Studies on the stereochemistry of 1,2,6-trimethyl-4-piperidone

Article abstract of DOI:10.1016/j.tet.2005.05.030

In the effort to create new derivatives of analgesically active spiropiperidines intermediate 1,2,6-trimethyl-4-piperidone was synthesized. The substitution of the skeleton gives rise to configurational as well as conformational isomerism. Despite the symmetry of 1,2,6-trimethyl-4-piperidone two different sets of signals were present in the ¹H and ¹³C NMR spectra. They were supposed to arise from a cis/trans mixture of 1,2,6-trimethyl-4-piperidone. In contrast to this explanation only two signals of the methyl groups and hydrogens at carbon atoms 2 and 6 were observed in the ¹H and ¹³C NMR spectra, normally expecting one for the cis- and two for the trans-isomer. To solve this discrepancy, the kind of isomeric mixture of 1,2,6-trimethyl-4-piperidone leading to the ¹H and ¹³C NMR spectra was examined. Energy differences between chair conformations of both the cis- and the trans-isomer of 1,2,6-trimethyl-4- piperidone and the potential energy surface of the equilibration process of the trans-isomer of 1,2,6-trimethyl-4-piperidone between its chair conformers were determined by quantum chemical calculations. The barrier height of the equilibration process was measured by high and low temperature NMR measurements to confirm the theoretical outcome. The results of all investigations agree nicely and proved a cis-/trans-mixture of 1,2,6-trimethyl-4-piperidone being present at room temperature.

Full text of DOI:10.1016/j.tet.2005.05.030

Tetrahedron 61 (2005) 6993–7001
Studies on the stereochemistry of 1,2,6-trimethyl-4-piperidone
a,
Florian Diwischek,a Mario Arnone,b Bernd Engelsb, and Ulrike Holzgrabe
*
*
a
¨ ¨ ¨ ¨
Institut fur Pharmazie und Lebensmittelchemie, Universitat Wurzburg, Am Hubland, 97074 Wurzburg, Germany
b
¨
¨
¨
¨
Institut fur Organische Chemie, Universitat Wurzburg, Am Hubland, 97074 Wurzburg, Germany
Received 7 February 2005; revised 10 May 2005; accepted 10 May 2005
Available online 4 June 2005
Abstract—In the effort to create new derivatives of analgesically active spiropiperidines intermediate 1,2,6-trimethyl-4-piperidone was
synthesized. The substitution of the skeleton gives rise to configurational as well as conformational isomerism. Despite the symmetry of
1,2,6-trimethyl-4-piperidone two different sets of signals were present in the 1H and 13C NMR spectra. They were supposed to arise from a
cis/trans mixture of 1,2,6-trimethyl-4-piperidone. In contrast to this explanation only two signals of the methyl groups and hydrogens at
carbon atoms 2 and 6 were observed in the 1H and 13C NMR spectra, normally expecting one for the cis- and two for the trans-isomer. To
solve this discrepancy, the kind of isomeric mixture of 1,2,6-trimethyl-4-piperidone leading to the 1H and 13C NMR spectra was examined.
Energy differences between chair conformations of both the cis- and the trans-isomer of 1,2,6-trimethyl-4-piperidone and the potential
energy surface of the equilibration process of the trans-isomer of 1,2,6-trimethyl-4-piperidone between its chair conformers were determined
by quantum chemical calculations. The barrier height of the equilibration process was measured by high and low temperature NMR
measurements to confirm the theoretical outcome. The results of all investigations agree nicely and proved a cis-/trans-mixture of 1,2,6-
trimethyl-4-piperidone being present at room temperature.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
interest. In the effort to create new derivatives of new
analgetically active spiropiperidines5 the synthetic pathway
via 1,2,6-trimethyl-4-piperidone (1) was chosen. This
piperidone was achieved by a Mannich procedure starting
from dimethyl oxoglutarate, acetaldehyde and methylamine
followed by a decarboxylation to give 1 (Fig. 1).6
The high pharmacological concern about 4-piperidones is
due to their important role as intermediates in the synthesis
of many drugs, especially opioid analgesics. Not only
preparation of reversed esters of pethidine is done via
piperidones1 but also of drugs possessing high affinity for
the ORL1-receptor,2 discovered in 1994.3 The pharmaco-
logical effect of potential drugs depends sensitively on the
stereochemistry and ring conformation especially in the
case of 2,6-disubstituted 4-piperidones.4 Therefore, elucida-
tion of the stereochemistry of these piperidones is of great
Due to the symmetry of 1 half a set of signals should be
expected in 1H and 13C NMR spectra. Despite of this
symmetry two different sets of signals, which may occur in a
slightly different ratio from sample to sample, are present.
This was explored previously and supposed to result from a
Figure 1. Synthesis of 1,2,6-trimethyl-4-piperidone.
Keywords: Piperidones; Stereochemistry of piperidones; Energy pathway.
*
Corresponding authors. Tel.: C49 931 8885394; fax: C49 931 8884606 (B.E.); tel.: C49 931 8885460; fax: C49 931 8885494 (U.H.); e-mail
addresses: bernd@chemie.uni-wuerzburg.de; u.holzgrabe@pharmazie.uni-wuerzburg.de
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.030

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F. Diwischek et al. / Tetrahedron 61 (2005) 6993–7001
Figure 2. (a) 1H NMR spectrum of 1,2,6-trimethyl-4-piperidone (1) synthesized as in Figure 1 (index a for the cis- and index b for the trans-isomer). (b) 1H
NMR spectrum of 1,2,6-trimethyl-4-piperidone (1) with the predominating cis isomer synthesized by hydrogenation.
cis/trans mixture of 1,2,6-trimethyl-4-piperidone (1).4,6 In
the case of the cis/trans mixture, each set of signals would
consist of a signal for the methylene hydrogens on carbon
atoms 3/5 (Fig. 2a; index a for the cis- and index b for the
trans-isomer) and one for the methyl group at the nitrogen
(position 9). In addition, for the methyl groups and
hydrogens on carbon atoms 2/6 one signal each in the
case of the cis-isomer and two signals each in case of the
trans-isomer are expected.
The observed (Fig. 2a) and the expected spectra were only
identical concerning methylene hydrogens at carbon atoms
3 and 5 and the methyl group at the nitrogen (in position 9).
For methyl groups and hydrogens on carbon atoms 2 and 6
1
only two signals were observed in both H and 13C NMR
Figure 3. (a) Representation of the proposed6 conformational equilibrium
of the trans-isomer7. (b) Representation of the possible conformational
equilibrium of the cis-isomer7.
spectra (Fig. 2a), thus missing one signal for the methyl
groups and one for the hydrogens in position 2/6.

F. Diwischek et al. / Tetrahedron 61 (2005) 6993–7001
6995
An explanation for these findings can be the presence of two
configurational isomers with a fast conformational equi-
librium for one of the diastereomers at room temperature
(Fig. 3), because due to the fast equilibration the methyl
groups and the hydrogens on position 2 and 6 would appear
to be equal.
signals for a cis/trans isomerism in 1H and 13C NMR spectra
of 1 due to a different position for the methyl groups and
hydrogens on carbon atoms 2 and 6 (Fig. 2a) of the trans-
isomer, was also observed by Langlois et al.6 A fast
equilibrium of the piperidone ring of the trans-isomer
(Fig. 3a) was assumed providing an equivalence of the
substituents and therefore having no possibility to differen-
tiate between the positions of methyl groups and hydrogens
on carbon atoms 2 and 6 of the trans-isomer. Overlapping of
the second signal of the trans- with the cis-isomer signal
could also be excluded due to the integrals being observed.
Different stable conformational isomers of only one
configurational isomer can also explain the signals found
in the NMR spectrum (Fig. 2a). Thus, the purpose of this
study was to gain more insight into the kind of isomeric
1
mixture of 1 being present in the H and 13C NMR spectra
by quantum chemical calculations as well as high and low
temperature NMR measurements.
1,2,6-Trimethyl-4-piperidone (1) could be obtained also by
a different synthetic route starting from dehydroacetic acid
to the corresponding pyrone followed by catalytic hydro-
genation and a Swern oxidation8 to yield 1,2,6-trimethyl-4-
piperidone (Fig. 4) mostly as the cis-isomer (Fig. 2b). These
findings suggest that the two sets of NMR signals obtained
after the Mannich reaction are caused by two configura-
tional rather than only one configurational isomer with
different conformers also being in accord with earlier
quantum chemical calculations of a series of differently
substituted piperidones, where cis and trans-isomers show
only slight energy differences9 and therefore being able to
be present at room temperature.
2. Results and discussion
In the case of the presence of only one configurational
isomer (cis or trans) with different conformers, the
measured NMR spectra could only be explained if an
unexpected large energy difference between the conformers
is assumed. High temperature NMR measurements could
prove this situation since it should lead to a calescence of the
signals (and therefore to a single set in the NMR spectra)
due to a fast equilibrium between both conformers. In the
opposite case of the presence of a cis/trans-mixture with
different conformers of at least one of the cis/trans-isomers,
a small energy difference between the conformers has to be
assumed to explain the spectra. Due to this small energy
difference a fast equilibrium between the conformers of one
of these configurational isomers at room temperature
occurred. This situation could be confirmed by low
temperature NMR measurements since a separation of the
signals of these conformers in the NMR spectrum would be
obtained.
The next step was to find out whether the spectrum (Fig. 2a)
can be assigned to a cis-/trans-isomeric mixture. In this
case, a fusion of the NMR signals of the methyl groups and
hydrogens at carbon atoms 2 and 6 in a single signal each
concerning the trans-isomer is expected. If the NMR
spectrum is assigned to a mixture of cis- and trans-1,2,6-
trimethyl-4-piperidone, the missing signals of the trans-
isomer for the methyl groups and hydrogens on C2/6 then
are probably due to the fast equilibrium (Fig. 3a) of the
piperidone ring of the trans-isomer.
2.2. Quantum chemical calculations
2.1. High temperature NMR
The fast conformational equilibrium of trans-1,2,6-tri-
methyl-4-piperidone (Fig. 3a), proposed by Langlois
et al.,6 provides an equivalence of the methyl substituents
and hydrogens at carbon atoms 2 and 6 (Fig. 2a) of the
trans-isomer of 1. In order to prove whether this equilibrium
of trans-1,2,6-trimethyl-4-piperidone is indeed present,
quantum chemical calculations were performed. The two
chair conformations (Fig. 3a) as the lowest lying points on
the potential surface were optimized and the energy
differences were calculated by different theoretical methods
(Table 1). The computations were performed as single point
To find out whether only one configurational isomer (cis or
trans) with different conformers or two configurational
isomers (cis and trans) with the equilibrium of one of the
diastereomers (Fig. 3) are present at room temperature, high
temperature NMR experiments were carried out at first.
Measurement of high temperature 1H NMR (C2D2Cl4,
400 MHz) spectra from 300 to 360 K (in steps of 10 K,
spectra being recorded 15 min after setting the temperature)
revealed no alteration concerning the position of any signal
indicating a cis/trans-mixture rather than conformational
isomerism of one configurational isomer. The missing
Figure 4. Synthesis of 1,2,6-trimethyl-4-piperidone via hydrogenation.

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F. Diwischek et al. / Tetrahedron 61 (2005) 6993–7001
Table 1. Energy differences between both conformers of the trans and both conformers of the cis isomers in kJ molK1 (the position after the point is only
presented for better differentiation between given values)
Type of calculation
DE trans-isomers (kJ molK1
)
DE cis-isomers (kJ molK1
)
RI-BLYP/SVP10,11,12,15
RI-BLYP/TZVP10,11,15,16
B3LYP/TZVP11,16,17
AM113
1.8
2.1
3.4
2.9
3.3
12.0
15.7
17.4
2.0
RI-MP2/TZVP18
17.2
Figure 5. Energy pathway of the equilibration process of trans-1,2,6-trimethyl-4-piperidone with structures of the obtained minima and the highest
maximum. Values of the single point calculations with the B3LYP-functional11,17 and TZVP16 basis set are shown in the diagram (further details are discussed
in Section 4).
calculations employing geometries obtained with a BLYP/
SVP10–12 approach (for further details see Section 4).
Semiempirical AM113 optimizations were used to test its
reliability to describe such systems. In addition, for the sake
of comparison energy differences between the two possible
cis-conformers (Fig. 3b) were calculated. AM1 optimiz-
ations were found to be appropriate for the trans-, but not for
the cis-isomers.
computational investigations were executed to evaluate
the energy barriers of the equilibration of the chair
conformers of trans-1,2,6-trimethyl-4-piperidone and its
energy pathway (for further details Section 4). For each
conformer (one with an equatorial (NEQ) and the other with
axial (NAX) positioned methyl group on the nitrogen atom
(Fig. 3a)) of trans-1,2,6-trimethyl-4-piperidone one chair
(conformer 1 (NEQ) and 11 (NAX) in Fig. 5/Table 2), one
boat (conformer 3 (NEQ) and 9 (NAX)) and one twisted
conformation (conformer 5 (NEQ) and 7 (NAX)) were
All applied types of calculation except AM113 show similar
tendencies of energy values. The difference between both
trans-conformers is comparably low with respect to those
obtained for the cis-conformers. Due to the fact of one
conformer of the cis-1,2,6-trimethyl-4-piperidone posses-
sing an 1,3-diaxial interaction of the methyl groups in 2 and
6 position and the other conformer having both methyl
groups in the equatorial position as the more favourable
one,14 a larger difference between the cis-conformers was
expected in comparison to the conformers of trans-1,2,6-
trimethyl-4-piperidone. The differences between the trans-
and the cis-isomers indicate the proposed equilibrium
between the conformers of trans-1,2,6-trimethyl-4-
piperidone at room temperature and therefore also the
explanation for the missing signals in the 1H NMR
spectrum. Since these values represent only energy
differences between the chair conformers, further
Table 2. Energy values of Figure 5 given in kJ molK1 (the position after the
point is only presented for better differentiation between given values)
Conformer
DE to 1 B3LYP/
DE to 1 RI-BLYP/TZVP10,11,15,16
TZVP11,16,17
1
0
0
2
3
4
5
6
7
8
9
17.6
17.2
25.5
16.0
29.9
15.5
16.6
16.1
20.8
3.4
16.1
16.2
24.8
15.4
28.9
14.6
16.0
15,7
19,2
2.1
10
11

F. Diwischek et al. / Tetrahedron 61 (2005) 6993–7001
6997
obtained as minima. Furthermore, transition states between
the calculated minima were determined (chair-boat (2), boat-
twisted (4); NEQ-twisted-NAX-twisted (6); NAX-twisted-
NAX-boat (8), NAX-boat-NAX-chair (10)) and the whole
energy pathway of the equilibration process of trans-1,2,6-
trimethyl-4-piperidone with the required activation energy
barrier was obtained.
given temperature from the first NMR measurement (T1)
(see below).
As presented in Figure 6, the splitting of the single signal of
the methyl groups in position 7 and 8 (Fig. 2a) of the trans-
isomer and therefore freezing of the ring inversion process
of trans-1,2,6-trimethyl-4-piperidone (Fig. 3a) can be seen
at the coalescence temperature (TC) of 162 K of both methyl
groups for the first low temperature NMR experiment (T1).
The second low temperature NMR measurement (T2,
300 MHz) revealed a coalescence temperature (TC) of
155 K for the methyl groups. At 145 K a good separation
of the methyl groups of trans-1,2,6-trimethyl-4-piperidone
is achieved (Fig. 6), the signal representing the methyl
groups of the cis-isomer is still present as a single signal. In
the case of the equilibrium of the chair conformers of trans-
1,2,6-trimethyl-4-piperidone (Fig. 3a), the activation barrier
was calculated using the Eyring equation 1, where DGs is
the free activation enthalpy, R the universal gas constant
(8.31 J/K), T the absolute temperature (K), NA Avagadro’s
number (6.022!1023 molK1) and h is the Planck’s constant
(6.6256!10K34 J/s).
In Figure 5, the optimized minima and transition states are
given. In addition, structures of the minima and the highest
maximum are shown. The corresponding relative energy
values for all points (minima and maxima) are displayed in
Table 2. It contains the computations employing the
RI-BLYP10,11,15 and the B3LYP11,17 functional in combi-
nation with the TZVP16 basis. The energy pathway shows
that both chair conformations of trans-1,2,6-trimethyl-4-
piperidone are the most stable geometries (no. 1 for the
conformer with an equatorial position of the methyl group
on the nitrogen (NEQ), and no. 11 for the conformer with an
axial-positioned methyl group attached to the nitrogen
(NAX)). The boat conformations (no. 3 (NEQ) and no. 9
(NAX)) show the highest energy values of all minima. The
twist conformations (no. 5 (NEQ) and no. 7 (NAX)) are only
slightly lower. Concerning twist and boat structures, the
conformers with an axial methyl group at the nitrogen are
more favourable. This is in contrast to the chair confor-
mations, where an equatorial position of the methyl group
on the nitrogen shows a lower energy condition.
s
RT
k Z
eKDG =RT
(1)
NAh
At the point of coalescence, the following (Eq. 2) is
available:19
To obtain the free activation enthalpy DGs for the
equilibration process of the piperidone-ring of trans-1,2,6-
trimethyl-4-piperidone the energies for the lowest minimum
(no. 1 in Fig. 5) and the highest maximum (no. 6) were zero
point energy and entropy corrected. Thus, DGs was
received as 27 kJ molK1 with the B3LYP11,17 functional
showing the expected small influence of the entropy on the
process. Due to the unpolar solvent used in the NMR-
experiments, insensitivity to the solvent environment should
also be given.
DGs Z 19:1!10K3TCð9:97 Clog TC KlogjnA KnBjÞ
(2)
Thus, the free activation enthalpy for the ring inversion
process of trans-1,2,6-trimethyl-4-piperidone (Fig. 3a) was
calculated to be 32 kJ molK1 (T1) and 31 kJ molK1 (T2) for
the methyl groups in position 7 and 8 (Fig. 2a), being quite
in accordance with the result obtained by the earlier
discussed quantum chemical calculations. In addition to
that, the hydrogens on carbon atoms 2 and 6 (Fig. 2a) of the
piperidone ring of trans-1,2,6-trimethyl-4-piperidone
showed splitting into two signals (data not shown). Since,
these signals show different splitting Dd, they also possess
slightly different TC values (168 K for T1 and 163 K for T2).
Using this data the activation barrier for the equilibrium
of the chair conformations of trans-1,2,6-trimethyl-4-
piperidone (Fig. 3a) was also found to be 32 kJ molK1
(T1) and 31 kJ molK1 (T2) for the corresponding hydrogens
attached to carbon atoms 2 and 6 (Fig. 2a). Because all
obtained values are within a close range of energy values
and differ less than 2 kJ molK1 even though obtained by two
different low temperature NMR experiments, they confirm
the corresponding values obtained by quantum chemical
calculations (see above) for the activation barrier of the ring
inversion process of trans-1,2,6-trimethyl-4-piperidone
(Fig. 3a).
2.3. Low temperature NMR experiments
Low temperature NMR experiments were performed to
verify the theoretically calculated activation barrier of the
ring inversion and the proposed fast equilibration
between the piperidone conformers of trans-1,2,6-tri-
methyl-4-piperidone (Fig. 3a). Due to freezing of the
equilibrium between the two different chair conformers of
trans-1,2,6-trimethyl-4-piperidone (1), splitting of the
single signal for both methyl groups on carbon atoms 2
and 6 (Fig. 2a) into two signals is expected as well as
splitting of the hydrogens attached to the same carbon atoms
as the methyl groups. NMR spectra of 1 were recorded
every 10 K downwards, starting from 296 K, later on in
steps of 5 K and close to the coalescence of the signals a
spectrum was measured in one degree K steps. NMR spectra
were recorded 15 min after setting the corresponding
temperature. Due to the fact of measuring below the normal
freezing point of CD2Cl2 as the solvent, low temperature
experiments were executed twice and in every case
measuring was possible that low, indicating a subcooled
3. Conclusions
Due to the investigations executed the earlier stated
cis/trans isomerism4,6 could not only be verified, but also
the activation barrier values for the conformational
1
solution of the samples. Figure 6 shows a selection of H
NMR spectrum expansions of the region of interest at the

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F. Diwischek et al. / Tetrahedron 61 (2005) 6993–7001
Figure 6. Low temperature 1H NMR peaks (CD2Cl2, 400 MHz) of the 2,6 methyl groups at given temperatures from the first low temperature experiment T1.

F. Diwischek et al. / Tetrahedron 61 (2005) 6993–7001
6999
equilibrium of trans-1,2,6-trimethyl-4-piperidone could be
obtained (Fig. 3a). Quantum chemical calculations were
carried out to obtain energy differences between both chair
conformers of cis- and trans-isomers and to obtain
information about the activation barrier and the energy
pathway of the ring inversion process of trans-1,2,6-
trimethyl-4-piperidone. The activation barrier of this
equilibrium of trans-1,2,6-trimethyl-4-piperidone was
verified by low temperature NMR experiments.
employed with the BLYP10,11 functional, the SVP12 basis
set and the RI15 approximation performed with the
TURBOMOLE21 program package. Furthermore, a semi-
empirical AM113 optimization was used for comparison.
Single point calculations for the energy difference were
carried out with the TZVP16 basis set and the RI-BLYP,10,11,15
B3LYP11,17 and RIMP218 method on the BLYP/SVP10,11,12
geometry.
To obtain the energy pathway of trans-1,2,6-trimethyl-4-
piperidone a conformational search22 applying the
MMFF94s23 force field in the MacroModel 8.024 program
was executed to locate the minima on the energy surface of
trans-1,2,6-trimethyl-4-piperidone. The obtained structures
were reoptimized by DFT calculations employing the RI-
BLYP10,11,15 functional in combination with the SVP12
basis set. Single point calculations were done with the
BLYP10,11 and B3LYP11,17 functional and the TZVP16 basis
set. These stationary points were verified as local minima by
the absence of imaginary frequencies (AOFORCE21).
Transition states were obtained by Gaussian 0325 QST2
calculations applying the BLYP/SVP10,11,12 level of theory
and were also confirmed by AOFORCE21 calculations as
transition states (imag. freq.Z1). Reoptimizations of
the calculated transition states were executed with
TURBOMOLE21 and the RI-BLYP/SVP10,11,12,15 method
(STATPT), single point calculations with the BLYP10,11 and
B3LYP11,17 functional and the TZVP16 basis set. To connect
the so far obtained minima and transition states, further
quantum chemical calculations were performed between
boat-boat and twist-twist conditions, that were calculated as
transition states as above. Thus, the whole energy pathway
of the equilibration process of trans-1,2,6-trimethyl-4-
piperidone with the required activation energy barrier
(Fig. 6) was obtained.
The quantum chemically calculated values show good
agreement to those determined by low temperature NMR
spectroscopy and confirm the equilibrium (Fig. 3a) of the
conformers of trans-1,2,6-trimethyl-4-piperidone at room
temperature. Therefore, both theory and experiment prove
that a cis/trans isomeric mixture is present at room
temperature in the spectrum of 1,2,6-trimethyl-4-piperidone
(Fig. 2a) when synthesised as in Figure 1. Considering the
pharmacological aspects, the affinity to a corresponding
receptor should not be influenced by the different con-
formers (Fig. 3a) of trans-1,2,6-trimethyl-4-piperidone,
because they can be easily converted into each other due
to their low energy difference. However, a cis-/trans-
mixture should be avoided for pharmacological evaluation,
because a conversion is impossible due to a bond cleavage
being necessary to transform one into another. Isolation of a
mixture with the cis-isomer predominating can only be
achieved by a different synthetic pathway (Fig. 4).
4. Experimental
4.1. NMR investigations
1
All synthesised compounds were characterized by H and
1
13C NMR spectroscopy. H NMR spectra were performed
on a Bruker DRX 300 (300.13 MHz) and Bruker Avance
400 (400.13 MHz), respectively. The temperatures of the
probe were calibrated by a low temperature calibration with
4% methanol in [D4] methanol.20 13C NMR spectra were
4.2.1. 1,2,6-Trimethylpiperidin-4-one (1) via 1,2,6-tri-
methyl-4-piperidone-3,5-dimethyldicarboxylate. Syn-
thesis was executed by a modified instruction of Langlois
et al.6 5.22 g (30.0 mmol) of 1,3-acetone dicarboxylate
(97%) was added to an ice-cold mixture of 2.02 g
(30.0 mmol) methylamine hydrochloride in 10 ml of water
and 2.73 g (62.0 mmol) acetaldehyde. After warming to
room temperature, the solution was stirred for additional
16 h, the solvent was completely removed in vacuo and a
small amount of acetone was added to precipitate 6.25 g
(21.3 mmol) of 1,2,6-trimethyl-4-piperidone-3,5-dimethyl-
dicarboxylate after cooling. 1,2,6-Trimethyl-4-piperidone-
3,5-dimethyldicarboxylate (2.00 g (6.81 mmol)) were dis-
solved in 20 ml 6 M HCl and stirred for 20 h at 80 8C. After
neutralisation with a saturated KOH solution, the reaction
mixture was extracted three times with 20 ml CH2Cl2,
organic phases were dried with Na2SO4 and the solvent was
removed in vacuo. The oily, orange residue was distilled by
vacuum distillation and 0.69 g (4.89 mmol) of 1 was
obtained as a colourless oil (bp 30 8C (0.1!10K2 mbar)).
1
performed on a Bruker Avance 400 (100.62 MHz). For H
NMR spectra with the Bruker Avance 400 (T1,
400.13 MHz) [DRX 300 (T2, 300.13 MHz)], 32 [16] scans
were collected into 64 K [72 K] data points giving a digital
resolution of 0.25 Hz [0.16 Hz] per point. The spectral
width was 8278 Hz [6188 Hz], the transmitter offset
6.18 ppm [6.18 ppm]. Using an acquisition time of 3.96 s
[5.99 s] and an additional delay of 1 s [1 s], a pulse
repetition period of 4.96 s [6.99 s] results. An appropriate
window function was applied before Fourier transformation
in order to enhance the spectral resolution. For 13C NMR
spectra 512 scans were collected into 64 K data points,
giving a digital resolution of 0.73 Hz per point. The spectral
width was 23981 Hz and the transmitter offset 100 ppm.
Using an acquisition time of 1.37 s and an additional delay
of 2 s, a pulse repetition period of 3.37 s results. An
appropriate window function was applied before Fourier
transformation in order to enhance the spectral resolution.
1H NMR (400 MHz, CDCl3, dZppm, JZHz): Isomer A:
3.03–3.12 (m, 2H, H2,6), 2.42 (dd, 2H, overlapping with
H2,6 Isomer B, JZ13.9, 4.54 Hz, H3,5eq), 2.33 (s, 3H, H9),
2.11 (dd, 2H, JZ13.9, 6.68 Hz, H3,5ax), 0.97 (d, 6H, JZ
6.56 Hz, H7,8); Isomer B: 2.39–2.45 (m, overlapping with
H3,5 Isomer A, H2,6), 2.18–2.29 (m, overlapping with H3,5
4.2. Quantum chemical calculations
For the geometry optimizations of the two chair confor-
mations density functional theory (DFT) calculations were

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F. Diwischek et al. / Tetrahedron 61 (2005) 6993–7001
Isomer A, H3,5), 2.22 (s, 3H, H9), 1.13 (d, 6H, JZ6.32 Hz,
H2,6); 13C NMR (100 MHz, CDCl3, dZppm): Isomer A:
209.28 (C4), 54.10 (C2,6), 47.63 (C3,5), 38.07 (C9), 16.45
(C7,8); Isomer B: 208.37 (C4), 58.60 (C2,6), 48.15 (C3,5),
34.57 (C9), 21.15 (C2,6).
630. The authors wish to thank Dr. Ru¨diger Bertermann for
measuring low temperature NMR experiments and Dr.
Ralph Deubner for measuring high temperature NMR
experiments.
4.2.2. 3-Acetyl-6-methyl-pyran-2,4-dion (dehydracetic
acid) (2). Synthesis of 2 followed the preparation of Arndt
et al.26 Freshly distilled ethyl acetoacetate (100 g
(0.77 mol)) and 50 mg sodium carbonate were heated to
200–210 8C. The formed ethanol was removed by distilla-
tion by a modified dry-ice condenser connected with an
additional condenser set for distillation. The modified
condenser was filled with toluene, and a reflux condenser
was attached to the top to keep the rest of the solution in the
reaction mixture. The reaction was maintained for 7–8 h at
that temperature followed by vacuum distillation of the
remaining brown solution while still being hot to yield
53.06 g (0.32 mol) of 2 (mp 110 8C (lit.:26 104–110 8C)).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.05.
030
The supporting information material contains Cartesian
Coordinates, computed total energies and the imaginary
frequencies (where applicable) of the obtained structures in
Table 1 (conformers A–D) and in Table 2 (conformers
1–11).
4.2.3. 1,2,6-Trimethyl-1H-pyridin-4-one (N-methylluti-
done) (3). The title compound 3 was synthesised as
executed by Iguchi et al.27 A sealed tube was charged
with 3.67 g (0.02 mol) dehydracetic acid 2 and 20 ml
aqueous methylamine solution (25%) was added and heated
to 110 8C for 6 h. After cooling, the raw product precipitated
as white needles. After filtration and recrystallisation from
hot water, 3 was dried at 115 8C in vacuo. The title
compound 3 (2.17 g (15.8 mmol)) was obtained (mp 248 8C
(lit.27: 245 8C)).
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