-phenylethylamine (10) were obtained according to our previous procedure [17] in 90% and 98%
yields, respectively. The analytical data for imine 9 match the literature [17]. Imine 10: nD20 1.5634, []D20 -40°
(c 3.8, С6Н6). IR spectrum, cm-1: 1680 (C=N). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.46 (3Н, d, J = 7.0,
СН(СH3)Ph); 2.47-2.50 (8Н, m, 2,3,5,6-СH2); 3.53 (2Н, s, CH2Ph); 4.30 (1Н, q, J = 7.0, СH(Me)Ph); 7.26-7.29
(5Н, m, H Ph). Found, m/z: 293.3996 [M+H]+. С19Н24N2, Calculated, m/z: 292.4080.
742

TABLE 7. Major Torsion Angles () in Compound 18a Molecule
Angle
θ, deg.
Angle
θ, deg.
C(7)–N(2)–С(1)–С(5)
C(7)–N(2)–C(1)–С(2)
N(2)–C(1)–C(2)–C(3)
C(5)–C(1)–C(2)–C(2)
N(2)–C(1)–C(2)–C(15)
C(15)–C(2)–C(3)–N(1)
C(1)–C(2)–C(3)–N(1)
C(4)–N(1)–C(3)–C(2)
C(6)–N(1)–C(3)–C(2)
C(3)–N(1)–C(4)–C(5)
N(1)–C(4)–C(5)–C(1)
N(2)–C(1)–C(5)–C(4)
C(2)–C(1)–C(5)–C(4)
C(1)–N(2)–C(7)–C(9)
C(1)–N(2)–C(7)–C(8)
90.3(10)
-144.0(8)
176.7(8)
-56.7(11)
70.8(12)
-68.7(11)
58.4(10)
-61.7(11)
174.4(8)
60.2(12)
-58.6(12)
-177.1(8)
57.8(11)
-62.4(12)
172.2(8)
C(8)–C(7)–C(9)–C(10)
N(2)–C(7)–C(9)–C(10)
C(8)–C(7)–C(9)–C(14)
N(2)–C(7)–C(9)–C(14))
C(14)–C(9)–C(10)–C(11)
C(7)–C(9)–C(10)–C(11)
C(9)–C(10)–C(11)–C(12)
C(10)–C(11)–C(12)–C(13)
C(7)–C(9)–C(14)–C(13)
C(1)–C(2)–C(15)–C(16)
C(2)–C(15)–C(16)–C(17)
C(21)–C(16)–C(17)–C(18)
C(17)–C(16)–C(21)–C(20)
C(15)–C(16)–C(21)–C(20)
C(19)–C(20)–C(21)–C(16)
-117.9(11)
117.6(11)
57.7(13)
-66.8(13)
2.4(16)
178.2(11)
-2.0(2)
1.0(2)
178.0(10)
177.6(9)
-81.4(12)
-1.8(16)
3.9(16)
-177.4(10)
-3.6(18)
Hydride Reduction of Z-(3S,R)-forms of Imines 5, 11-13. The cis and trans Isomers of 1,3-Dialkyl-
piperidin-4-yl-N-[(1S)-1-phenylethyl]amines 6, 14-16 a-c (General Method) (see also our previous work
[4]). A solution of imine 9 or 10 (3.00 g, 13.9 mmol) in absolute THF (5 ml) was added over 10 min with
stirring at -10°C to a solution of LiNEt3 obtained from HNEt2 (1.32 g, 18.0 mmol) in absolute THF (20 ml) and
1.6 N BuLi (11.3 ml, 18.0 mmol) in hexane. The reaction mixture was stirred for 30 min at -10°C. After cooling
to -80°C, alkyl halide (18.0 mmol) was added, and the reaction mixture was stirred for 30 min. Then, absolute
ethanol (2 ml) and NaBH4 (0.50 g, 13.9 mmol) were added consecutively. The reaction mixture was stirred for
1 h at -80°C and then brought to room temperature. The solvents were distilled off in vacuum. The residue was
decomposed by carefully adding 6 N hydrochloric acid and then 10 ml water. The reaction mixture was brought
to pH 12 by adding 20% aqueous NaOH and extracted with methylene chloride (230 ml). The organic
extracts were combined and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was
subjected to chromatography on an alumina column with gradient elution using 30:1 to 1:1 hexane–ethyl
acetate.
The reaction of imine 9 with MeI gave 1.42 g (44%) of the cis pair (3R,4S)-6a and (3S,4R)-6b, Rf 0.6,
and 0.68 g (21%) of the trans isomer (3R,4R)-6c, Rf 0.2. The Rf values were obtained with a 1:1 hexane–acetone
eluent. An analytical sample of isomers 6a,b was separated by GC/MS, and the obtained spectral data
corresponded to the literature values [4]. Dipicrate of trans isomer 6c was obtained by mixing ethereal
solutions of the amine 6c and picric acid. The precipitate obtained was filtered off and recrystallized from
ethanol. Found, %: C 47.10; H 4.37; N 16.06. C15H24N2·2C6H3N3O7. Calculated, %: C 46.96; H 4.38; N 16.23.
Treatment of the amine 6c dipicrate with aqueous potassium carbonate and subsequent extraction with ether
1
gave the free base of trans isomer 6c with de > 98%, as indicated by H NMR spectroscopy. The spectral and
analytical data corresponded to the literature values [4].
cis- and trans-1-Benzyl-3-methylpiperidin-4-yl-N-[(1S)-1-phenylethyl]amine (14). Isomers of the
amine 14 were obtained in a similar way from the imine 10 and MeI. Chromatographic separation gave 0.34 g
(8%) of the cis isomer (3R,4S)-14a (de 90%, GC/MS), 0.84 g (20%) of the cis isomer (3S,4R)-14b (de 98%,
1
GC/MS) and 1.10 g (26%) of the trans isomer (3R,4R)-14c (de > 98%, H NMR, GC/MS). cis Isomer 14a:
Rf 0.8 (2:1 hexane–acetone), []D20 -31.6° (c 3.48, С6Н6). 1Н NMR spectrum (С6D6), , ppm (J, Hz): 0.97 (3H, d,
J = 6.8, 3-CH3); 1.23 (3H, d, J = 6.6, CH(CH3)Ph); 1.54-1.57 (2H, m, Н-3e,5a); 1.73-1.75 (1Н, m, H-5e);
2.40-2.43 (2Н, m, Н-2a,6a); 2.70-2.71 (1Н, m, H-2e); 2.46 (1Н, ddd, J3e,4a = 4.0, J4a,5e = 4.0, J4a,5a = 8.0, H-4a);
2.51-2.53 (1Н, m, H-6e); 3.27 (2H, dd, J = 13.2, CH2Ph); 3.74 (1Н, q, J = 6.8, CH(Me)Ph); 7.10-7.40 (10Н, m,
H Ph). Mass-spectrum (τ 16.30 min), m/z (Irel, %): 308 [M]+ (<1), 203 [M-CH(CH3)C6H5]+ (62), 105
[CH(CH3)C6H5]+ (31), 91 [CH2C6H5]+ (100). cis Isomer 14b: Rf 0.75, []D -69.6° (c 3.16, С6Н6). Н NMR
20
1
743

spectrum (CD2Cl2), , ppm (J, Hz): 1.05 (3Н, d, J = 6.9, 3-CH3); 1.20 (3Н, d, J = 6.6, CH(CH3)Ph); 1.33-1.35
(1Н, m, H-5e); 1.49-1.51 (1Н, m, H-5a); 1.75-1.77 (1Н, m, H-6a); 1.86-1.87 (1Н, m, H-3e); 2.29-2.31 (1Н, m,
H-2e); 2.41-2.43 (1Н, m, Н-2a,6a); 2.40 (1Н, ddd, J3e,4a = 4.1, J4a,5e = 4.1, J4a,5a = 8.7, H-4a); 2.51-2.53 (1Н, m,
H-6e); 3.17 (2Н, dd, J = 13.3, CH2Ph); 3.71 (1Н, q, J = 6.5, CH(Me)Ph); 7.10-7.40 (10Н, m, H Ar). Mass-
spectrum (τ 16.11 min), m/z (Irel, %): 308 [M]+ (<1), 203 [M-CH(CH3)C6H5]+ (79), 105 [CH(CH3)C6H5]+ (33), 91
1
[CH2C6H5]+ (100). trans Isomer 14c: Rf 0.5, []D20 -63.2° (c 8.29, С6Н6). Н NMR spectrum (C6D6), , ppm
(J, Hz): 0.88 (3Н, d, J = 6.5, 3-CH3); 1.18 (3Н, d, J = 6.5, CH(CH3)Ph); 1.37 (1Н, d, J2a,3a = 10.7, H-2a);
1.49-1.50 (1Н, m, H-5a); 1.51-1.53 (1Н, m, H-3a); 1.59 (1Н, ddd, J6a,6e = 11.7, J6a,5a = 11.7, J6a,5e = 2.5, H-6a);
1.80 (1Н, ddd, J4a,3a = 10.2, J4a,5a = 10.2, J4a,5e = 4.1, H-4a); 1.93-1.95 (1Н, m, H-5e); 2.68-2.69 (1Н, m, H-2e);
2.73-2.76 (1Н, m, H-6e); 3.26 (2Н, s, CH2Ph); 3.84 (1Н, q, J = 6.5, CH(Me)Ph); 7.05-7.25 (10Н, m, H Ph).
Mass spectrum (τ 16.28 min), m/z (Irel, %): 308 [M]+ (<1), 203 [M-CH(CH3)C6H5]+ (22), 105 [CH(CH3)C6H5]+
(27), 91 [CH2C6H5]+ (100). Dipicrate of the diastereomer mixture 14a-c was obtained analogously to the
dipicrate of amine 6c, mp 235-236 °C (EtOH). Found, %: C 51.59; H 4.39; N 14.37. C21H28N2·2C6H3N3O7.
Calculated, %: C 51.70; H 4.47; N 14.62.
cis- and trans-3-Allyl-1-methylpiperidin-4-yl-N-[(1S)-1-phenylethyl]amine (15). Stereoisomers of
amine 15 were obtained analogously from the imine 9 and allyl bromide. Chromatographic separation gave 1.83 g
(51%) of the cis diastereomer pair (3R,4S)-15a and (3S,4R)-15b and 0.96 g (27%) of the trans isomer (3R,4R)-
20
15c. The cis pair: Rf 0.7 (1:1 hexane–acetone), []D -47.0° (c 2.0, benzene). Isomer 15a (de 38%, GC/MS)
1
predominates in the cis pair. cis Isomer 15a: Н NMR spectrum (CDCl3), , ppm (J, Hz): 1.23-1.24 (1H, m,
Н-5а); 1.29 (3H, d, J = 7.1, CH(CH3)Ph); 1.51-1.57 (2Н, m, H-3е,2а); 1.64-1.71 (2H, m, H-6a,
CHАHВCH=CH2); 1.72 (1H, ddd, J4а,3а = 10.0, J4а,5а = 10.0, J4а,5е = 3.7, H-4a); 2.03-2.05 (1H, m, H-5e); 2.22 (3H,
s, 1-CH3); 2.74-2.80 (3H, m, H-2e,6e, CHАHВCH=CH2); 3.82 (1H, q, J = 7.1, CH(Me)Ph); 5.65-5.67 (2H m,
CH2CH=CH2); 5.85-5.87 (1H, m, CH2CH=CH2); 7.10-7.35 (5H, m, H Ph). Mass spectrum (τ 14.53 min), m/z
(Irel, %): 258 [M]+ (1), 153 [M-CH(CH3)C6H5]+ (73), 105 [CH(CH3)C6H5]+ (61), 96 (100). cis Isomer 15b:
1Н NMR spectrum (CDCl3), , ppm (J, Hz): 1.27-1.29 (1H, m, H-5a); 1.31 (3Н, d, J = 7.1, CH(CH3)Ph); 1.33
(3H, d, J = 6.0, 3-CH3); 1.46-1.53 (2H, m, H-2a,3е); 1.63-1.77 (2H, m, H-6a, CHАHВCH=CH2); 1.84 (1H, ddd,
J4а,3а = 11.9, J4а,5а = 11.9, J4а,5е = 3.7, H-4a); 2.12 (1H, m, H-5e); 2.17 (3H, s, 1-CH3); 2.65-2.70 (1H, m,
CHАHВCH=CH2); 2.74-2.80 (2H, m, H-2e,6e); 3.80 (1H, q, J = 7.1, CH(Me)Ph); 4.94-5.00 (2H, m) and
5.65-5.69 (1H, m, CH=CH2); 5.70-5.72 (1H, m, CH2CH=CH2); 7.10-7.35 (5H, m, Н Ph). Mass spectrum (τ
14.60 min), m/z (Irel, %): 258 [M]+ (1), 153 [M-CH(CH3)C6H5]+ (58), 105 [CH(CH3)C6H5]+ (57), 96 (100). trans
20
1
Isomer 15c: de > 98%, Rf 0.3 (1:1 hexane–acetone), []D -57° (c 2.0, С6Н6). Н NMR spectrum (CDCl3), ,
ppm (J, Hz): 1.40-1.50 (2H, m, H-2a,3a); 1.45-1.48 (1H, m, H-5a); 1.66-1.77 (2H, m, H-6a, CHAHBCH=CH2);
1.84 (1H, ddd, J4a,3a = 10.2, J4a,5a = 10.2, J4a,5e = 3.7, H-4a); 2.12-2.14 (1H, m, H-5e); 2.65-2.69 (1H, m,
CHAHBCH=CH2); 2.74-2.80 (2H, m, H-2e,6e); 3.96 (1H, q, J = 6.6, CH(Me)Ph); 4.94-5.00 (2H, m) and
5.70-5.73 (1H, m, CH=CH2); 7.20-7.35 (5H, m, H Ph). Mass spectrum (τ 4.60 min), m/z (Irel, %): 258 [M]+ (2),
153 [M-CH(CH3)C6H5]+ (26), 105 [CH(CH3)C6H5]+ (38), 96 (100). Dipicrate of trans isomer 15c was obtained
analogously to dipicrate of the amine 6c. Found, %: C 48.45; H 4.48; N 15.67. C17H26N2·2C6H3N3O7.
Calculated, %: C 48.61; H 4.50; N 15.64.
cis- and trans-1-Methyl-3-(methoxymethyl)piperidin-4-yl-N-[(1S)-1-phenylethyl]amine (16).
Stereoisomers of the amine 16 were obtained by an analogous procedure from the imine 9 and chloromethyl
methyl ether. Chromatographic separation gave 1.53 g (42%) of the cis diastereomer pair (3R,4S)-16a and
(3S,4R)-16b, and 0.76 g (21%) of the trans isomer (3R,4R)-16c. Isomer 16a (de 71%, 1H NMR) predominates in
20
1
the cis pair. cis Isomer 16a: Rf 0.65 (1:1 hexane–acetone), []D -33.0° (c 4.0, PhMe). Н NMR spectrum
(DMSO-d6, 60 °С), , ppm (J, Hz): 1.26 (3H, d, J = 6.6, CH(CH3)Ph); 1.48-1.53 (2H, m, Н-3е,5а); 1.71-1.73
(1Н, m, Н-5е); 2.11 (3H, s, 1-CH3); 2.32-2.40 (2Н, m, Н-2а,6а); 2.51-2.57 (1Н, m, Н-6е); 2.65 (1Н, ddd,
J
3e,4a = 3.9, J4a,5e = 3.9, J4a,5a = 7.1, H-4а); 2.73-2.80 (1Н, m, Н-2е); 3.20 (3H, s, OCH3); 3.42 (2Н, dd, J = 7.8,
1
J = 4.4, CH2OMe); 3.81 (1H, q, J = 6.6, CH(Me)Ph); 7.16-7.35 (5H, m, Н Ph). cis Isomer 16b: Н NMR
spectrum (CDCl3), , ppm (J, Hz): 1.31 (3Н, d, J = 6.5, CH(CH3)Ph); 1.58-1.60 (2Н, m, H-3e,5a); 1.68-1.72
744

(1Н, m, H-5e); 2.23 (3Н, s, 1-CH3); 2.30-2.35 (2Н, m, H-2a,6a); 2.46-2.48 (1Н, m, H-6e); 2.60 (1Н, ddd,
3e,4a = 3.9, J4a,5e = 3.9, J4a,5a = 7.0, H-4a); 2.68-2.70 (1Н, m, H-2e); 3.29 (3Н, s, OCH3); 3.45 (2Н, dd, J = 9.7,
J
J = 4.8, CH2OMе); 3.80 (1Н, q, J = 6.5, CH(Me)Ph); 7.58-7.75 (5Н, m, H Ph). Dihydrobromide of isomers
16a,b was obtained by adding a solution of the isomers 16a,b in ether to a saturated solution of HBr in ether at
0°C. The precipitate formed was filtered off, dried in vacuum over P2O5 and then over NaOH, and recrystallized
from absolute ethanol. Found, %: C 45.40; H 6.34; N 5.97. C16H26N2О·2HBr. Calculated, %: C 45.48; H 6.20;
N 6.62. trans Isomer 16c: de > 98% (1H NMR spectrum), Rf 0.35 (1:1 hexane–acetone), dr > 98% (1Н NMR
20
1
spectrum), Rf 0.35 (hexane–acetone, 1:1), []D -81.0° (c 3.7, PhMe). Н NMR spectrum (CDCl3), , ppm (J,
Hz): 1.31 (3H, d, J = 6.6, CH(CH3)Ph); 1.29 (1H, ddd, J5a,4a = 11.9, J5a,6a = 9.4, J5a,6e = 3.7, H-5а); 1.36-1.39
(1Н, m, Н-3а); 1.58 (1H, d, J2a,3a = 11.0, H-2а); 1.89-1.92 (1Н, m, Н-4а); 1.99 (1H, dd, J6a,5a = 9.4, J6a,5e = 4.1,
H-6а); 2.12 (1H, ddd, J5e,4a = 2.3, J5e,6a = 4.1, J5e,6e = 3.6, H-5е); 2.19 (3H, s, 1-CH3); 2.76 (1H, dd, J6e,5a = 3.7,
J6e,5e = 3.6, H-6е); 2.83 (1H, dd, J2e,3a = 3.8, J6e,2e = 1.9, H-2е); 3.20 (1H, dd, J = 9.7, J = 6.2) and 3.53 (1H, dd,
J = 9.7, J = 4.8, СН2ОMе); 3.30 (3H, s, ОCH3); 3.93 (1H, q, J = 6.6, CH(Mе)Ph); 7.19-7.35 (5H, m, H Ph). 13С
NMR spectrum (CDCl3), , ppm: 25.7; 31.8; 42.1; 46.2; 53.7; 54.1; 54.7; 58.3; 58.7; 74.2; 126.5, 126.6, 128.2,
146.0. Mass spectrum, m/z (Irel, %): 262 [M]+ (<5), 157 [M-CH3CHC6H5 ]+ (37), 105 [CH3CHC6H5]+ (100).
Hydride Reduction of the E-(3S,R) Form of Imine 5. The cis and trans Isomers of 1,3-dimethyl-
piperidin-4-yl-N-[(1S)-1-phenylethyl]amine (6). Methyl iodide was added to a solution of 3-methylimine 5
obtained as described in the general method above, and the reaction mixture was maintained for 30 min at
-10°C. The mixture was then cooled to -30°C, and a solution of lithium diethylamide, obtained from HNEt2
(4.10 g, 56 mmol) and 1.6 N BuLi in hexane (35 ml, 56 mmol), in absolute THF (50 ml) was added. The
reaction mixture was stirred for 45 min at -30°C, and then 45 min at 25°C. The mixture was cooled to -80°C,
and absolute ethanol (3 ml) and NaBH4 (0.68 g, 18 mmol) were added. The mixture was stirred for 1 h at -80°C,
and then allowed to warm to room temperature with vigorous stirring. The solvents were removed in vacuum,
and the residue was decomposed by carefully adding 6 N hydrochloric acid until hydrogen no longer evolved.
Then water (10 ml) was added. The mixture was brought to pH 12 by adding 20% aqueous NaOH and extracted
with CH2Cl2 (2×30 ml). The organic extracts were combined and dried over anhydrous sodium sulfate. The
solvent was evaporated in vacuum. The residue was subjected to chromatography on an alumina column with
gradient elution from 30:1 to 1:1 hexane–ethyl acetate. The Rf values of isomers 6a-d are given above. This
procedure gave 2.02 g (68%) of the cis pair (3R,4S)-6a and (3S,4R)-6b with predominance of the isomer 6b (de
69%), and 0.80 g (25%) of the trans pair (3R,4R)-6c and (3S,4S)-6d with predominance of the isomer 6d (de
87%). The cis pair: []D20 -48° (c 2.0, benzene; The trans pair: []D20 +1° (c 5.9, toluene). The trans isomer 6d:
1Н NMR spectrum (CDCl3), , ppm (J, Hz): 0.99 (3H, d, J = 6.4, 3-CH3); 1.26-1.28 (1H, m, H-5а); 1.29 (3H, d,
J = 6.4, CH(CH3)Ph); 1.54 (1H, ddd, J3a,2a = 10.8, J3a,4a = 11.7, J3a,2e =3.4, H-3а); 1.63 (1H, d, J2a,3a = 10.8,
Н-2а); 1.73 (1H, ddd, J5e,4a = 2.6, J5e,6a = 4.0, J5e,6e = 3.3, Н-5е); 1.81 (1H, ddd, J4a,3a = 11.7, J4a,5a = 11.7,
J
4a,5e = 2.6, Н-4а); 2.01 (1H, dd, J6a,5a = 10.1, J6a,5e = 4.0, Н-6а); 2.19 (3H, s, 1-CH3); 2.68-2.75 (2H, m,
Н-2е,6е); 3.86 (1H, q, J = 6.4, CH(Me)Ph); 7.17-7.34 (5H, m, H Ph). 13С NMR spectrum (CDCl3), , ppm:
16.5; 23.9; 33.1; 37.8; 46.0; 55.2; 56.2; 58.8; 63.0; 126.4; 126.5; 128.1; 147.0.
cis-(3R,4S)-1-Methyl-3-(4-methylbenzyl)piperidin-4-yl-N-[(1S)-1-phenylethyl]amine
(18a).
A
solution of imine 9 (3.00 g, 13.9 mmol) in absolute THF (5.0 ml) was added at -10°C with stirring over 10 min
to a solution of LiNEt2 obtained from HNEt2 (1.32 g, 18.0 mmol) in absolute THF (20 ml) and 1.6 N solution of
BuLi in hexane (11.3 ml, 18.0 mmol). The reaction mixture was stirred for 30 min at -10°C and then cooled to -
80°C. 4-MeC6H4Cl (2.56 g, 18.0 mmol) was added. The obtained solution was stirred at -10°C for 30 min and
then cooled to -30°C. A solution of lithium diethylamide, obtained from Et2NH (4.10 g, 56.0 mmol) and 1.6 N
BuLi in hexane (35.0 ml, 56.0 mmol), in absolute THF (50 ml) was then added. The reaction mixture was left
to warm to room temperature with stirring. The solvent was distilled off. The residue was dissolved in absolute
ethanol (20 ml), and Raney nickel (W4 activity), freshly prepared from Ni/Al alloy (2.8 g) was added. The
reaction mixture was then hydrogenated for seven days at 5 bar hydrogen pressure and 40°C. The catalyst was
745

filtered off, and the solvent was evaporated. Then, 5% aqueous NaOH (20 ml) was added to the residue, and the
mixture was extracted with CH2Cl2 (230 ml). The organic extracts were combined and dried over anhydrous
sodium sulfate. The solvent was evaporated. The residue was dissolved in ethanol (10 ml) and brought to pH ~3
by adding concentrated hydrobromic acid. The solution was evaporated. The residue was dried in vacuum over
P2O5, and then over NaOH. Crystallization from 2:1 ethanol–ether gave 3.00 g (47%) of the cis-(3R,4S)-isomer
18a dihydrobromide with de > 98%, mp 222-224°C. Isolation of the free base of cis isomer 18a: a solution of
18a dihydrobromide (0.135 g, 0.3 mmol) in water (1 ml) was brought to pH 10 by adding aqueous potassium
carbonate and extracted with CH2Cl2 (4×3 ml). The combined extract was dried over anhydrous sodium sulfate.
The solvent was evaporated in vacuum and the residue was dried in vacuum at 40°C for 30 min, to give 0.090 g
(74%) of the cis isomer 18a as a viscous oil, []D20 -106° (c 2.5, EtOH). 1Н NMR spectrum (CDCl3), , ppm (J, Hz):
1.18 (3H, d, J = 7.0, CH(CH3)Ph); 2.26 (3H, s, 1-CH3); 2.75 (1H, dd, J4е,3а = 7.6, J4е,5а = 6.5, H-4e); 1.33-1.35 (1H,
m, H-5a); 1.36-1.39 (1Н, m, H-3a); 1.66-1.69 (1Н, m, H-6a); 2.02 (1Н, d, J4a,5е = 6.5, H-4a); 2.08-2.10 (1Н, m,
H-5e); 2.85-2.89 (2Н, m, H-2e,6a); 7.30-7.40 (9Н, m, H Ar). Found, %: C 81.74; H 9.21; N 8.74. C22H30N2.
Calculated, %: C 81.94; H 9.38; N 8.69.
cis Isomer 6a dihydrobromide was obtained in a similar manner to the previous procedure, by using
methyl iodide (1.1 ml, 2.56 g, 18.0 mmol) as the alkylating agent. The hydrogenation was carried out in the
presence of Raney nickel obtained from Ni/Al alloy (3.00 g) over 120 h at 20 bar hydrogen pressure and room
temperature. Isomer 6a dihydrobromide: yield 3.01 g (55%); mp 210-212°C (EtOH). The free base of isomer
6a was isolated from its dihydrobromide salt (0.12 g, 0.3 mmol) analogously to the previous procedure. Yield
0.04 g (55%). The physicochemical and spectral data of this product correspond to the literature values [4].
(+)-cis-(3R,4S)-1,3-Dimethylpiperidin-4-ylamine (19a). A solution of the cis-(3R,4S)-isomer 6a (1.18 g,
5.1 mmol) in ethanol (20 ml) was hydrogenated over 10% Pd/C (0.40 g) for 24 h at 1 bar hydrogen pressure and
20°C. The catalyst was filtered off. The solution was brought to pH ~3.5 by adding a saturated solution of
hydrogen chloride in methanol. The solvents were removed by evaporation. The residue was dried in vacuum
over P2O5 and then NaOH. The obtained precipitate was crystallized from 2:1 absolute ethanol–ether to give
0.75 g (73%) of cis-(3R,4R)-1,3-dimethyl-4-aminopiperidine (19a) dihydrochloride, mp 156-157°C, []D20 -12°
(c 8.6, H2O). The free base of the amine 19a was isolated from its dihydrochloride (0.75 g) in water (2 ml) by
adding dry potassium carbonate to bring the solution to pH 9. The mixture was extracted with CH2Cl2 (2×2 ml)
and dried over sodium sulfate. The solvent was evaporated in vacuum to give the amine 19a. Yield 0.40 g
20
1
(84%). Colorless oil, Rf 0.4 (CH2Cl2–MeOH, 3:1 + 0.1% NH3), []D -43° (c 5.3, С6Н6). Н NMR spectrum
(DMSO-d6, 60°С), , ppm (J, Hz): 0.87 (3H, d, J = 7.0, 3-CH3); 2.08 (1H, dd, J3а,2а = 10.8, J2е,3а =3.9, H-2е);
1.29 (2Н, s, NH2); 1.37-1.49 (1H, m, H-5а); 1.53 (1H, ddd, J3а,2е = 2.1, J3а,2а = 10.8, J3а,4а = 12.0, H-3а); 2.11
(3H, s, 1-СН3); 2.20 (1H, d, J2а,3а = 7.6 H-2а); 2.39-2.41 (1H, m, H-6е); 2.75 (1H, dd, J4е,3а = 3.8, J4е,5а = 3.8,
H-4e); 2.85-2.91 (2Н, m, H-6a,5e). 13С NMR spectrum (DMSO-d6, 60°С), , ppm: 13.3; 31.5; 34.3; 45.8; 48.4;
51.5; 58.5. Amine 19a dihydrochloride. Found, %: C 41.63; H 9.28; N 13.94. C7H16N2·2HCl. Calculated, %:
C 41.80; H 9.02; N 13.93.
(-)-trans-(3R,4R)-1,3-Dimethylpiperidin-4-ylamine (19c). 10% Pd/C (0.40 g) and dry ammonium
formate (7.38 g, 117.0 mmol) in three portions of 2.46 g each were added consecutively to a solution of the
trans-(3R,4R)-isomer 6c (0.91 g, 3.9 mmol) in methanol (15 ml), and the obtained mixture was heated at reflux
for 2 h until the complete disappearance of ammonium formate. The reaction end-point was determined by thin-
layer chromatography by the disappearance of the spot for isomer 6c. The catalyst was filtered off and the
reaction solution was brought to pH ~3.5 by adding a saturated solution of hydrogen chloride in methanol. The
solvents were evaporated. The residue was dried in vacuum over P2O5, and then over NaOH. The residue was
crystallized to give 0.44 g (56%) of the trans-(3R,4R)-1,3-dimethylpiperidin-4-ylamine (19c) dihydrochloride,
20
mp 229-231°C (2:1 abs. ethanol–ether), []D -17° (c 3.3, Н2О). The free base of the amine 19c was isolated
20
1
similarly to the isomer 19а, Rf 0.3 (CH2Cl2–MeOH, 3:1 + 0.1% NH3), []D -28° (c 1.6, MeOH). Н NMR
spectrum (CDCl3), , ppm (J, Hz): 0.94 (3Н, d, J = 6.7, 3-СН3); 1.26 (2Н, s, NH2); 1.37-1.49 (2H, m, H-3а,5а);
1.62 (1H, d, J2a,3a = 11.1, H-2a); 1.80 (1H, ddd, J5e,4a = 2.6, J5e,6e = 2.6, J5e,6a = 4.4, H-5е); 1.95 (1H, ddd,
746

J4a,3a = 11.9, J4a,5a = 11.9, J4a,5e= 2.6, H-4а); 2.17 (1Н, dd, J6a,5a = 9.7, J6a,5e = 4.1, H-6а); 2.25 (3H, s, N-СН3); 2.75
1Н, d, J2e,3a = 3.8, H-2е); 2.84-2.89 (1H, m, H-6е). 13С NMR spectrum (CDCl3), , ppm: 16.3; 29.7; 35.6; 39.7;
46.1; 55.5; 62.7. Found, %: C 41.67; H 9.17; N 13.99. C7H16N2·2HCl. Calculated, %: C 41.80; H 9.02; N 13.93.
X-ray Structural Study of 18a Dihydrobromide. Monoclinic crystals of compound 18a were grown
in ethanol (C24H40Br2N2O2, M 548.40). Unit cell parameters at 173 K: a = 12.771(7), b = 7.393(3), c = 14.160(6) Å,
 = 90.94(4)°, V = 1336.8(11) Å3, space group P21, Z = 2, dcalc = 1.362 g/cm3, (MoK) = 30.53 mm-1,
F(000) = 568. A total of 3663 reflections were measured on a Syntex 21 four-circle diffractometer (MoK,
graphite monochromator, /2 scanning, max = 28.06°), of which 3442 independent reflections (Rint = 0.0268)
were used to decipher and refine the structure. The structure was deciphered by the direct method and refined
relative to F2 by the full-matrix method of least squares in the anisotropic-isotropic approximation. The
hydrogen atoms were located from the difference maps for the solvate water and ethanol molecules and
calculated for the dication using the "horse-rider" model. The final probability factors were: wR2 = 0.1927 over
all the reflections, R1 = 0.0778 and GOOF = 0.972 (for 2067 reflections). The complete crystallographic data
were deposited at the Cambridge Crystallographic Data Center (CCDC 882510). The major interatomic
distances, bond and deformation angles are given in Tables 5-7.
This work was carried out with the financial support of the Russian Foundation for Basic Research
(projects 8-03-0026a and 11-03-01034a).
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