Axially chiral thioamides of acrylic acid: Correlated and uncorrelated internal rotations

Article abstract of DOI:10.1016/S0957-4166(98)00373-5

In acrylic thioamides (Scheme 1), two intramolecular motions are possible: thiocarbonyl-nitrogen (=C-N) and alkenyl-carbonyl (=C-C=) rotations. Since the two mobile molecular fragments can interact by steric and by resonance effects, we intended to demons

Full text of DOI:10.1016/S0957-4166(98)00373-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3629–3645
Axially chiral thioamides of acrylic acid: correlated and
uncorrelated internal rotations
Margit Kuttenberger, Markus Frieser, Martin Hofweber and Albrecht Mannschreck ∗
Institut für Organische Chemie, Universität Regensburg, Universitätsstraße 31, D-93040 Regensburg, Germany
Received 8 July 1998; accepted 15 September 1998
Abstract
In acrylic thioamides (Scheme 1), two intramolecular motions are possible: thiocarbonyl–nitrogen (_C–N) and
alkenyl–carbonyl (_C–C_) rotations. Since the two mobile molecular fragments can interact by steric and by
resonance effects, we intended to demonstrate the existence of correlated in addition to the above uncorrelated
motions. For each of the three thioamides chosen, at least two of the four stereoisomers were enriched by
crystallization and by liquid chromatography on nonracemic sorbents. Thereby axial chirality of acrylic thioamides
was proven for the first time. Thermal equilibrations were monitored quantitatively by time-dependent 1H NMR
spectroscopy in the presence of a nonracemic additive, a method which, to our knowledge, has not previously
been described. These kinetic results were evaluated by a simulation program with reference to uncorrelated and
correlated rotations (Figs. 4–6). We have shown that all of these motions occur in thioamide 14. The enantiomers of
thioamide 13 do not interconvert directly. However, indirect, two-step enantiomerizations in 13 have been proven
one of the two steps consisting of correlated rotations. The latter are, therefore, possible in acrylic thioamides,
a class of compounds which differ considerably from the molecules for which correlated motions were hitherto
known. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Intramolecular motions of many types have been investigated in considerable detail during the last
thirty years.1,2 In the case of the occurrence of several such processes in the same molecule, these
will often occur independently of each other, i.e. they will be uncorrelated. However, some molecular
systems are known in which certain motions are coupled, i.e. they are correlated. This field of research
has been pioneered by Mislow and his coworkers. It comprises mainly molecular propellers3,4 (1,1,1-
triaryl compounds) and bis(triptycyl)methanes.3 For many such systems, clear-cut evidence in favor of
correlation or non-correlation has been obtained.
∗
Corresponding author. Fax: (941) 943 4617.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00373-5

3630
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
We asked the question whether such correlations may occur more frequently than hitherto supposed,
particularly in cases where the mobile molecular fragments are sufficiently close to one another for
interactions by steric and, possibly, by resonance effects. In some 2-(dialkylamino)-benzamides and
thioamides, aryl–nitrogen and aryl–carbon rotations turned out to be uncorrelated, in others uncorrelated
and correlated motions were both shown to be possible,5 but further conclusions were not attainable.
Therefore, we considered carbonyl–nitrogen (_C–N) and alkenyl–carbonyl (_C–C_) rotations in
amides and thioamides (Scheme 1) of acrylic acids which could potentially use uncorrelated (k1, k2, k3
and k4) or correlated (k5 and k6) pathways. Their mobile fragments, the alkenyl, thiocarbonyl and amino
groups, are indeed close to one another and interact sterically and by π overlap in the respective ground
(Scheme 1) and transition states of the above two types of rotation. Because of the amide resonance,
these molecules show6 the usual1,2 diastereomers (E) and (Z) (Scheme 1, R=CH3) and their _C–N
interconversions. In addition, we demonstrated6,7 for the first time that acrylic thioamides consist of
enantiomers (M) and (P) (Scheme 1, R=CH3) which exhibit _C–C_ interconversions. The detection
of this type of axial chirality in solution at room temperature requires that the C_C fragment and the
nitrogen atom bear substituents other than hydrogen, i.e. some steric hindrance is required. In this respect,
acrylic thioamides resemble axially chiral 1,3-dienes8 and oxalic dithioamides.9 In a similar way, 1-
naphthoic analogues can also be considered. The 1-naphthyl group has the same symmetry properties
as the alkenyl moiety which means that the stereostructural and kinetic situation10 fits Scheme 1. For
1-naphthoic N,N-dimethylthioamide,11 enantiomers were detected in solution at room temperature and
they showed _C–C_ interconversion.12
Scheme 1.
For some acrylic thioamides, the barriers ∆G‡, corresponding to the rate constants k1, k2, k3 and k4 in
Scheme 1, were known,6,13 the considerable heights of which had required time-dependent measurements
of concentrations during thermal equilibrations. Consequently, we planned to monitor the interconversion
of the two diastereomers14 quantitatively by NMR spectroscopy and to extend this technique to the
enantiomers15 by adding a nonracemic auxiliary. The choice of suitable compounds was limited by the
following conditions: R=CH3 (Scheme 1) in order to create diastereomers; both diastereomers to be
detectable in sufficient concentration after equilibration; significant enrichment of a single stereoisomer

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3631
to be possible, from which the equilibration can start; at least one NMR signal of each stereoisomer to
be present during equilibration, suitable for quantitative measurement of the four intensities; the NMR
signals to be assigned to the relative configurations, which requires the enrichment of more than one of
the four stereoisomers. The syntheses given in Schemes 2–4 resulted in thioamides 13–15 as candidates
for the present project, whereas a considerable number of further compounds6,13 failed to meet the above
conditions.
Scheme 2.
Scheme 3.
Therefore, we intended to enrich at least one stereoisomer of each of these three thioamides, to monitor
the thermal equilibrations as suggested above and to evaluate the results with reference to the uncorrelated
and correlated rotations indicated in Scheme 1.

3632
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
Scheme 4. LR: Lawesson’s reagent=2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
2. Synthesis and separation of stereoisomers
Acids 7 (Scheme 2) and 9 (Scheme 3) were unknown, 8 was known. These were converted into 13–15
(Scheme 4) by general methods. In all cases, recrystallization yielded one of the two racemic diastereo-
mers in pure form which was analyzed. For the three thioamides, analytical liquid chromatography (e.g.
Fig. 1) on several nonracemic sorbents was performed. Semipreparative enrichment of enantiomers was
obtained on microcrystalline triacetylcellulose7 or tribenzoylcellulose.16 These enantiomers were charac-
terized by their enantiomeric purities, circular dichroism spectra, and, if possible, specific rotations. Only
the samples to be used for the kinetics of stereoisomerization appear in the Experimental, i.e. (−)-(E)-13,
(+)-(E)-14, and (+)-(Z)-15. (+)-(E)-14 was a colorless oil, whereas melting points are given for the other
two enriched enantiomers. Together with our earlier findings,6,7 this is the first time that enantiomers of
substituted acrylic thioamides have been described, i.e. that the axial chirality of this class of compounds
is proven.

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3633
Fig. 1. Analytical liquid chromatogram of 0.6 mg of 14. Microcrystalline tribenzoylcellulose, MeOH, flow rate 0.5 ml/min,
pressure 24 bar. k0: Retention factor. A: Absorbance in V at 320 nm. α: Rotation angle at 405 nm. Top: Soon after dissolution
of crystals of (ꢀ)-(Z)-14. Bottom: Equilibrium mixture after keeping the above sample at 50°C for 1 h

3634
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3. Assignment of the stereoisomers to 1H NMR signals
NOE effects in the model thioamides 166 and 176 (Scheme 5) served to assign the 1H NMR CH3 shifts
to the positions of these groups. Transfer of this information to 13, 14 and 15 resulted in assignments
of shifts to the diastereomers (E) and (Z), given in the Experimental. These were in agreement with
benzene-induced shifts carried out for (E)- and (Z)-14 and further acrylic thioamides. For (E)- and (Z)-
15, the assignments in CDCl3 solution had to be transferred to a d8-toluene solution because a solvent
boiling at a higher temperature than does CDCl3 was required for the equilibrations (see below). This
transfer took into account d8-toluene-induced shifts and resulted in the δ-values for 15 in d8-toluene in
the Experimental. The addition of 6.0 equiv. of (+)-(S)-1-(9-anthryl)-2,2,2-trifluoroethanol 18 renders
1
the enantiomers visible in the H NMR spectra (e.g. Fig. 2) in addition to the two diastereomers. The
corresponding assignments (Table 1) resulted from one or more of the following pieces of information.
(E) and (Z) were assigned via relative signal intensities after equilibration (see K-values in Figs. 4–6) and
their comparison with the known intensities in the absence of (+)-(S)-18; thus, the major diastereomer
1
is (Z) in the cases of 13 and 14 and (E) in the case of 15. All enantiomers in equilibrium showed H
NMR peaks with equal intensities. (In the presence of a nonracemic additive, unequal intensities have
been observed occasionally.17–19 ) For 14 and 15, all four stereoisomers were enriched preparatively and
1
examined by H NMR in the presence of (+)-(S)-18, by circular dichroism and by polarimetry which
provided the assignments in Table 1. For 13, (+)- and (−)-(E) were enriched preparatively and analyzed
as above. The low abundance of (ꢀ)-(Z)-13 after synthesis rendered preparative enrichments difficult but
analytical HPLC with polarimetric detection resulted in the required information.
Scheme 5. NOE effects are indicated by arrows, 1H NMR shifts in CDCl3 at 21°C by numbers close to protons. Only one of the
enantiomers is shown
1
4. Equilibration of stereoisomers, monitored by signal intensities in enantioselective H NMR
The enriched enantiomers mentioned above were equilibrated at suitable temperatures, i.e. at 21–90°C,
depending upon the substituents of the substrate molecules, in the presence of 6.0 equiv. of (+)-(S)-1-
(9-anthryl)-2,2,2-trifluoroethanol 18. To our knowledge, the application of this technique has not yet
1
been described. Soon after dissolution, the extent of enrichment was determined by H NMR signal
intensities (e.g. in Fig. 2, top). The end of the isomerizations (cf. Fig. 2, bottom) was attained after 6–137
h, depending upon the substrate. During this period, 15 further measurements of intensities were carried
out, i.e. the relative concentrations of the stereoisomers were monitored quantitatively as a function of

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3635
1
Fig. 2. H NMR at 400 MHz of the _C–CH3 groups for the stereoisomers of 14 in CDCl3 in the presence of 6.0 equiv. of
(+)-(S)-18. The formula of one of the stereoisomers is shown. See Fig. 3 for relative concentrations. Top: Soon after dissolution
of a sample, containing enriched (+)-(E)-14. Bottom: Equilibrium mixture after keeping the above sample at 21°C for several
days
Table 1
Assignments of stereoisomers to NMR shifts δ of _CCH3 protons in the presence of 6.0 equiv. of
(+)-(S)-1-(9-anthryl)-2,2,2-trifluoroethanol (18). In the case of 13, cis _CCH3 (Scheme 4) was chosen.
Signs of polarimetric rotation refer to 436 nm

3636
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
Fig. 3. Relative concentrations x of the stereoisomers of 14 in CDCl3 in the presence of 6.0 equiv. of (+)-(S)-18 as a function
of time t. The formula of one of the stereoisomers is shown. Points represent 1H NMR measurements (cf. Fig. 2), curves were
obtained by computer simulation of the experiments (see text)
time (e.g. the points in Fig. 3). Table 1 shows the protons chosen for these measurements as well as their
1H NMR shifts.
5. Individual rates of stereoisomerization, obtained by computer simulation of the experimental
equilibrations
The relative concentrations of stereoisomers as a function of time (e.g. the points in Fig. 3) cannot be
transformed analytically into the six rate constants given in Scheme 1. However, methods20 are known
to obtain k1–k6 via a first simulation of the experimental equilibrations by the use of six preliminary
rate constants and their subsequent iterative improvement via an improved fit between simulation and
experiment. For this procedure, we chose the program SimFit (Nonlinear Curve-Fitting by Dynamic
Simulation), written by von Kiedrowski.21,22 It furnishes final k-values and their standard deviations ∆k
(Figs. 4–6) as well as the corresponding relative concentrations as a function of time (e.g. the curves
in Fig. 3), as early as the program is unable to provide further improvement of the fit. In addition,
SimFit gives the R-factor of the final simulation. All reasonable alternative kinetic possibilities were
tried, without success, as sets of preliminary rate constants, in addition to the sets of k-values in Figs. 4–
6. The kinetic schemes in these figures are simplified by the fact mentioned above that all enantiomers
1
in equilibrium showed H NMR peaks with equal intensities. The legends give equilibrium constants
K between (E)- and (Z)-stereoisomers which were obtained at the end of the isomerizations. The
errors of the barriers ∆G‡ in Figs. 4–6 were calculated by propagation of ∆k (see above) and ∆T (see
Experimental).
For thioamide 14, a simulation without k5 and k6, i.e. the correlated rotations, showed clear-cut graphic
deviations from the experimental points in Fig. 3 and an R-factor of 1.8%. Participation of all six rate
constants resulted in a better graphic fit (Fig. 3), an R-factor of only 0.8% and the k-values of Fig. 5.
For thioamide 13, participation of all six rate constants yielded extremely low values for k1 and k2

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3637
Fig. 4. k- and ∆G‡-values for rotations in 13 [CDCl3, 55°C, 6.0 equiv. of (+)-(S)-18]. K=0.33ꢀ0.02=k4/k3=k6/k5
Fig. 5. k- and ∆G‡-values for rotations in 14 [CDCl3, 21°C, 6.0 equiv. of (+)-(S)-18]. K=0.79ꢀ0.03=k4/k3=k6/k5
which are due to the enantiomerizations by _C–C_ rotations. When these motions were forbidden
completely (k1=k2=0), the R-factor dropped tremendously to 0.8%, resulting in the k-values of Fig. 4.
For thioamide 15, participation of all six rate constants yielded a very low value for k1 which is due to
the enantiomerization by _C–C_ rotation in the diastereomer (E)-15. When this motion was forbidden
completely (k1=0), two sets of k-values resulted: (a) the set given in Fig. 6 with small values for k5 and
k6 which are due to the correlated rotations, with acceptable graphic fit and with an R-factor of 1.5%; and
(b) a second set with k5=k6=0, with a less perfect graphic fit and with an R-factor of 1.7%. This means
that some extent of correlated rotations is probable in the case of 15. A possible coupling between the two
processes in Fig. 6 has been discussed23 for a thiobenzamide and for a corresponding non-thioamide.24

3638
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
Fig. 6. k- and ∆G‡-values for rotations in 15 [d8-toluene, 90.5°C, 6.0 equiv. of (+)-(S)-18]. K=1.36ꢀ0.04=k4/k3=k6/k5
6. Discussion of the barriers to stereoisomerizations
We did not find a way to measure the individual barriers in the absence of a nonracemic auxiliary.
Therefore, these cannot be compared with the ∆G‡-values in Figs. 4–6 which were determined in the
presence of (+)-(S)-18. Somewhat more limited information about the influence of this additive upon
barriers can be obtained in the following way, exemplified for thioamide 14. Crystalline (ꢀ)-(Z)-14
undergoes a slow (E)/(Z) equilibration14 at 24°C after dissolution in CDCl3 in the absence of an auxiliary.
Monitoring of 1H NMR signals as a function of time results14 in ∆G‡=98.4ꢀ0.7, (E)-→(Z), and 99.3ꢀ0.8
kJ mol−1, (Z)-→(E).13 The corresponding values, referring to the presence of (+)-(S)-18, were determined
from the data in Fig. 3 by summing up the relative concentrations of (+)- and (−)-(E) as well as the
ones of (+)- and (−)-(Z). These united (E) and united (Z) concentrations were treated as an (E)/(Z)
equilibration14 as above, resulting14 in ∆G‡=99.9ꢀ0.7, (E)-→(Z), and 100.5ꢀ0.8 kJ mol−1, (Z)-→(E)13 at
21°C in CDCl3. This means that the presence of the additive increased the above barriers by approx. 1
kJ mol−1. For thioamide 13, the increase was even less, for 15 no change of barriers by (+)-(S)-18 was
observed within error limits.13 Similar results had been obtained for related systems,25 showing again
that the influence of nonracemic alcohols upon the ∆G‡-values must not be taken into account in the
following semiquantitative discussion of Figs. 4–6.
All the barriers for uncorrelated rotations, corresponding to k1, k2, k3 and k4 in 14 amount to ca. 101 kJ
mol−1 (Fig. 5), whereas ∆G‡5 and ∆G‡6 are close to 103 kJ mol−1. This means that the four independent
motions occur more frequently than the two correlated ones, although the existence of the latter has been
demonstrated beyond doubt in the above section on individual rates.
In that section, it has also been stated that some extent of correlated rotations is probable in 15 (Fig. 6).
The corresponding values ∆G‡ and ∆G‡ are as high as ca. 129 kJ mol−1, i.e. these motions occur
5
6
much less frequently than the observed uncorrelated rotations (∆G‡ , ∆G‡ and ∆G‡ ). According to
2
3
4
our experimental results, the enantiomers of (E)-15 do not interconvert directly, which means that the
barrier to _C–C_ rotation (∆G‡ ) must be very high. The two possible transition states for this motion
1
would be close to planar; in these, the voluminous N–CHMe2 substituent would meet either the _C–CH3

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3639
group or an ortho-proton of the fluorenylidene moiety (cf. formula in Fig. 6). Such repulsions are less
severe in the corresponding transition states of the diastereomer (Z)-15, in which the smaller N–CH3
substituent interacts with the _C–CH3 group or the fluorenylidene moiety.
In 13, the enantiomers of (E)-13 again do not interconvert, but unlike the situation in 15, this is true for
(Z)-13 too (Fig. 4). The four possible transition states of _C–C_ rotation would be close to planar and
would experience severe repulsion of substituents (cf. formula in Fig. 4). In spite of the absence of direct
enantiomerizations (∆G‡ and ∆G‡ ), indirect ones do occur. They are two-step processes, e.g. via the
1
2
∆G‡3 and the ∆G‡6 barriers, ∆G‡3 representing the uncorrelated _C–N motion and ∆G‡6 the correlated
rotations.
Independent semiquantitative support for some enantiomerization process comes from thermal trans-
formation of (−)-(E)-13 into a mixture of all four stereoisomers, i.e. from equilibration. The latter
was monitored by polarimetry, i.e. by the dependence of the angle α of rotation upon time t. For
(−)-(E)-13 in CHCl3 at 55°C, this procedure gives an α/t dependence developing towards α=0, the
approximate first-order evaluation of which results in ∆G‡=112.7 kJ mol−1. A curvature of this α/t
dependence clearly indicates the occurrence of a faster and a slower process. We do not see an easy way
to evaluate such measurements quantitatively but conclude that they are in agreement with the above
two-step enantiomerization and with the facts given in Fig. 4, i.e. with correlation. Similar experiments
and conclusions were performed for 14 and 15.
Semiempirical calculations26 by the AM1, PM3 and MINDO3 methods for 2,3-dimethyl-2-butenoic
N-benzyl-N-methylthioamide as a model molecule resulted in the energy surfaces for the _C–N and
the _C–C_ rotations corresponding to Scheme 1. All transition states were confirmed. Full theoretical
support of all experimental results would require more sophisticated methods applied to the molecules
13 and 14 themselves.
For the first time, we have proven the above combined rotations in thioamides of acrylic acid. Thus,
the known examples3,4 of correlated motions have now been extended to a completely different class of
compounds.
7. Experimental
7.1. General methods
1
Column chromatography was carried out on ICN silica gel 60 F254 (63–200 µm). H NMR spectra
were recorded on Bruker AW-80, AC-250 or ARX-400 instruments at 31, 24 or 21°C with tetramethyl-
silane (δ=0 ppm) as an internal standard. Temperatures were determined by samples of 1,2-ethanediol.27
The NRE and NRZ groups in amides and thioamides were assigned by benzene-induced shifts28,29 and/or
NOE. IR spectra were measured on Beckmann Acculab 1, UV spectra on Hitachi U 2000, mass spectra
(MS) on Finnigan (MAT 90, 70 eV) or Varian (MAT CH 5, 70 eV) spectrometers. The enrichments
of stereoisomers were performed by liquid chromatography30,31 on microcrystalline triacetylcellulose7
(TAC) for 13 and 14 in EtOH/H2O 96/4 at 22°C and on microcrystalline tribenzoylcellulose16 (TBC)
for 15 in MeOH at 22°C. See lit.32 for the definition of the retention factor k0. Diastereomeric purities
1
were measured via H NMR spectroscopy. Enantiomeric purities [P] were either determined by liquid
1
chromatography on nonracemic sorbents or via H NMR in the presence of 6.0 equiv. of (+)-(S)-1-
(9-anthryl)-2,2,2-trifluoroethanol 18. Specific rotations [α0] were measured for enriched stereoisomers
at 21°C on a Perkin–Elmer 241 polarimeter at certain wavelengths. Similarly, circular dichroism was
recorded on a Jasco J-40 A dichrograph, differential absorption coefficients ∆ε0 of maxima being given

3640
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
in l mol−1 cm−1. [α0] and ∆ε0 are calculated for [P]=100%. Melting points were determined on a Büchi
SMP-530 apparatus and are not corrected. (+)-(E)-14 was stereoisomerized and analyzed in the probe
head of an NMR spectrometer at (21ꢀ2)°C. The isomerization of (−)-(E)-13 at 55°C was monitored
in this way only during the first half-life time; they were continued in a thermostat (∆T=ꢀ0.5°C), i.e.
after certain time intervals the sample was cooled rapidly to 0°C (in order to quench the equilibration)
1
and analyzed by H NMR at 21°C. In the case of (+)-(Z)-15, the latter procedure was performed in a
thermostat at (90.5ꢀ0.5)°C, starting from the beginning of the isomerization. After several further half-
life times, all four samples were brought to equilibrium by thermostatting. All 1H NMR analyses included
intensities and spectra; no decomposition products were detected.
7.2. General procedures
(A) Acrylic amides. SOCl2 (11 mmol) in dry ether was added dropwise to the solution of an acid (10
mmol) and pyridine (12 mmol) in dry ether over a period of 20 min at 0°C. After additional stirring over
a period of 4 h at room temperature, colorless pyridinium chloride precipitated and was filtered off. A
solution of benzylmethylamine (25 mmol) in dry ether was added dropwise at 0°C and the mixture was
stirred for 1 h at room temperature. The precipitate was removed and the filtrate washed with H2O, dil.
HCl, Na2CO3, H2O and dried (Na2SO4). After removing the solvent, the remaining oil was characterized
and subjected to thionation.
(B) Acrylic thioamides. The amide (10 mmol) in dry pyridine (40 ml) was refluxed with P4S10 (3.5
mmol) over a period of 20 h. Monitoring of the reaction by thin-layer chromatography showed the
completeness of the reaction. The mixture was cooled and the solvent removed. The residue was extracted
several times with hot petroleum ether (PE) 40/60 (3×50 ml), the solvent removed and this second residue
recrystallized or purified by column chromatography.
7.3. Compounds used
Compounds 1,33 3,34 434 and 835 (Schemes 2–4) were prepared as described in the literature.
7.4. 2,5-Dimethylhexan-3-one 2
A solution of Na2Cr2O7 (2.0 g, 6.7 mmol) in sulfuric acid (1.5 ml) and H2O (10 ml) was added
gradually to 2,5-dimethylhexan-3-ol 1 (2.6 g, 20 mmol) in ether at 0°C and stirred for 2.5 h at room
temperature. The water layer was separated, extracted twice with ether and the combined organic phases
were washed with sat. NaHCO3 solution, water and dried (Na2SO4). Evaporation of the ether afforded
pure 2 (2.3 g, 90%) as a colorless liquid, b.p. 64°C /6400 Pa (lit.36 67°C/6400 Pa). IR (film): 2960, 2930,
2870 (C–H), 1700 cm−1 (C_O). 1H NMR (CDCl3): δ 0.90 (6H, d, 3J=6.5 Hz, –CH(CH3)2), 1.05 (6H, d,
3J=6.5 Hz, –CH(CH3)2), 2.3 (2H, m, –CO–CH2–CH), 2.30 (1H, h, 3J=6.5 Hz, –CH(CH3)2), 2.60 (1H,
h, 3J=6.5 Hz, –CH (CH3)2).
7.5. Ethyl 2-(9-hydroxyfluoren-9-yl)-propanoate 5
20% of a solution of 9-fluorenone (40.0 g, 222 mmol) and ethyl 2-bromopropanoate (28.0 g, 155
mmol) and a small crystal of iodine37 in 75 ml of abs. toluene were refluxed under vigorous stirring in
the presence of zinc powder (12.1 g, 185 mmol) which had been previously activated by washing it with
hot NaOH (25%), H2O, dil. acetic acid, H2O, ethanol, acetone and ether and finally by drying it over

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3641
KOH. The remaining 80% of the above solution was added dropwise over a period of 30 min. After 8 h
of additional stirring, the mixture was allowed to cool to room temperature and then poured into ice-cold
H2SO4 (10%, 92 ml). The mixture was filtered, extracted with ether and the organic layer was washed
with dil. H2SO4 (5%, 2×100 ml), Na2CO3 (10%, 2×100 ml) and H2O, then dried (Na2SO4) and the
solvent removed. The remaining oil was twice submitted to column chromatography (PE/MeOH 11/1,
last fraction). Slightly orange oil (39.4 g, 90%). IR (film): 3700–3200 (O–H), 3060, 3040, 3020 (Car–H),
2980, 2870 (Cal–H), 1720, 1700 cm−1 (C_O). 1H NMR (CDCl3): δ 0.80 (3H, d, 3J=7.1 Hz, –CH–CH3),
3
3
3
1.22 (3H, t, J=7.0 Hz, –O–CH2–CH3), 3.19 (1H, q, J=7.1 Hz, CH–CH3), 4.20 (2H, q, J=7.0 Hz,
–O–CH2–CH3), 7.0–7.6 (8H, m, CHarom).
7.6. Ethyl 2-fluoren-9-ylidenepropanoate 6
A solution of ethyl 2-(9-hydroxyfluoren-9-yl)-propanoate (5) (38.32 g, 136 mmol) in dry toluene (170
ml) was added to a cold solution of P4O10 (38.00 g, 134 mmol) in H3PO4 (85%, 380 g) and refluxed for
4 h. The mixture was washed with water (300 ml), the aqueous layer was extracted with ether and the
combined organic phases were washed with NaCl (5%). While removing the solvent slowly, a brown oil
and colorless crystals precipitated and were filtered off. Further evaporation afforded an orange oil that
crystallized after addition of ether (5 ml). The product was filtered and dried in vacuo at 40°C for 4 h
to give yellow crystals (23.69 g, 66%), m.p. 78.5–80.5°C. IR (KBr): 3070 (Car–H), 2990, 2910 (Cal–H),
1710 cm−1 (C_O). 1H NMR (CDCl3): δ 1.45 (3H, t, 3J=7.0 Hz, –O–CH2–CH3), 2.55 (3H, s, _C–CH3),
4.40 (2H, q, 3J=7.0 Hz, –O–CH2–CH3), 7.5 (8H, m, CHarom).
7.7. 2-Isopropyl-3-methyl-2-butenoic acid 7
The ester 4 (10.5 g, 67 mmol) and LiI (45.0 g, 336 mmol) were heated in dry DMF under an N2
atmosphere for 30 h. The reaction mixture was poured into water (50 ml), acidified with hydrochloric
acid and extracted thrice with ether. After purification by column chromatography (PE/ethyl acetate
1
(EA) 1/1, first fraction), evaporation of the ether afforded pure 7 (6.9 g, 72%) as a colorless liquid. H
NMR (CDCl3): δ 1.13 (6H, d, 3J=7.0 Hz, –CH(CH3)2), 1.78 (3H, s, _C–CH3), 1.87 (3H, s, _C–CH3),
3
2.85 (1H, h, J=7.0 Hz, –CH(CH3)2), 10.2–10.4 (1H, br, COOH). IR (film): 3400–2800 (O–H), 2960,
2930, 2870 (C–H), 1680 cm−1 (C_O). MS (70 eV): m/z=142 (61, M+), 127 (100, M+−CH3), 97 (79,
M+−COOH).
7.8. 2-Fluoren-9-ylidenepropanoic acid 9
To a solution of 6 (23.7 g, 89.5 mmol) in isopropanol (380 ml), water (330 ml) and toluene (40 ml)
was added a solution of KOH (10.8 g, 193 mmol) in 40 ml of isopropanol/water (1/1, 40 ml). After 4
h of reflux and removal of the solvent, water (1000 ml) was added and by-products were extracted with
PE (2.42 g of 6 could be reisolated from this extract by crystallization). The aqueous phase was acidified
with hydrochloric acid and extracted twice with ether. After evaporation of the ether a yellow–brown
solid remained. Recrystallization from CHCl3/PE afforded 9 (15.6 g, 74%) as yellow needles, m.p.
179.5–183°C. IR (KBr): 3600–3000 (O–H), 3080, 3030 (Car–H), 2930, 2900 (Cal–H) 1680 cm−1 (C_O).
1H NMR (CDCl3): δ 2.60 (3H, s, _C–CH3), 7.0–8.0 (8H, m, CHarom), OH-signal could not be detected.

3642
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
7.9. (E,Z)-2-Isopropyl-3-methyl-2-butenoic N-benzyl-N-methylamide 10
Reaction of 7 yielded (E,Z)-10 according to method A. The residue was purified by column chro-
matography (SiO2; PE/EA 3/1). Evaporation of the solvents afforded pure 10 as a slightly orange oil
[75%, KE/Z (24°C)=0.3]. IR (film): 3040, 3000 (Car–H), 2940, 2900 (Cal–H), 2840 (NC–H), 1610 cm−1
(C_O). MS (70 eV): m/z=245 (40, M+), 230 (100, M+−CH3). (E)-10: 1H NMR (CDCl3): δ 1.03 (3H, d,
3
3J=7.0 Hz, –CH–CH3), 1.20 (3H, d, J=7.0 Hz, –CH–CH3), 1.69 (3H, s, cis38 _C–CH3), 1.73 (3H, s,
trans38 _C–CH3), 2.84 (1H, h, 3J=7.0 Hz, –CH(CH3)2), 2.89 (3H, s, NCH3), 4.51 (1H, d, 2JAB=15.5 Hz,
NCHAHB, 7.2–7.3 (5H, m, CHarom). (Z)-10: 1H NMR (CDCl3): δ 1.00 (3H, d, 3J=6.9 Hz, –CH–CH3),
1.21 (3H, d, 3J=6.9 Hz, CH–CH3), 1.58 (3H, s, cis38 _C–CH3), 1.71 (3H, s, trans38 _C–CH3), 2.84 (3H,
s, NCH3), 2.84 (1H, h, 3J=6.9 Hz, –CH(CH3)2), 4.61/4.71 (2H, d/d, 2JAB=14.4 Hz, NCHAHB), 7.2–7.3
(5H, m, CHarom).
7.10. (E,Z)-2-Cyclohexylidenepropanoic N-benzyl-N-methylamide 11
Reaction of 8 yielded (E,Z)-11 according to method A as a slightly yellow oil [81%, KE/Z
(31°C)=0.7]. IR (film): 3070, 3040 (Car–H), 2940 (Cal–H), 2860 (NC–H), 1630 cm−1 (C_O). (E)-
1
11: H NMR (CDCl3): δ 1.50 (6H, m, –CH2–(CH2)3–CH2–), 1.85 (3H, s, _C–CH3), 2.15 (4H,
m, –CH2–(CH2)3–CH2–), 2.89 (3H, s, NCH3), 4.40 (2H, br, NCH2), 7.2 (5H, m, CHarom). (Z)-
1
11: H NMR (CDCl3): δ 1.50 (6H, m, –CH2–(CH2)3–CH2–), 1.85 (3H, s, _C–CH3), 2.15 (4H, m,
–CH2–(CH2)3–CH2–), 2.82 (3H, s, NCH3), 4.60 (2H, s, NCH2), 7.2 (5H, m, CHarom).
7.11. (Z)-2-Fluoren-9-ylidenepropanoic N-isopropyl-N-methylamide 12
Reaction of 9 with isopropylmethylamine according to method A yielded pure (Z)-12 (59%), according
1
to H NMR (CDCl3). M.p. 114–120°C after recrystallization from CH2Cl2/n-hexane. IR (KBr): 3060
(Car–H), 2980, 2930 (Cal–H), 2870 (NC–H), 1615 cm−1 (C_O). Thermal equilibration yielded (E,Z)-
1
3
12 [KE/Z (24°C)=1.44]. (E)-12: H NMR (CDCl3): δ 0.92 (3H, d, J=6.6 Hz, –CH–CH3), 1.19 (3H, d,
3J=6.6 Hz, –CH–CH3), 2.58 (3H, s, _C–CH3), 3.02 (3H, s, NCH3), 4.07 (1H, h, J=6.6 Hz, NCH),
3
1
3
7.2–7.9 (8H, m, Ar–H). (Z)-12: H NMR (CDCl3): 1.22 (3H, d, J=6.8 Hz, –CH–CH3), 1.27 (3H, d,
3J=6.8 Hz, –CH–CH3), 2.56 (3H, s, _C–CH3), 2.75 (3H, s, NCH3), 5.12 (1H, h, J =6.8 Hz, NCH),
3
7.2–7.9 (8H, m, Ar–H).
7.12. (ꢀ)-(E)-2-Isopropyl-3-methyl-2-butenoic N-benzyl-N-methylthioamide 13
Reaction of (E,Z)-10 yielded (ꢀ)-(E)-13 according to method B. The residue was purified by column
chromatography (PE/EA 2/1). Recrystallization from PE 40/60 afforded pure (ꢀ)-(E)-13 (30%) as
1
3
colorless crystals, m.p. 100–103°C. H NMR (CDCl3): δ 1.09 (3H, d, J=7.0 Hz, –CH–CH3), 1.32
(3H, d, J=7.0 Hz, –CH–CH3), 1.65 (3H, s, cis38 _C–CH3), 1.75 (3H, s, trans38 _C–CH3), 2.85 (1H,
3
3
2
h, J=7.0 Hz, –CH(CH3)2), 3.33 (3H, s, NCH3), 4.77/4.85 (2H, d/d, JAB=15.3 Hz, NCHAHB), 7.3
(5H, m, CHarom). IR (KBr): 3060, 3030 (Car–H), 2960, 2930 (Cal–H), 2870 (NC–H), 1200 cm−1 (C_S).
UV (MeOH) λmax/nm (log εmax): 227 (4.00), 280 (4.10). MS (70 eV): m/z=261 (60, M+), 246 (100,
M+−CH3). Anal. calcd for C16H23NS (261.5): C 73.49, H 8.88, N 5.36; found: C 73.14, H 8.88, N
5.37%.

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3643
7.13. (ꢀ)-(Z)-2-Isopropyl-3-methyl-2-butenoic N-benzyl-N-methylthioamide 13
1
1
Signals of the H NMR of (ꢀ)-(Z)-13 were taken from the spectrum of an equilibrium mixture. H
3
3
NMR (CDCl3): δ 1.01 (3H, d, J=6.9 Hz, –CH–CH3), 1.36 (3H, d, J=6.9 Hz, –CH–CH3), 1.60 (3H,
s, cis38 _C–CH3), 1.73 (3H, s, trans38 _C–CH3), 2.83 (1H, h, J=6.9 Hz, –CH(CH3)2), 3.05 (3H, s,
3
NCH3), 5.27/5.44 (2H, d/d, 2JAB=14.1 Hz, NCHAHB), 7.3 (5H, m, CHarom).
7.14. (−)436-(E)-2-Isopropyl-3-methyl-2-butenoic N-benzyl-N-methylthioamide 13
Semipreparative enrichment of the stereoisomer was performed by liquid chromatography on
TAC/EtOH, flow rate 3.5 ml/min, 4 bar, with k0=0.4, yielding colorless crystals, m.p. 102–103.5°C.
[P]LC=85ꢀ5%; [α0]436=−405ꢀ60, [α0]405=0, [α0]365=+565ꢀ80 (MeOH, 24°C, c=0.1 g/l); CD (MeOH,
24°C) λmax/nm (∆ε): 273 (−3.6), 365 (−2.8).
7.15. (ꢀ)-(Z)-2-Cyclohexylidenepropanoic N-benzyl-N-methylthioamide 14
Reaction of (E,Z)-11 yielded (ꢀ)-(Z)-14 as colorless crystals (65%), m.p. 73.5–75.5°C, according to
method B. 1H NMR (CDCl3): δ 1.60 (6H, m, –CH2–(CH2)3–CH2–), 1.91 (3H, s, _C–CH3), 2.10 (4H, m,
2
–CH2–(CH2)3–CH2–), 3.10 (3H, s, NCH3), 5.28/5.39 (2H, d/d, JAB=14.3 Hz, NCHAHB), 7.3 (5H, m,
CHarom). IR (film): 3080, 3040 (Car–H), 2970, 2940 (Cal–H), 2870 cm−1 (NC–H). UV (EtOH) λmax/nm
(log εmax): 225 (4.00), 280 (4.06). Anal. calcd for C17H23NS (273.5): C 52.35, H 5.42, N 4.70; found: C
52.15, H 5.69, N 4.53%.
7.16. (ꢀ)-(E)-2-Cyclohexylidenepropanoic N-benzyl-N-methylthioamide 14
1
Signals of the H NMR of (ꢀ)-(E)-14 were taken from the spectrum of an equilibrium mixture.
1H NMR (CDCl3): δ 1.60 (6H, m, –CH2–(CH2)3–CH2–), 1.95 (3H, s, _C–CH3), 2.10 (4H, m,
2
–CH2–(CH2)3–CH2–), 3.33 (3H, s, NCH3), 4.60/5.07 (2H, d/d, JAB=15.2 Hz, NCHAHB), 7.3 (5H,
m, CHarom).
7.17. (+)436-(E)-2-Cyclohexylidenepropanoic N-benzyl-N-methylthioamide 14
Semipreparative enrichment of the stereoisomer was performed by liquid chromatography of an
equilibrium mixture on TAC/EtOH, flow rate 3.5 ml/min, 4 bar, with k0=0.6, yielding a colorless oil.
[P]NMR=85ꢀ3%; because of the rapid interconversion of the isomers, only circular dichroism could be
obtained (non-calibrated on-line measurement39,40); CD (24°C, TBC/MeOH, flow rate 1.0 ml/min, 38
bar) λmax/nm (∆A): 275 (+5.8), 304 (0.0), 370 (+2.7).
7.18. (E,Z)-2-Fluoren-9-ylidenepropanoic N-isopropyl-N-methylthioamide 15
The amide 12 (10 mmol) in dry toluene (200 ml) was refluxed with 2,4-bis(4-methoxyphenyl)-1,3-
dithia-2,4-diphosphetane-2,4-disulfide (Lawesson’s reagent, 20 mmol) until thin-layer chromatography
showed the completeness of the reaction (after 15 h). The cold mixture was filtered and the solvent
removed. Purification by column chromatography (CH2Cl2/toluene 1/4) and crystallization from the
eluent afforded (E,Z)-15 [36%, KE/Z (105°C)=1.38] as yellow crystals, m.p. 101–131°C. IR (KBr): 3100,
3060 (Car–H), 2980, 2930 (Cal–H), 2880 (NC–H), 1110 cm−1 (C_S). UV (MeOH) λmax/nm (log εmax):

3644
M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
232 (4.60), 250 (4.49), 258 (4.55), 275 (4.25), 303 (4.02), 321 nm (4.07). MS (70 eV): m/z=307 (77,
M+), 292 (79, M+−CH3), 165 (100, [fluorene]+). Anal. calcd for C20H21NS (307.5): C 78.14, H 6.89, N
4.56; found: C 78.05, H 6.78, N 4.68%.
7.19. (ꢀ)-(Z)-2-Fluoren-9-ylidenepropanoic N-isopropyl-N-methylthioamide 15
Recrystallization of one portion of (E,Z)-15 from PE yielded long (up to 12 mm) bent needles
aggregated to feathers, m.p. 149–150.5°C with a content of 100% (Z)-15. IR (KBr): identical with the
1
3
3
spectrum of (E,Z)-15. H NMR (CDCl3): δ 1.30 (3H, d, J=6.8 Hz, –CH–CH3), 1.36 (3H, d, J=6.8
3
Hz, –CH–CH3), 2.62 (3H, s, _C–CH3), 2.95 (3H, s, NCH3), 5.99 (1H, h, J=6.8 Hz, NCH), 7.2–7.8
1
3
3
(8H, m, Ar–H). H NMR (d8-toluene): δ 0.84 (3H, d, J=6.8 Hz, –CH–CH3), 0.92 (3H, d, J=6.8 Hz,
–CH–CH3), 2.25 (3H, s, _C–CH3), 2.34 (3H, s, NCH3), 6.01 (1H, h, 3J=6.8 Hz, NCH), 7.0–7.9 (8H, m,
Ar–H).
7.20. (ꢀ)-(E)-2-Fluoren-9-ylidenepropanoic N-isopropyl-N-methylthioamide 15
One portion of (E,Z)-15 was equilibrated in xylene at 140°C for 2 h to increase the content of (E)-15.
Enrichment by column chromatography (toluene), followed by recrystallization from CH2Cl2/n-hexane
1/4 and afterwards from ether/n-hexane (1/2) afforded yellow needles, m.p. 136–138°C with a content
1
of 96% (E)-15. IR (KBr): identical with the spectrum of (E,Z)-15. H NMR (CDCl3): δ 0.97 (3H, d,
3J=6.6 Hz, –CH–CH3), 1.22 (3H, d, 3J=6.6 Hz, –CH–CH3), 2.66 (3H, s, _C–CH3), 3.43 (3H, s, NCH3),
4.50 (1H, h, 3J=6.6 Hz, NCH), 7.0–7.9 (8H, m, Ar–H). 1H NMR (d8-toluene): δ 0.42 (3H, d, 3J=6.6 Hz,
–CH–CH3), 0.55 (3H, d, 3J=6.6 Hz, –CH–CH3), 2.39 (3H, s, _C–CH3), 3.03 (3H, s, NCH3), 4.06 (1H,
h, 3J=6.6 Hz, NCH), 7.0–7.9 (8H, m, Ar–H).
7.21. (+)436-(Z)-2-Fluoren-9-ylidenepropanoic N-isopropyl-N-methylthioamide 15
Semipreparative enrichment of the stereoisomer was performed by liquid chromatography on
TBC/MeOH, flow rate 3.5 ml/min, 2 bar, with k0=2.0, yielding a light yellow solid, m.p. 140–146°C.
[P]NMR=88ꢀ3%; [α0]546=−135ꢀ24, [α0]436=+470ꢀ70, [α0]405=+1610ꢀ210 (MeOH, 22°C, c=0.4 g/l);
CD (MeOH, 24°C) λmax/nm (∆ε): 235 (+7.9), 259 (+1.0), 277 (−16.5), 365 (+2.6).
Acknowledgements
Professor G. von Kiedrowski, Freiburg, kindly provided his excellent SimFit program. We are indebted
to Dr. R. Koller for her basic work on acrylic amides bearing two identical N-substituents. Dr. T.
Burgemeister contributed all his know-how concerning the application of NMR to enantiomers and to
kinetics. We thank Mr. F. Kastner and Mrs. N. Pustet for valuable 1H NMR and HPLC work and Mrs. C.
Hübner for skillful typing.
References
1. Oki, M. Recent advances in atropisomerism; In Topics in Stereochemistry, Vol. 14; Allinger, N. L.; Eliel, E. L.; Wilen, S.
H., Eds; Interscience: New York, 1983; p. 1.
2. Oki, M. Applications of Dynamic NMR Spectroscopy to Organic Chemistry; VCH: Weinheim, 1985.

M. Kuttenberger et al. / Tetrahedron: Asymmetry 9 (1998) 3629–3645
3645
3. Eliel, E.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley-Interscience: New York, 1994; pp. 1156, 1162.
4. Rappoport, Z.; Biali, S. E. Acc. Chem. Res. 1997, 30, 307.
5. Kiefl, C.; Zinner, H.; Burgemeister, T.; Mannschreck, A. Recl. Trav. Chim. Pays-Bas 1996, 115, 125.
6. Koller, R.; Kuttenberger, M.; Mannschreck, A., unpublished results.
7. Mannschreck, A.; Koller, H.; Wernicke, R. Kontakte (Darmstadt) 1985, 1, 40; Chem. Abstr. 1985, 103, 110495.
8. Becher, G.; Mannschreck, A. Chem. Ber. 1983, 116, 264.
9. Mannschreck, A.; Talvitie, A.; Fischer, W.; Snatzke, G. Monatsh. Chem. 1983, 114, 101.
10. Cf. Berg, U.; Sandström, J.; Jennings, W. B.; Randall, D. J. Chem. Soc., Perkin Trans. 2, 1980, 949.
11. Berg, U. Acta Chem. Scand. 1976, B30, 695.
12. Eiglsperger, A.; Kastner, F.; Mannschreck, A. J. Mol. Struct. 1985, 126, 421.
13. Kuttenberger, M.; Frieser, M.; Hofweber, M., unpublished results.
14. Kölle, U.; Kolb, B.; Mannschreck, A. Chem. Ber. 1980, 113, 2545, and references cited therein.
15. Häkli, H.; Mintas, M.; Mannschreck, A. Chem. Ber. 1979, 112, 2028.
16. Mannschreck, A.; Wernicke, R. Labor-Praxis 1990, 14, 730; Chem. Abstr. 1990, 113, 218 852.
17. Dogan, I.; Burgemeister, T.; Içli, S.; Mannschreck, A. Tetrahedron 1992, 35, 7157.
18. Naruse, Y.; Watanabe, H.; Inagaki, S. Tetrahedron: Asymmetry 1992, 3, 603.
19. Kiefl, C.; Hofweber, M.; Burgemeister, T.; Mannschreck, A., unpublished measurements.
20. Zupan, J. Algorithms for Chemists, 1st. edn; Wiley: New York, 1989.
21. Terfort, A.; von Kiedrowski, G. Angew. Chem. 1992, 104, 627; Angew. Chem., Int. Ed. Engl. 1992, 31, 654.
22. von Kiedrowski, G. SIMFIT, Version 1.0ß — A Program for the Analysis of Kinetic Data, Preliminary Manual, 1989–1995.
23. Lozac’h, R.; Legrand, L.; Sandström, J. Org. Magn. Resonance 1975, 7, 54.
24. Clayden, J., personal communication. Cf. Clayden, J.; Pink, J. H.; Yasin, S. A. Tetrahedron Lett. 1998, 39, 105.
25. Mannschreck, A.; Jonas, V.; Kolb, B. Angew. Chem. 1973, 85, 994; Angew. Chem., Int. Ed. Engl. 1973, 12, 909. Küspert,
R.; Mannschreck, A. Org. Magn. Resonance 1982, 19, 6.
26. Knorr, A.; Kuttenberger, M., unpublished calculations.
27. Geet, A. L. Anal. Chem. 1968, 40, 914; 1970, 42, 679.
28. Lewin, A. H.; Frucht, M. Org. Magn. Resonance 1975, 5, 206.
29. Stewart, W. E.; Siddall, T. H. Chem. Rev. 1970, 70, 517.
30. Harié, G.; Samat, A.; Guglielmetti, R.; Van Parys, I.; Saeyens, W.; De Keukeleire, D.; Lorenz, K.; Mannschreck, A. Helv.
Chim. Acta 1997, 80, 1122.
31. Loncar-Tomaskovic, L.; Mintas, M.; Trötsch, T.; Mannschreck, A. Enantiomer 1998, 2, 459.
32. Allenmark, S. Chromatographic Enantioseparation, Methods and Applications, 2nd edn; Ellis Horwood: New York, 1991;
pp. 51, 113.
33. Pines, H.; Ipatieff, V. N. J. Am. Chem. Soc. 1947, 69, 1337.
34. Wagner, R. B.; Moore, J. A. J. Am. Chem. Soc. 1950, 72, 974.
35. Britelli, D. R. J. Org. Chem. 1981, 46, 2514.
36. Wagner, R. B.; Moore, J. A. J. Am. Chem. Soc. 1950, 72, 3655.
37. Shriner, R. L. Org. React. 1942, 1, 1.
38. See Scheme 4 for definition of cis and trans positions.
39. Brandl, G.; Kastner, F.; Fritsch, R.; Zinner, H.; Mannschreck, A. Monatsh. Chem. 1992, 123, 1059.
40. Mannschreck, A. Trends Anal. Chem. 1993, 12, 220.