Atropisomerization Barriers of Configurationally Unstable Biaryl Compounds, Useful Substrates for Atroposelective Conversions to Axially Chiral Biaryls

Article abstract of DOI:10.1021/jo9913356

Configurationally unstable biaryl lactones of type (M)-1 ? (P)-1 and ring-opened 2-acyl-2′-hydroxy biaryl compounds of type (M)-4 ? (P)-4 are versatile precursors for the atroposelective preparation of axially chiral biaryls. The activation barriers of their atropisomerization process, which constitutes a fundamental precondition for the dynamic kinetic resolution, were determined by dynamic NMR spectroscopy for rapid processes and by HPLC-monitored racemization of enantiomerically enriched material for smaller interconversion rates. For the lactones, the free activation energies ΔG^?₂₉₈ increase with the steric demand of the substituent R ortho to the biaryl axis in the series H < OMe (t_1/2 ≈ ms) < Me (t_1/2 ≈ s) < Et < i-Pr (t_1/2 ≈ min) < t-Bu (t_1/2 ≈ d). The formally ring-opened 2-acyl-2′-hydroxy biaryls, which interconvert via the lactol isomers 5 as the cyclic (and thus configurationally less stable) intermediates, have a significantly slower atropisomerization rate as a result of the high loss in activation entropy ΔS^? as a consequence of the required intermediate ring closure 4 → 5.

Full text of DOI:10.1021/jo9913356

722
J . Org. Chem. 2000, 65, 722-728
Atr op isom er iza tion Ba r r ier s of Con figu r a tion a lly Un sta ble Bia r yl
Com p ou n d s, Usefu l Su bstr a tes for Atr op oselective Con ver sion s to
Axia lly Ch ir a l Bia r yls†
Gerhard Bringmann,* Markus Heubes, Matthias Breuning, Lothar Go¨bel, Michael Ochse,
Bernd Scho¨ner, and Olaf Schupp
Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received August 24, 1999
Configurationally unstable biaryl lactones of type (M)-1 h (P)-1 and ring-opened 2-acyl-2′-hydroxy
biaryl compounds of type (M)-4 h (P)-4 are versatile precursors for the atroposelective preparation
of axially chiral biaryls. The activation barriers of their atropisomerization process, which constitutes
a fundamental precondition for the dynamic kinetic resolution, were determined by dynamic NMR
spectroscopy for rapid processes and by HPLC-monitored racemization of enantiomerically enriched
material for smaller interconversion rates. For the lactones, the free activation energies ∆Gq
298
increase with the steric demand of the substituent R ortho to the biaryl axis in the series H < OMe
(t1/2 ≈ ms) < Me (t1/2 ≈ s) < Et < i-Pr (t1/2 ≈ min) < t-Bu (t1/2 ≈ d). The formally ring-opened 2-acyl-
2′-hydroxy biaryls, which interconvert via the lactol isomers 5 as the cyclic (and thus configuration-
ally less stable) intermediates, have a significantly slower atropisomerization rate as a result of
the high loss in activation entropy ∆Sq as a consequence of the required intermediate ring closure
4 f 5.
Sch em e 1
In tr od u ction
A most efficient method for the stereoselective con-
struction of axially chiral biaryls is the “lactone ap-
proach”,1 which is based on the dynamic kinetic resolu-
tion of configurationally unstable biaryl lactones2 of type
1 (Scheme 1). As a consequence of the steric repulsion
between the naphthalene moiety and the ortho substitu-
ent R in the phenolic part, the lactones 1 are helically
distorted and thus exist as a racemic mixture of their
two enantiomeric forms, (M)-1 and (P)-1.1,3 The bridging
lactone function, however, dramatically lowers the atro-
pisomerization barrier compared with that of the ring-
opened target molecules, so that the two lactone enan-
tiomers interconvert more or less rapidly. Out of this
enantiomeric equilibrium, 1 can be cleaved atropselec-
tively by using chiral O- or N-nucleophiles4 or hydride
transfer reagents5 to give the corresponding esters,
amides, or alcohols, 2 or 3, in excellent atropisomeric
† Part 84 of the series “Novel Concepts in Directed Biaryl Synthesis”.
For part 83, see: Bringmann, G.; Wuzik, A.; Go¨bel, L.; Stowasser, R.;
Rummey, C.; Stalke, D.; Pfeiffer, M.; Schenk, W. A. Organometallics
1999, 18, 5017.
* Tel: +49 931 888 5323. Fax: +49 931 888 4755. E-mail:
ratios of up to 99:1.1 The scope of this method has
meanwhile been proven in the atroposelective synthesis
of a broad series of naturally occurring biaryls and axially
chiral auxiliaries.1
bringman@chemie.uni-wuerzburg.de.
(1) (a) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525.
(b) Bringmann, G.; Tasler, S. In Current Trends in Organic Synthesis;
Scolastico, C., Nicotra, F., Eds.; Plenum Publishing Corporation: New
York, 1999; p 105. (c) Bringmann, G.; Schupp, O. S. Afr. J . Chem. 1994,
47, 83.
(2) Bringmann, G.; Hartung, T.; Go¨bel, L.; Schupp, O.; Ewers, C. L.
J .; Scho¨ner, B.; Zagst, R.; Peters, K.; von Schnering, H. G.; Burschka,
C. Liebigs Ann. Chem. 1992, 225.
Like the lactones 1, but in contrast to the amides and
esters 2,6 the formally related 2-acyl-2′-hydroxy biaryls
(3) For the now recommended M/ P-denotion for axially chiral
compounds, see: Helmchen, G. In Methods of Organic Chemistry
(Houben Weyl), 4th ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J .,
Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E21a, p 11.
(4) (a) Bringmann, G.; Breuning, M.; Walter, R.; Wuzik, A.; Peters,
K.; Peters, E.-M. Eur. J . Org. Chem. 1999, 3047, 7. (b) Seebach, D.;
J aeschke, G.; Gottwald, K.; Matsuda, K.; Formisano, R.; Chaplin, D.
A.; Breuning, M.; Bringmann, G. Tetrahedron 1997, 53, 7539. (c)
Bringmann, G.; Breuning, M.; Tasler, S.; Endress, H.; Ewers, C. L. J .;
Go¨bel L.; Peters, K.; Peters, E.-M. Chem. Eur. J . 1999, 5, 3029.
(5) (a) Bringmann, G.; Hartung, T. Angew. Chem., Int. Ed. Engl.
1992, 31, 761. (b) Bringmann, G.; Hartung, T. Tetrahedron 1993, 49,
7891. (c) Bringmann, G.; Breuning, M. Tetrahedron: Asymmetry 1999,
10, 385.
(6) Since a “chemical” atropisomerization via cyclic intermediates
as for the acyl compounds 4 is less feasible for the corresponding less
reactive esters and amides 2, these compounds are usually configu-
rationally stable (for an exception involving esters of MeOH as a very
small alcohol, see: Bringmann, G.; Reuscher, H. Angew. Chem., Int.
Ed. Engl. 1989, 28, 1672).
10.1021/jo9913356 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/15/2000

Configurationally Unstable Biaryl Compounds
J . Org. Chem., Vol. 65, No. 3, 2000 723
Sch em e 2
Sch em e 3
the presence of a pair of diastereotopic groups in the
molecule, which serve as an internal DNMR probe, is
essential. Among the standard lactones 1 (Scheme 1)
previously introduced,2 only two representatives, 1d (R
) Et) and 1e (R ) i-Pr), fulfill this basic requirement.
For this reason, we synthesized a new type of biaryl
lactones 9-11 with two different substituents in the
phenolic part providing three advantages simultaneously
(Scheme 3): first, the variation of the ortho substituent
R allows a stepwise enhancement of the steric hindrance
at the biaryl axis; second, the dynamic behavior is
monitored by the diastereotopic group R′ (or, alterna-
tively, by R); and third, with the 1,4-substitution pattern
chosen, a regioselectivity in the coupling of the esters 6-8
is guaranteed by blocking one of the two ortho positions
in the phenolic part. By Pd-catalyzed aryl coupling the
preparation of the lactones 9 (R′ ) Me), 10 (R′ ) Et),
and 11 (R′ ) i-Pr) was achieved smoothly and in good
yields (62-84%).
2. P r ep a r a tion of th e En a n tiom er ica lly En r ich ed
Bia r yls. The activation parameters of the more hindered,
less rapidly atropisomerizing biaryls were determined by
HPLC measurement of the racemization rates of (almost)
enantiomerically pure samples, which were prepared in
different ways. Lactone (P)-9e (see Scheme 3) was
obtained by simple crystallization of racemic 9e from
petroleum ether/dichloromethane,12 whereas the steri-
cally even more highly hindered and thus only very
slowly helimerizing lactones (M)-1f and (P)-1f were
synthesized in a three-step procedure starting from
racemic 1f (Scheme 4). Ring cleavage with the lithium
alkoxide of (1S)-menthol [(S)-12] gave the configuration-
ally stable diastereomeric esters (M,S)-13 and (P,S)-13
(dr ) 54:46, 84% yield), which were separated by column
chromatography.13 Hydrolysis of the two separate atro-
pisomers gave the acids (P)-14 and (M)-14 (er ) 99:1
each), which were both recyclized back to the now
enantiomerically enriched lactones (P)-1f (er ) 96:4) and
(M)-1f (er ) 95:5), respectively.
4, as the primary cleavage products of 1 with H- and
C-nucleophiles, are configurationally unstable at the axis
(Scheme 2).1 Their atropisomerization, however, does not
proceed via a direct, “physical” rotation around the biaryl
axis but is a consequence of a ring-closure f atropi-
somerization f ring-opening process (M)-4 h (M)-5 h
(P)-5 h (P)-4, which involves the bridged and thus again
configurationally unstable lactols 5.7-9 Like the lactones
1, biaryls of type 4 have also been used successfully as
precursors for atroposelective biaryl synthesis, e.g., for
atroposelective CBS-reductions,10 including applications
in natural products synthesis.11
The configurational instability of the biaryl lactones 1
and of the hydroxyaldehyde/lactol intermediates, as well
as related 2-acyl-2′-hydroxy biaryls in general, is thus a
fundamental basis for these atropenantiomer-differenti-
ating reactions. For this reason, an investigation of the
isomerization barriers of these processes is a crucial
precondition for directed further improvements of this
remarkably efficient methodology. In this paper, we thus
report on the atropisomerization barriers of several
configurationally unstable biaryls of types 1, 4, and 5,
which vary by the degree of steric hindrance at the axis
(due to the different sizes of the ortho substituent R), the
nature of the bridge (lactone vs lactol), and the mecha-
nism of isomerization (merely “physical” rotation around
the axis, cp. Scheme 1, vs the “chemical” three-step
mechanism of the ring-opened biaryls, cp. Scheme 2). In
the case of the configurationally unstable lactones, the
activation parameters were determined by dynamic NMR
spectroscopy (DNMR) and for the enantiomerically en-
riched, less rapidly isomerizing biaryls prepared by
HPLC measurement of the rates of decrease in enantio-
meric purity. For the former purpose, new lactones were
synthesized, equipped with suitably located ethyl or
isopropyl groups as the “DNMR probes”.
The enantiomerically enriched biaryl acetophenone
derivative (P)-17 (Scheme 5) was obtained by ring cleav-
age of the configurationally unstable racemic lactone 1c
with the homochiral lithium sulfoxide (R)-15 and subse-
quent crystallization of the crude diastereomeric mixture,
which gave the â-ketosulfoxide (P,R)-1614 (dr ) 96:4) in
Resu lts a n d Discu ssion
1. Syn th esis of Bia r yl La cton es 9-11. For the
observation of enantiomerization processes via DNMR,
(7) Bringmann, G.; Hartung, T. Liebigs Ann. Chem. 1994, 313.
(8) Bringmann, G.; Breuning, M.; Endress, H.; Vitt, D.; Peters, K.;
Peters, E.-M. Tetrahedron 1998, 54, 10677.
(9) Bringmann, G.; Vitt, D.; Kraus, J .; Breuning, M. Tetrahedron
1998, 54, 10691.
(10) Bringmann, G.; Breuning, M. Synlett 1998, 634.
(11) Bringmann, G.; Saeb, W.; Ru¨benacker, M. Tetrahedron 1999,
55, 423.
(12) Peters, K.; Peters, E.-M.; von Schnering, H. G.; Bringmann, G.;
Schupp, O. Z. Kristallogr. 1995, 210, 49.
(13) For a directed atropisomer-selective synthesis of 1f by kinetic
resolution of rac-1f using chiral H-nucleophiles, see ref 1a and:
Bringmann, G.; Hinrichs, J .; Kraus, J .; Wuzik, A.; Schulz, T. J . Org.
Chem., submitted for publication.
(14) Peters, K.; Peters, E.-M.; Bringmann, G.; Scho¨ner, B. Z.
Kristallogr. NCS 1998, 213, 337.

724 J . Org. Chem., Vol. 65, No. 3, 2000
Bringmann et al.
Sch em e 4
Sch em e 6
at different temperatures due to the presence of ap-
propriate substituents (here Et or i-Pr), with nuclei that
may serve as probes for a chiral vs achiral character of
the molecules, by their diastereotopic vs enantiotopic
character within the time scale of the exchange process.
Depending on the steric demand of the substituent R
1
ortho to the stereogenic axis, the H DNMR spectra of
compounds 9-11 showed different behaviors of these
nuclei at room temperature: The signals of the diaste-
reotopic protons in 10b, 11a , and 11b were found to be
isochronous (and thus formally, i.e., on an average,
enantiotopic), indicating a fast exchange relative to the
NMR time scale, while those in 1d , 9d , 9e, 10c, 11c, and
11d are clearly separated as the result of a very slow
rate of exchange (or even configurational stability).
For the investigated lactones 11a (R ) H) and 11b (R
) OMe), the limit of slow exchange regimes (i.e., to attain
decoalescence) could not be reached. The rates of 1d -f
(R ) Et, i-Pr, and t-Bu), by contrast, were too slow for
observation by DNMR. The signals of the diastereotopic
ethyl CH2 protons in 1e did not appear completely
separated because of the small shift difference even in
the slow exchange region but remained superimposed,
so that rate constants could not be evaluated from the
DNMR spectra. The same problem occurred for the
diastereotopic [CH(CH3)2] protons of the i-Pr group of 9d .
The spectra of 10b, 10c, 11c, 11d , and 9e, by contrast,
proved to be well suited for DNMR investigations and
were thus carefully simulated and iterated by line-shape
analysis16 to give the rate constants. Exemplarily for
lactone 11d , which is equipped with both types of probes,
H atoms (R ) Et) and methyl groups (R ) i-Pr), selected
parts of the experimental and the iterated proton spectra
are depicted in Figure 1.
Sch em e 5
73% yield. Reductive removal of the sulfinyl group in
(P,R)-16 led to the target biaryl (P)-17 with an er of 93:7
(yield 63%).
Upon standing in solution, the configurationally un-
stable biaryls (M)-1f, (P)-1f, (P,R)-16, and (P)-17 started
racemizing.
The biaryl compounds (M)-18 and (M)-19 (Scheme 6,
top) were prepared according to literature procedures.7,15
As a closely related analogue of the nondetectable lactol
intermediates in the atropisomerization process of 19 (cp.
Scheme 2), the O-protected and thus ring-opening hin-
dered acetal 20 was synthesized.8 In this case, the
interconversion ax-20 h eq-20 constitutes a diastere-
omerization process, due to the additional stereocenter
at the acetalic carbon atom (Scheme 6, bottom; only the
6-(S)-enantiomers are shown). Of the two diastereomeric
forms, the isomer ax-20, which has the methoxy group
in an axial position, is more stable in the equilibrium (dr
) 91:9) than eq-20.8
The activation parameters of the highly enantiomeri-
cally enriched biaryls 1f, 9e, and 17 were determined by
HPLC measurements of the decrease of the er at different
temperatures.17 The quantitative evaluation of the acti-
vation parameters was done using a first-order rate
equation, even for the ring-opened compounds 17 and 19
despite their three-step atropisomerization mechanism
(cp. Scheme 2), because the population of the intermedi-
ate lactols of type 5 was undetectably low and thus
negligible.8
(16) (a) Binsch, G. Band-Shape Analysis. In Dynamic Magnetic
Resonance Spectroscopy; J ackman, L. M., Ed.; Academic Press: New
York 1975; p 45. (b) Sandstro¨m, J . Dynamic NMR Spectroscopy;
Academic Press: New York 1980.
(17) For similar investigations on 18 and 19, see refs 7 and 15,
respectively.
3. Mea su r em en t of th e Ra te Con sta n ts. A precon-
dition for DNMR investigations is a change in the spectra
(15) Bringmann, G.; Scho¨ner, B.; Schupp, O.; Peters, K.; Peters, E.-
M.; von Schnering, H. G. Liebigs Ann. Chem. 1994, 91.

Configurationally Unstable Biaryl Compounds
J . Org. Chem., Vol. 65, No. 3, 2000 725
Ta ble 1. Activa tion P a r a m eter sa a n d Ha lf-Lives (t1/2) a t 298 K of th e Atr op isom er iza tion of Con figu r a tion a lly Un sta ble
Bia r yls
ortho
substituent
next to axis
biaryl
∆Hq
∆Sq
∆Gq
298
compound
method
[kJ mol-1
]
[J K-1 mol-1
]
[kJ mol-1
]
t1/2
11a
H
DNMR
DNMR
DNMR
DNMR
DNMR
DNMR
b
10b
11b
10c
11c
11d
OMe
OMe
Me
Me
Et
26.6 ( 0.3
-92.9 ( 0.2
54.4 ( 0.1
0.4 ms
b
57.9 ( 1.1
43.9 ( 0.4
71.8 ( 2.7c
75.3 ( 1.5d
84.5 ( 0.9
82.1 ( 9.7
91.6 ( 3.6
61.1 ( 0.4
53.5 ( 0.2
54.9
-47.4 ( 3.3
-101 ( 1.2
-37.7 ( 7.1
-28.0 ( 4.0
-22.3 ( 3.1
72.1 ( 0.2
73.9 ( 0.1
83.0 ( 0.6
83.7 ( 0.3
91.1 ( 1.8
92.3 ( 20.2
104.4 ( 6.8
79.2 ( 1.2
73.2 ( 0.5
98.8
0.5 s
1.0 s
39.5 s
52.4 s
17.3 min
28.1 min
2.2 d
8.5 s
0.8 s
6.5 h
1815
9e
1f
20 (eq f ax)
(ax f eq)
197
“benzo”
i-Pr
t-Bu
HPLC
DNMR
HPLC
DNMR
-34.1 ( 35.1
-43.1 ( 10.8
-60.8 ( 3.1
-66.0 ( 1.1
-150
Me
Me
Me
HPLC
HPLC
17
51.3 ( 0.3
-161 ( 1.0
99.2 ( 0.5
7.6 h
a
b
The reported errors are statistical errors. Limit of slow exchange could not been reached. c Using the ethyl group as the DNMR
d
probe. Using the isopropyl group as the DNMR probe.
rate of atropisomerization was found for the lactones. The
free energy of activation ∆Gq
increased within the
298
sequence H < OMe < Me < Et < i-Pr < t-Bu. The
methoxy-substituted compound 10b showed the smallest
measurable ∆Gq298 of 54.4 kJ mol-1. For the lactones with
R ) alkyl, every carbon unit added raises the free
activation energy ∆Gq by ca. 10 kJ mol-1, from ca. 73
298
kJ mol-1 for R ) Me up to 104 kJ mol-1 for R ) t-Bu. As
obvious from the ∆Gq
value (91.1 kJ mol-1) of the
298
binaphthyl lactone 18,15 its annulated additional ring has
a steric demand comparable to that of an isopropyl group.
Furthermore, this series of activation barriers experi-
mentally found qualitatively agrees with the one theo-
retically calculated for the lactones 1.18
The influence of the biaryl structure on the atropi-
somerization rate was investigated for the compounds
10c, 11c, 17, 19, and 20, all of which are identical with
respect to the presence of a methyl group next to the
biaryl axis. The enthalpies of activation ∆Hq are all in
the same order of magnitude, between 44 and 60 kJ
mol-1, but the bridged biaryls 10c, 11c, and 20 differ
remarkably from the ring-opened ones, 17 and 19, in the
entropies of activation ∆Sq (g -100 J K-1 mol-1 vs <
-150 J K-1 mol-1) and, thus, also in the free energies of
activation (∆∆Gq ≈ 25 kJ mol-1). This jump in ∆Sq is
298
caused by the different atropisomerization mechanisms.
Whereas the enantiomeric forms of the lactones 10c and
11c and of the acetal 20 interconvert “physically”, by
direct rotation around the axis (cp. Scheme 1), the
enantiomerization of the acyl compounds 17 and 19
occurs “chemically”, via the cyclic lactol species of type 5
(cp. Scheme 2).7-9 This ring closure strongly reduces the
number of degrees of freedom and thus causes higher ∆Sq
1
F igu r e 1. Selected parts of the experimental and iterated H
NMR spectra of the ethyl group (left side) and the isopropyl
group (right side) of 11d at different temperatures.
For a complete list of the activation parameters thus
measured by DNMR and HPLC, see Table 1.
and ∆Gq values, which finally leads to a much slower
298
isomerization process. If the phenolic OH-group in 19 is
“sealed”, e.g., by O-methylation, the “chemical” atropi-
somerization is blocked, and thus no atropisomerization
is observed.1,7
Because the acetal 20, whose structure is closely
related to that of lactol 5, possesses a ∆Gq298 value (73.2-
79.2 kJ mol-1) remarkably lower than that of the ring-
opened compounds 17 and 19, (≈ 99 kJ mol-1) and, thus,
an interconversion rate (M)-20 h (P)-20 corresponding
to a half-life about 5000 times smaller than that of the
4. Discu ssion of th e Activa tion P a r a m eter s. Ex-
emplarily for the lactones 10c and 11c, which have
comparable steric constraints at the biaryl axis (R ) Me),
we have investigated whether different substituents in
other positions, here next to the phenolic oxygen, do
significantly affect the exchange rate. Such an unfavor-
able influence was excluded because the free energies of
activation ∆Gq showed very similar values [10c (R′ )
298
Et) ∆Gq ) 72.1 kJ mol-1 and 11c (R′ ) i-Pr) ∆Gq
)
298
298
73.9 kJ mol-1].
On this basis, the expected relation between the steric
(18) Bringmann, G.; Busse, H.; Dauer, U.; Gu¨ssregen, S.; Stahl, M.
demand of the substituent R ortho to the axis and the
Tetrahedron 1995, 51, 3149.

726 J . Org. Chem., Vol. 65, No. 3, 2000
Bringmann et al.
(20 cm), eluent: petroleum ether f diethyl ether]. Crystal-
lization from dichloromethane/petroleum ether gave the spec-
troscopically pure lactones 9-11 as colorless or slightly yellow
solids. Yields are reported in Scheme 3.
“complete” process of (M)-17 h (P)-17 and (M)-19 h (P)-
19, the rate-determining step of the latter atropisomer-
ization processes as depicted in Scheme 2 must be the
ring closure and the ring opening, respectively. These
observations and the undetectably low concentrations of
the intermediate lactol justify the former assumption
(vide supra) made for the evaluation of the dynamic
HPLC measurements, viz., to treat the overall intercon-
versions of (M)-17 h (P)-17 and (M)-19 h (P)-19 as first-
order processes.
1-Eth yl-4-m eth yl-6H-ben zo[b]n a p h th o[1,2-d ]p yr a n -6-
on e (9d ). Mp 149 °C; IR (KBr) ν 3040, 2950, 2900, 1710 cm-1
;
1H NMR (200 MHz, [D8]toluene) δ 0.65 (t, 3H, J ) 7.4 Hz),
2.30 (s, 3H), 2.22-2.62 (m, 2H), 6.90 (d, 1H, J ) 7.9 Hz), 6.98
(d, 1H, J ) 7.9 Hz), 7.06-7.24 (m, 2H), 7.40 (d, 1H, J ) 8.4
Hz), 7.44 (d, 1H, J ) 8.0 Hz), 7.78 (d, 1H, J ) 8.2 Hz), 8.25 (d,
1H, J ) 8.5 Hz); MS (EI) m/z 288 (100) [M+], 273 (91) [M+
-
CH3], 202 (33), 101 (33). Anal. Calcd for C20H16O2: C, 83.31;
H, 5.59. Found: C, 82.92; H, 5.31.
It is noteworthy that the free activation energy ∆Gq
298
of the acetal 20 (∆Gq298 ≈ 74-79 kJ mol-1) is very similar
1-Isopr opyl-4-m eth yl-6H-ben zo[b]n aph th o[1,2-d]pyr an -
6-on e (9e). Mp 137-138 °C; IR (KBr) ν 3030, 2970, 2940, 1710
to that of corresponding lactones 10c and 11c (∆Gq
≈
298
73 kJ mol-1), showing that the hybridization of the carbon
atom in the bridge (sp2 in the lactone group vs. sp3 in
the acetal group) does not remarkably influence the
atropisomerization rate.
1
cm-1; H NMR (200 MHz, CDC13) δ 0.62 (d, 3H, J ) 6.7 Hz),
1.53 (d, 3H, J ) 6.7 Hz), 2.51 (s, 3H), 3.24 (sept, 1H, J ) 6.7
Hz), 7.30 (d, 1H, J ) 7.8 Hz), 7.38 (d, 1H, J ) 7.8 Hz), 7.52
(ddd, 1H, J ) 8.5, 7.2, 1.4 Hz), 7.63 (ddd, 1H, J ) 8.6, 7.2, 1.2
Hz), 7.90 (d, 1H, J ) 8.5 Hz), 7.92 (d, 1H, J ) 8.6 Hz), 8.11 (d,
1H, J ) 8.6 Hz), 8.28 (d, 1H, J ) 8.6 Hz); MS (EI) m/z 302
(100) [M+], 287 (71) [M+ - CH3], 272 (47) [M+ - C2H6], 259
(38) [M+ - C3H7]. Anal. Calcd for C21H18O2: C, 83.42; H, 6.00.
Found: C, 83.43; H, 6.17. Crystallization of the racemic
mixture of 9e from petroleum ether/dichloromethane resulted
in crystals of enantiomerically pure (P)-9e and crystals of (M)-
9e. Atropisomerization experiments were performed on (P)-
9e (absolute configuration known from multiple scattering
X-ray experiments).12,25
Con clu sion s
By variation of the substituents ortho to the biaryl axis,
the interconversion rates of the lactones can be modified
stepwise. The atropisomerization barriers measured
increase with the steric demand of the substituents in
the series H < OMe < Me < Et < i-Pr < t-Bu. Corre-
sponding to these rates, the half-lives range from mil-
liseconds (R ) OMe) to days (R ) t-Bu). As a consequence,
lactones containing ortho substituents R < i-Pr can be
cleaved atroposelectively to give configurationally stable
axially chiral biaryls by a dynamic kinetic resolution (see
introduction), whereas the largely helically distorted
lactones with R ) t-Bu (or even more bulky residues) are
useful precursors for “normal” (i.e., nondynamic) kinetic
resolutions.1 The configurationally unstable ring-opened
2-acyl-2′-hydroxy biaryls, which show a slower isomer-
ization as a result of the smaller entropies of activation,
are suited for dynamic kinetic resolutions only if R has
a very low steric demand (typically R ) H).10
4-E t h yl-1-m et h oxy-6H-b en zo[b]n a p h t h o[1,2-d ]p yr a n -
6-on e (10b). Mp 186-187 °C; IR (KBr) ν 3040, 2950, 2920,
1
1710 cm-1; H NMR (250 MHz, CDC13) δ 1.33 (t, 3H, J ) 7.5
Hz), 2.93 (q, 2H, J ) 7.5 Hz), 3.80 (s, 3H), 6.88 (d, 1H, J ) 8.4
Hz), 7.37 (d, 1H, J ) 8.4 Hz), 7.45-7.68 (m, 2H), 7.90 (d, 1H,
J ) 8.0 Hz), 7.94 (d, 1H, J ) 8.5 Hz), 8.04 (d, 1H, J ) 8.5 Hz),
8.37 (d, 1H, J ) 8.5 Hz); MS (EI) m/z 304 (67) [M+], 289 (100)
[M+ - CH3], 273 (19) [M+ - OCH3], 189 (24). Anal. Calcd for
C
20H16O3: C, 78.86; H, 5.26. Found: C, 78.58; H, 5.31.
4-Eth yl-1-m eth yl-6H-ben zo[b]n a p h th o[1,2-d ]p yr a n -6-
on e (10c). Mp 60-62 °C; IR (KBr) ν 3040, 2940, 2850, 1710
1
cm-1; H NMR (200 MHz, [D8]toluene) δ 1.22 (t, 3H, J ) 7.5
Hz), 1.88 (s, 3H), 2.59-2.96 (m, 2H), 6.81 (d, 1H, J ) 7.8 Hz),
6.97 (d, 1H, J ) 7.7 Hz), 7.02-7.27 (m, 2H), 7.41 (d, 1H, J )
8.2 Hz), 7.45 (br. d, 1H, J ) 6.8 Hz), 7.58 (br. d, 1H, J ) 8.2
Hz), 8.23 (d, 1H, J ) 8.5 Hz); MS (EI) m/z 288 (100) [M+], 273
(75) [M+ - CH3], 202 (28). Anal. Calcd for C20H16O2: C, 83.31,
H, 5.59. Found: C, 82.53; H, 5.44.
Exp er im en ta l Section
Sou r ces. Compounds 18,15 19,8 20,7 1-bromo-2-naphthale-
necarboxylic acid,19 5-ethyl-2-phenol,20 5-ethyl-2-methoxyphe-
nol,21 2-hydroxy-4-methoxyacetophenone,22 and 5-ethyl-2-
isopropylphenol23 were prepared according to literature
procedures. The esters 6-8 were synthesized in analogy to ref
2; for details see Supporting Information.
4-Isop r op yl-6H -b en zo[b]n a p h t h o[1,2-d ]p yr a n -6-on e
(11a ). Mp 108 °C; IR (KBr) ν 3030, 2950, 2910, 2850, 1710
1
cm-1; H NMR (200 MHz, CDC13) δ 1.38 (d, 6H, J ) 6.9 Hz),
3.79 (sept, 1H, J ) 6.9 Hz), 7.37 (dd, 1H, J ) 7.7, 7.7 Hz),
7.49 (dd, 1H, J ) 7.7, 1.2 Hz), 7.69 (m, 2H), 7.93 (d, 1H, J )
8.6 Hz), 8.08 (m, 1H), 8.33 (d, 1H, J ) 8.6 Hz), 8.35 (d, 1H, J
) 7.7 Hz), 8.90 (m, 1H); MS (EI) m/z 288 (73) [M+], 273 (100)
[M+ - CH3], 202 (30) [M+ - C4H7O2]. Anal. Calcd for
C2H16O2: C, 83.31; H, 5.59. Found: C, 83.64; H, 5.71.
In str u m en ta tion . NMR: 600 MHz spectrometer equipped
with a temperature control assembly ((0.1 K) and a probe
head heater; 200 MHz spectrometer with a variable temper-
ature unit ((1 K). HPLC-UV: columns, Chiracel OF (200 mm
× 4.6 mm) and Chiracel OD (260 mm × 4.6 mm).
4-Isop r op yl-1-m eth oxy-6H-ben zo[b]n a p h th o[1,2-d ]p y-
r a n -6-on e (11b). Mp 156-157 °C; IR (KBr) ν 3030, 2940, 1710
Gen er a l P r oced u r e for th e P r ep a r a tion of th e La c-
ton es 9-11 (2.5-30 m m ol Sca le). A mixture of the ester 6,
7, or 824 (1.0 equiv), Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv),
and NaOAc (2.0 equiv) was added to N,N-dimethylacetamide
(DMA, 7.5 mL/mmol ester, freshly distilled from CaH2), and
the reaction mixture was heated to 130 °C for 18 h. After
removal of the solvent in vacuo, the residue was purified by
column chromatographic filtration [charcoal (1 cm), silica gel
1
cm-1; H NMR (200 MHz, CDCI3) δ 1.37 (d, 6H, J ) 6.9 Hz),
3.72 (sept, 1H, J ) 6.9 Hz), 3.76 (s, 3H), 6.87 (d, 1H, J ) 8.6
Hz), 7.41 (d, 1H, J ) 8.6 Hz), 7.47 (ddd, 1H, J ) 7.5, 7 7, 1.4
Hz), 7.61 (ddd, 1H, J ) 7.5, 7.5, 1.2 Hz), 7.85-8.02 (m, 3H),
8.26 (d, 1H, J ) 8.6 Hz); MS (EI) m/z 318 (39) [M+], 303 (100)
[M+ - CH3], 287 (13) [M+ - OCH3]. Anal. Calcd for C21H18O3:
C, 79.23; H, 5.70. Found: C, 79.03; H, 5.96.
4-Isopr opyl-1-m eth yl-6H-ben zo[b]n aph th o[1,2-d]pyr an -
6-on e (11c). Mp 36 °C; IR (KBr) ν 3050, 2950, 1715 cm-1; 1H
NMR (200 MHz, CDC13) δ 1.35 (d, 3H, J ) 6.9 Hz), 1.38 (d,
3H, J ) 6.9 Hz), 2.23 (s, 3H), 3.72 (sept, 1H, J ) 6.9 Hz), 7.22
(d, 1H, J ) 7.8 Hz), 7.40 (d, 1H, J ) 7.8 Hz), 7.56 (ddd, 1H, J
) 8.5, 6.7, 1.5 Hz), 7.66 (ddd, 1H, J ) 8.2, 6.7, 1.4 Hz), 7.92-
(19) Hellwinkel, D.; Bohnet, S. Chem. Ber. 1987, 120, 1151-1173.
(20) Fischer, A.; Henderson, G. N.; Thompson, R. J . Aust. J . Chem.
1978, 31, 1241-1247.
(21) Minami, N.; Kijima, S. Chem. Pharm. Bull. 1979, 27, 1490-
1495.
(22) Vyas, G. N.; Shah, M. N. Org. Synth. 1963, 4, 836-838.
(23) Kawase, Y.; Royer, R.; Hubert-Habart, M.; Cheutin, A.; Rene´,
L.; Buisson, J .-P. Bull. Soc. Chim. Fr. 1964, 3131-3140.
(24) For the preparation of the esters 6-8 see Supporting Informa-
tion.
(25) Lange, J .; Burzlaff, H.; Bringmann, G.; Schupp, O. Tetrahedron
1995, 51, 9361-9366.

Configurationally Unstable Biaryl Compounds
J . Org. Chem., Vol. 65, No. 3, 2000 727
8.00 (m, 3H), 8.29 (d, 1H, J ) 8.6 Hz); MS (EI) m/z 302 (56)
[M+], 287 (100) [M+ - CH3], 228 (18) [287 - C2H3O2], 215 (33)
[M+ - C4H7O2]. Anal. Calcd for C21H18O2; C, 83.42; H, 6.00.
Found: C, 83.24; H, 5.99.
(M,S)-13: mp 134-135 °C; [R]20D +30.4 (c 0.64, chloroform);
CD λmax (∆ꢀ) 204 (+96.4), 213 (-193.7), 217 (-178.0), 225
(-223.7) 249 (+93.2), 261 (+40.7), 278 (+89.6); IR (KBr) ν
3280, 2940, 1680, 1650 cm-1 1H NMR (200 MHz, CDCl3) δ
;
0.68 (d, J ) 6.9 Hz, 3H), 0.80 (d, J ) 6.6 Hz, 3H), 0.84 (d, J )
7.0 Hz, 3H), 0.89, (s, 9H), 0.70-1.25 (m, 9H), 1.38 (s, 9H), 4.25
(s, 1H), 4.68 (ddd, J ) 10.6, 10.6, 4.4 Hz, 1H), 6.90, (d, J ) 1.9
Hz, 1H), 7.23 (d, J ) 1.9 Hz, 1H), 7.38-7.62 (m, 3H), 7.85-
1-Eth yl-4-isop r op yl-6H-ben zo[b]n a p h th o[1,2-d ]p yr a n -
6-on e (11d ). Mp 90 °C; IR (KBr) ν 3040, 2910, 1710, 1580
1
cm-1; H NMR (200 MHz, CDC13) δ 0.90 (t, 3H, J ) 7.5 Hz),
1.33 (d, 3H, J ) 6.9 Hz), 1.40 (d, 3H, J ) 6.9 Hz), 2.53 (m,
1H), 2.82 (m, 1H), 3.72 (sept, 1H, J ) 6.9 Hz), 7.31 (d, 1H, J
) 8.1 Hz), 7.49-7.58 (m, 1H), 7.60-7.73 (m, 1H), 7.94 (d, 1H,
J ) 7.8 Hz), 8.04 (d, 1H, J ) 8.3 Hz) 8.30 (d, 1H, J ) 8.6 Hz,
1 H); MS (EI) m/z 316 (62) [M+], 301(100) [M+ - CH3], 273
(16), 215 (18). Anal. Calcd for C22H20O2: C, 83.52; H, 6.37.
Found: C, 83.65; H, 6.41.
8.04 (m, 3H); MS (EI) m/z 514 (28) [M+], 376 (87) [M+
-
C
10H18], 358 (100), 343 (33), 328 (11), 302 (49), 287 (24), 259
(14), 57 (99), 41(28). Anal. Calcd for C35H46O3: C, 81.67; H,
9.01. Found: C, 81.84; H 9.27.
(P,S)-13: mp 124-126 °C; [R]20D +72.2 (c 0.65, chloroform);
CD λmax (∆ꢀ) 213 (+362.2), 237 (+67.0), 240 (+69.4), 282
(-57.5); IR (KBr) ν 3420, 3040, 2900, 1655 cm-1; 1H NMR (200
MHz, CDCl3) δ 0.72 (d, J ) 6.9 Hz, 3H), 0.81 (d, J ) 7.0 Hz,
3H), 0.85 (d, J ) 6.6 Hz, 3H), 0.92, (s, 9H), 0.94-1.91 (m, 9H),
4.33 (s, 9H), 4.25 (s, 1H), 4.68 (ddd, J ) 10.6, 10.6, 4.4 Hz,
1H), 6.90, (d, J ) 1.9 Hz, 1H), 7.23 (d, J ) 1.9 Hz, 1H), 7.38-
7.62 (m, 3H), 7.85-8.04 (m, 3H); MS (EI) m/z 514 (28) [M+],
376 (87) [M+ - C10H18], 358 (100), 343 (33), 328 (11), 302 (49),
287 (24), 259 (14), 57 (99), 41(28). Anal. Calcd for C35H46O3:
C, 81.67; H, 9.01. Found: C, 81.84; H 9.27.
(P ,R)-1-(2′-Hyd r oxy-4′,6′-d im eth ylp h en yl)-2-[2-(4-tolyl-
su lfin yl)a ceto]n a p h th a len e [(P ,R)-16]. A solution of (R)-
methyl-p-toluyl sulfoxide (113 mg, 730 µmol) in absolute THF
(3 mL) was added dropwise under argon to a solution of LDA‚
THF complex (1.5 M in cyclohexane) in absolute THF (1.5 mL)
at -40 °C, stirred for 30 min at this temperature, and then
gently warmed to 0 °C. After the mixture cooled to -40 °C, a
solution of 1c2 in absolute THF (3 mL) was slowly added, and
the mixture was stirred for 1 h at -40 °C and for 2 h at 0 °C.
After hydrolysis with saturated aqueous NH4Cl, the phases
were separated, and the aqueous phase was extracted with
diethyl ether (2 × 5 mL). The combined organic layers were
dried with Na2SO4, and the solvent was evaporated to give a
50:50 diastereomeric mixture of (M,R)-16 and (P,R)-16. Slow
crystallization from petroleum ether/diethyl ether under isomer-
ization of (M,R)-16 to (P,R)-16 yielded the pure (according to
an X-ray structure analysis14) crystalline diastereomer (P,R)-
16 (314 mg, 730 µmol, 73%; initial dr in solution 96:4). Mp
139-140 °C; [R]23D +133.2 (c 0.50, dichloromethane/methanol
9:1); CD (ethanol) λmax (∆ꢀ) 208 (+154), 253 (-138), 312 (+32);
(M)-1-(2,4-Di-ter t-b u t yl-6-h yd r oxyp h en yl)-2-n a p h t h o-
ic Acid [(M)-14]. Water (5.4 mg, 300 µmol) was added at 0
°C to a suspension of potassium tert-butyl alcoholate (135 mg,
1.20 mmol) in absolute diethyl ether and stirred for 5 min. A
solution of the ester (M,S)-13 (77.2 mg, 150 µmol) in diethyl
ether (2 mL) was added. The suspension was warmed to room
temperature and stirred for 24 h. Aqueous sodium hydroxide
solution (1 M, 2 mL) was added to the suspension, and the
organic layer was separated. The aqueous layer was acidified
with hydrochloric acid (2 M) and extracted with diethyl ether
(3 × 3 mL). After drying with MgSO4 and removal of the
solvent in vacuo, the acid (M)-14 was obtained as a colorless
solid (50.4 mg, 134 µmol, 89%, er 99:1). Mp 139-140 °C; IR
(KBr) ν 3620-2550, 3040, 2940, 1680 cm-1; 1H NMR (200 MHz,
CDCl3) δ 0.92 (s, 9H), 1.41 (s, 9H), 6.84 (d, J ) 1.9 Hz, 1H),
7.23 (d, J ) 1.9 Hz, 1H), 7.40-7.63 (m, 3H), 7.85 (d, J ) 8.1
Hz, 1H), 7.96 (d, J ) 8.7 Hz, 1H), 8.12 (d, J ) 8.7 Hz, 1H); MS
(EI) m/z 376 (55) [M+], 358 (69), 343 (50), 328 (22), 302 (73),
287 (50), 259 (19), 57 (100), 41 (28). Anal. Calcd for C20H18O2:
C, 79.95; H, 7.50. Found C, 79.74; H 7.61.
1
IR (KBr) ν 3080, 2930, 2670, 1600 cm-1; H NMR (200 MHz,
CDCl3) δ 1.68 ppm (s, 3H), 2.30 (s, 3H), 2.38 (s, 3H), 3.48 (d,
J ) 14.4 Hz, lH), 4.03 (d, J ) 14.4 Hz, IH), 5.79 (s, 1H), 6.67
(s, 2H), 7.24 (m, 2H), 7.39-7.60 (m, 5H), 7.68 (d, J ) 8.6 Hz,
1H), 7.89 (m, 2H); MS (CI, ammonia) m/z 446 (100) [M+
+
NH4], 429 (4) [M+ + H], 308 (10), 289 (4) [M+ - C7H7SO], 140
(5) [C7H8SO-]. Anal. Calcd for C27H24O3S: C, 75.68; H, 5.65.
Found: C, 74.94; H, 5.43.
(P )-2-Acet o-1-(2′-h yd r oxy-4′,6′-d im et h ylp h en yl)n a p h -
th a len e [(P )-17]. Freshly prepared Raney-nickel (0.5 g) was
added to a solution of (P)-16 (25.0 mg, 58 µmol) in diethyl ether
(70 mL), and the mixture was stirred at room temperature
for 1 h. After removal of the catalyst by filtration, the solvent
was evaporated, and the residue was purified by preparative
TLC (silica 60 F254S, 20 cm × 20 cm × 1 mm, diethyl ether/
petroleum ether 3:1) to give (P)-17 as a yellow oil. Crystal-
lization from petroleum ether/dichloromethane yielded (P)-17
(dr 93:7, 10.7 mg, 37 µmol, 63%) as a white solid. Mp 122-
124 °C; CD (ethanol): λmax (∆ꢀ) 203 (-59), 221 (+88), 235
(P )-1-(2,4-Di-ter t-b u t yl-6-h yd r oxyp h en yl)-2-n a p h t h o-
ic Acid [(P )-14]. Analogous saponification of (P,S)-13 gave
(P)-14 (51.4 mg, 137 µmol, 91%, er 99:1), mp 138-140 °C.
(M)-1,4-Di-ter t-bu tyl-6H-ben zo[b]n a p h th o[1,2-d ]p yr a n -
6-on e [(M)-1f]. DMF (0.3 µL) and oxalyl chloride (8.00 µL,
11.8 mg, 93,0 µmol) were added at 0 °C to a solution of (M)-14
(30.0 mg, 79.7 µmol) in absolute dichloromethane (5 mL). The
solution was stirred at 0 °C for 30 min. Triethylamine (17.0
µL, 12.3 mg, 122 µmol) and 4-(dimethylamino)pyridine (DMAP,
a few crystals) were added, and stirring at 0 °C was continued
for 2 h. After removal of the solvent the residue was dissolved
in diethyl ether and purified by preparative TLC (silica 60
1
(-22), 251 (+7); IR (KBr) ν 3260, 3030, 2900, 1660 cm-1; H
NMR (250 MHz, CDCl3) δ 1.80 (s, 3H), 2.17 (s, 3H), 2.39 (s,
3H), 6.72 (d, J ) 0.6 Hz, 1H), 6.75 (d, J ) 0.6 Hz, 1H), 7.40-
7.60 (m, 3H), 7.76 (d, J ) 8.6 Hz, 1H), 7.92 (m, 2H); MS (EI)
m/z 290 (62) [M+], 275 (100) [M+ - CH3], 247 (29). Anal. Calcd
for C20H18O2: C, 82.73; H 6.25. Found C, 82.85; H 6.31.
F
254S, 20 cm × 20 cm × 1 mm, petroleum ether/diethyl ether
3:1) to yield (M)-1f (15.6 mg, 43.8 µmol, 55%, er 96:4) as a light
yellow solid. Mp 104-106 °C; [R]22D +63.5 (c 0.50, chloroform);
CD (ethanol) λmax (∆ꢀ) 227 (-382.4), 242 (-285.1), 274 (+64.1),
287 (-0.55), 324 (+97.2). The spectral data of (M)-1f were fully
identically to those of rac-1f.2
n -Bu tyl 1-(2,4-Di-ter t-bu tyl-6-h yd r oxyp h en yl)-2-n a p h -
th oa te [(M,S)-13, (P ,S)-13]. n-Butyllithium (2.5 M in hexane,
0.32 mL, 788 µmol) was added at 0 °C to (1S)-menthol (141
mg, 900 µmol) in absolute toluene (8.7 mL) and stirred for 1 h
at room temperature. The mixture was added slowly at -78
°C to a solution of rac-1f1,2 (161.3 mg, 450 µmol) in absolute
toluene (27 mL) and stirred at -60 °C for 7 d. Glacial acetic
acid (0.23 mL) was added at -78 °C, and the mixture was
warmed to 0 °C. After removal of the solvent and the excess
menthol in vacuo, the residue was purified by column chro-
matography (dichloromethane/petroleum ether 1:1) to yield
successively rac-1f (22.8 mg, 63.5 µmol, 14%), (M)-13 (107 mg,
208 µmol, 46%, dr 99:1), and (P)-13 (87.4 mg, 170 µmol, 38%,
dr 99:1). The esters were purified by recrystallization from
dichloromethane/petroleum ether to give colorless crystals.
(P )-1,4-Di-ter t-bu tyl-6H-ben zo[b]n a p h th o[1,2-d ]p yr a n -
6-on e [(P )-1f]. From (P)-14, (P)-1f (16.3 mg, 45.0 µmol, 57%,
er 95:5) was prepared analogously. Mp 105-106 °C; [R]22
-
D
63.1 (c 0.45, chloroform); CD (ethanol) λmax (∆ꢀ) 227 (+300.8),
241 (+213.6), 243 (+214.3), 275 (-67.5), 288 (-11.7), 325
(-89.5). The spectral data of (P)-1f were fully identically to
those of rac-1f.2
Det er m in a t ion of t h e R a t e Con st a n t s b y DNMR .
Samples were prepared from 20-50 mg of the compounds in
high precision 5 mm tubes (Varian 507 PP). At each temper-
ature the sample tubes were allowed to equilibrate thermally
for 15 min, and the proton frequency and the impedance of
the receiver circuit were carefully compensated before record-
ing a spectrum. Exact temperatures were measured with the

728 J . Org. Chem., Vol. 65, No. 3, 2000
Bringmann et al.
help of NMR-shift thermometers: methanol26 or semibull-
valene27 for low temperatures and ethylene glycol28 for high
temperatures. Zero filling to 4 times the number of measured
data points was performed to give 64 K data points. Particular
attention was paid to the phase and baseline corrections, since
small deviations from the optimum will result in considerable
errors in the rate constants. The rate constants k were
calculated from the NMR spectra by the Bruker computer
program WINDYNA. Reference half-widths were determined
if possible from the signals of nonexchanging molecule protons
or otherwise from the rest proton signals of the solvent. The
spectra were simulated in the slow exchange regime and then
iterated by the program to the experimental spectra of each
temperature. The k values were accepted when there was a
good optical agreement between the experimental and the
iterated spectrum, resulting in a conservatively estimated
error of 5%.
10c (200 MHz, J ) 14.6 Hz, [D8]toluene): k /s-1 (T /K) 2.8 (
0.3 (308), 5.4 ( 0.5 (313), 7.1 ( 0.5 (320), 9.1 ( 0.4 (324), 30
( 3 (334), 66 ( 2 (350), 73 ( 3 (360).
11a (200 MHz, CD2Cl2): the experiments showed fast
exchange even at 170 K.
11b (200 MHz, CD2Cl2): the experiments showed fast
exchange even at 170 K.
11c (200 MHz, J ) 6.9 Hz, [D8]toluene): k /s-1 (T /K) 0.75
( 0.05 (302), 0.90 ( 0.05 (321), 1.70 ( 0.05 (325), 4.25 ( 0.05
(337), 6.25 ( 0.08 (340), 8.00 ( 0.10 (344), 12.4 ( 0.10 (349),
12.7 ( 0.10 (350), 14.0 ( 0.30 (352), 20.5 ( 1.00 (361), 27.0 (
2.00 (366), 28.5 ( 2.00 (373), 66.0 ( 5.00 (385).
11d (200 MHz, [D8]toluene): k /s-1 (T /K) (a) probe CH(CH3)2
(J ) 6.9 Hz) 1.5 ( 0.2 (349), 3.1 ( 0.1 (362), 5.1 ( 0.3 (369),
9.2 ( 0.2 (376), 20.0 ( 1.0 (387); (b) probe CH2CH3 (J ) 14.5
Hz) 1.3 ( 0.3 (349), 3.6 ( 0.2 (362), 5.4 ( 0.3 (369), 8.8 ( 0.3
(376), 18.2 ( 0.7 (387).
Deter m in a tion of th e Ra te Con sta n ts by HP LC-UV
Mea su r em en ts. The time-dependent decrease of er was
measured over two half-lives at several temperatures. The
sample was kept at the given temperature ((1 K) using a
thermostat. The rates k were calculated by the first-order rate
equation (eq 1)
20 (600 MHz, [D6]DMSO): k /s-1 (T /K) (eq f ax; probe OMe)
8.20 (363), 24.1 (383), 42.1 (393), 67.4 (403), 107 (413); (eq f
ax; probe 6-Hax) 7.85 (363), 23.5 (383), 40.9 (393), 64.4 (403),
95.0 (413); (ax f eq; probe OMe) 9.61 (333), 57.1 (363), 129
(383), 238 (393), 310 (403); (ax f eq; probe 6-Heq) 8.86 (333),
52.2 (363), 124 (383), 213 (393), 306 (403).
At r op isom er iza t ion R a t e Con st a n t s Mea su r ed b y
HP LC-UV. (P)-17 Chiracel OD, flow 1 mL/min, eluent
n-hexane/2-propanol 95:5, detection at 280 nm, retention times
ti ln(c0/ci)
∑
k )
(1)
ti2
tR ) 40.2 min for (M)-17 and 46.2 min for (P)-17: k / (105 s-1
)
∑
(T /K) 3.16 ( 0.03 (300), 7.07 ( 0.05 (313), 14.1 ( (0.1) (323).
(M)-1f Chiracel OD, flow 0.5 mL/min, eluent n-hexane/2-
with the er c0 at the time t0 ) 0 and ci at ti, respectively.
Eyr in g p a r a m eter s listed in Table 1 were obtained by
least-squares fits of ln(k/T) vs 1/T data from eq 2, which results
propanol (100:1), detection at 280 nm, retention times tR
)
21.1 min for (M)-1f and 19.2 min for (P)-1f: k /(105 s-1) (T /K)
2.03 (314), 22.2 (335), 119 (354).
(M)-9e: the column was cooled to the corresponding tem-
perature ((1 K) by a thermostat filled with ethanol. Chiracel
OF, flow 0.5 mL/min, eluent petroleum ether/2-propanol (3:
1), detection at 280 nm, retention times tR ) 26.7 min for (M)-
9e and 35.8 min for (P)-9e: k /(106 s-1) (T /K) 3.57 (263), 24.4
(273), 374 (298).
kB
k
T
-∆Hq
R
1
T
∆Sq
R
ln
)
+ ln
+
(2)
h
from the Eyring and the Gibbs-Helmholtz equations with the
Boltzmann constant kB, the Planck constant h, and the gas
constant R. The errors given in Table 1 are statistical errors
that result from the regression analysis of the Eyring plot.
Atr op isom er iza tion Ra te Con sta n ts Mea su r ed by 1H
NMR. Compound 9d (200 MHz, [D8]toluene): the experiments
showed superimposed proton signals for the ethyl-CH2 group
at C-1 and the methyl group at C-4.
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft [SFB 347 “Selektive
Reaktionen Metall-aktivierter Moleku¨le” and Gra-
duiertenkolleg: “Magnetische Kernresonanz in vivo und
in vitro” (fellowship for M. H.)] and by the Fonds der
Chemischen Industrie (graduate research fellowship for
M. B. and research funds).
Su p p or tin g In for m a tion Ava ila ble: Preparation, 1H
NMR, IR, and MS data of 6d , 6e, 7b, 7c, 8a , 8b, 8c, and 8d .
This material is available free of charge via the Internet at
http://pubs.acs.org.
10b (200 MHz, J ) 14.5 Hz, CD2Cl2): k /s-1 (T /K) 5.0 ( 1.0
(186.1), 7.9 ( 0.3 (196.2), 9.2 ( 0.5 (200.4), 14.2 ( 0.5 (211.5),
15.5 ( 0.5 (213.0), 26.0 ( 1.0 (221.7), 29.5 ( 0.5 (223.2), 63.0
( 1.0 (230.6), 135 ( 5 (239.1), 160 ( 5 (241.5), 280 ( 10 (250.5)
(26) Van Geet, A. L. Anal. Chem. 1970, 42, 363.
(27) Quast, H.; Heubes, M.; Dunger, A.; Limbach, H.-H. J . Magn.
Reson. 1998, 134, 236.
(28) Van Geet, A. L. Anal. Chem. 1968, 40, 2227.
J O9913356