Thermal isomerization of isoborneols and dehydroisoborneols to new chiral building blocks in terpenoid synthesis

Article abstract of DOI:10.1002/hlca.200490179

The substituted isoborneols 1a-1g and 5,6-dehydroisoborneols 6a-6c, readily prepared in excellent yields from (+)-camphor and (+)-5,6-dehydrocamphor (2) by aryl, vinyl, or alkyl Grignard addition in the presence of stoichiometric amounts of CeCl₃, were thermally isomerized in a flow reactor system under DGPTI (dynamic gas-phase thermo-isomerization) conditions at temperatures between 480 and 630° to give the enantiomerically pure monocyclic carbonyl compounds 7a-7d, 19a,b, 23, and 24. In all cases, product formation proceeded highly regio- as well as stereoselectively. The absolute configurations of the new stereogenic centers were determined by ¹H-NOE measurements. DGPTI of the aryl substrates 1a-1d is proposed to effect initial cleavage of the weakest single bond in the molecule under formation of a diradical intermediate state followed by intramolecular H-abstraction to afford the acetophenone derivatives 7a-7d. This reaction path was further supported by a ²H-labeling study showing the OH group to be the exclusive H-source. In contrast, DGPTI of the vinyl substrates 1e and 6b allowed concerted retro-ene and oxy-Cope rearrangements. In the case of 5,6-dehydro-2-phenylisoborneol (6a), concomitant diradical and retro-Diels-Alder reaction pathways could be observed. In addition, a new route to (+)-rrans-a-campholanic acid (9) and (+)-trans-a-dihydrocampholytic acid (14) is presented by regioselective Baeyer-Villiger oxidation and subsequent hydrolysis of 7c and 7d, respectively.

Full text of DOI:10.1002/hlca.200490179

1968
Helvetica Chimica Acta Vol. 87 (2004)
Thermal Isomerization of Isoborneols and Dehydroisoborneols to New
Chiral Building Blocks in Terpenoid Synthesis
by Georg R¸edi1)* and Hans-J¸rgen Hansen
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
(phone: ‡4116354248; fax: ‡4116356853; e-mail: georg@access.unizh.ch)
The substituted isoborneols 1a 1g and 5,6-dehydroisoborneols 6a 6c, readily prepared in excellent yields
from (‡)-camphor and (‡)-5,6-dehydrocamphor (2) by aryl, vinyl, or alkyl Grignard addition in the presence of
stoichiometric amounts of CeCl3, were thermally isomerized in a flow reactor system under DGPTI (dynamic
gas-phase thermo-isomerization) conditions at temperatures between 480 and 6308 to give the enantiomerically
pure monocyclic carbonyl compounds 7a 7d, 19a,b, 23, and 24. In all cases, product formation proceeded highly
regio- as well as stereoselectively. The absolute configurations of the new stereogenic centers were determined
by 1H-NOE measurements. DGPTI of the aryl substrates 1a 1d is proposed to effect initial cleavage of the
weakest single bond in the molecule under formation of a diradical intermediate state followed by
intramolecular H-abstraction to afford the acetophenone derivatives 7a 7d. This reaction path was further
supported by a 2H-labeling study showing the OH group to be the exclusive H-source. In contrast, DGPTI of the
vinyl substrates 1e and 6b allowed concerted retro-ene and oxy-Cope rearrangements. In the case of 5,6-
dehydro-2-phenylisoborneol (6a), concomitant diradical and retro-DielsÀAlder reaction pathways could be
observed. In addition, a new route to (‡)-trans-a-campholanic acid (9) and (‡)-trans-a-dihydrocampholytic
acid (14) is presented by regioselective BaeyerÀVilliger oxidation and subsequent hydrolysis of 7c and 7d,
respectively.
1. Introduction. Recently, we have reported a diradical-mediated ring-opening
reaction of medium- and large-ring 1-phenylcycloalkanones A performed under
DGPTI (dynamic gas-phase thermo-isomerization) conditions at 6508 [1]. A reaction
mechanism via initial cleavage of the weakest single bond in the molecule resulted in
the formation of a a-hydroxybenzyl w-alkyl diradical. Intramolecular H-abstraction
within the transient diradical state furnished open-chain phenones B with the
corresponding chain length in excellent yields. This reaction pathway has been
confirmed by subjecting O-deuterated substrates to DGPTI. The label was found to be
fully incorporated into w-position of the alkyl chain (Scheme 1).
Impelled by the preparative and mechanistic importance associated with diradical-
mediated disproportionation reactions, we extended our investigations to optically
active substrates derived from camphor. The main interest of the present work is
focused on 1) whether phenylisoborneols might react under DGPTI conditions in a
similar manner to afford the corresponding open-chain products, and, if this is the case,
2) whether the cleavage of the weakest single bond occurs regioselectively, and 3)
whether the H-transfer proceeds stereoselectively under retention of the geometry of
the camphor framework. If this were the case, the procedure would provide a new and
1
)
Part of the PhD thesis of G. R., University of Z¸rich, 2004.
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 87 (2004)
1969
Scheme 1
very convenient access to a broad variety of chiral building blocks in terpenoid
synthesis.
2. Results and Discussion. 2.1. Synthesis ofMonoterpene Substrates 1a 1d and
6a 6c. The addition of both phenyl and vinyl Grignard reagents to (‡)-camphor in the
presence of anhydrous CeCl3 carried out in THF at room temperature provided the
optically pure tertiary exo-alcohols 1a 1e in good-to-excellent yields (Table 1). Except
for the 4-methoxyphenyl derivative 1c [2], which could be crystallized from hexane, all
compounds were obtained as liquids. Isoborneols with aliphatic substituents at C(2),
such as the i-Pr and the cyclohexyl group, were prepared accordingly in comparable
yields, but by means of the corresponding magnesium chlorides instead of the bromides.
As reported by Dimitrov et al. [3], the employment of a stoichiometric amount of CeCl3
as Lewis acid is essential for complete conversion. In the absence of CeCl3, the same
alcohols were formed, but with significantly lower conversion rates (30 40%) due to
competing enolization, giving back starting material.
Table 1. CeCl3-Mediated Addition of Grignard Reagents to (‡)-Camphor
R
Product 1
CeCl3
Time [h]
Yield [%]
Ph
a
b
c
d
e
f
1.2 equiv.
1.2 equiv.
1.0 equiv.
0.8 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
0.5
0.5
2.0
1.0
1.0
1.5
1.5
95
92
88
98
76
81
85
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
Vinyl
i-Pr
Cyclohexyl
g
The endo-configuration of the 2-aryl Grignard adducts 1a 1d was established by
1H-NOE experiments. According to Fig. 1, NOE effects were observed between the
ortho-H-atoms of the aromatic ring and both HendoÀC(3) and HendoÀC(6), respectively,

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Helvetica Chimica Acta Vol. 87 (2004)
and between the OHgroup and Me synÀC(7). Similarly, 2-vinylisoborneol (1e)
exhibited an NOE effect between the a-H-atom on the vinyl moiety at d(H) 6.03
and HendoÀC(3,6). The exclusive endo-attack of Grignard reagents on camphor is due
to the steric shielding by MesynÀC(7) of the rigid bicyclo[2.2.1]heptane skeleton.
Fig. 1. 1H-NOE Correlations ofisoborneols 1a e of endo-configuration
(‡)-5,6-Dehydrocamphor (2) was prepared according to the procedure described
by Hutchinson et al. [4][5] by treating commercially available (‡)-endo-3-bromocam-
phor (3) with chlorosulfonic acid (ClSO3H ) at 458 to afford rearranged (À)-endo-6-
bromocamphor (4) in 42% yield after crystallization from hexane (Scheme 2). It is
noteworthy that this isomerization reaction, involving several WagnerÀMeerwein
rearrangements as well as Me- and hydride-shift reactions, effects inversion of the
camphor skeleton. Subsequent dehydrobromination with KOHin DMSO/H O 7:1 at
2
1208 yielded the highly volatile dehydrocamphor 2 (45%). The low yield of 2 is due to
the competing formation of (À)-a-campholenic acid (5), which was produced in 38%
yield as the result of a Grob-like fragmentation. CeCl3-Assisted addition of phenyl or
vinyl magnesium bromide to (‡)-5,6-dehydrocamphor (2) proceeded smoothly to give
the corresponding endo-adducts 6a and 6b, respectively, in excellent yields (93 96%).
The i-Pr-substituted dehydroisoborneol derivative 6c was synthesized in the same
manner, but with i-Pr MgCl. In contrast to camphor as the substrate, only
substoichiometric amounts of CeCl3 (0.2 equiv.) were necessary for optimal conversion
to the products 6a 6c. Again, the endo-selectivity was approved by 1H-NOE
measurements (Fig. 2). Irradiation of the ortho-H-atoms of the aromatic ring in 6a
produced NOE effects for HendoÀC(3), HÀC(5), and HÀC(6). Comparable inter-
actions could be observed with 6b by irradiating the a-H-atom on the vinyl moiety at
d(H) 6.01, as well as with 6c when the Me groups at d(H) 0.8 of the i-Pr moiety were
irradiated. Furthermore, each compound exhibited an NOE effect between its OH
group and the syn-positioned Me group at C(7).
2.2. Rearrangements by DGPTI. The thermal isomerization experiments were
performed in a flow reactor system under vacuum conditions (2 4 Â 10À2 mbar) at
temperatures between 4008 and 7508. The substrates were evaporated in a Kugelrohr
oven heated at 80 1308, while a flow of N2 was applied (0.8 1.4 l/h). The rearrange-
ment products were collected in a cooling trap filled with liquid N2 and subsequently
subjected to column chromatography (for details, see Exper. Part).
2.2.1. DGPTI of2-Arylisoborneols. In order to find the optimal contact time and
temperature of the isoborneol substrates at the hot reactor zone, the DGPTI conditions

Helvetica Chimica Acta Vol. 87 (2004)
1971
Scheme 2.
a) ClSO3H , 458; 42%. b) KOH, DMSO, H2O, 1208; 45% (2), 38% (5). c) PhMgBr, CeCl3, THF; 93%.
d) C2H3MgBr, CeCl3, THF; 96%. e) i-PrMgBr, CeCl3, THF; 93%.
Fig. 2. 1H-NOE Correlations ofdehydroisoborneols 6a c of endo-configuration
for each substrate were established by varying both the reactor temperature and the
flow rate of the applied carrier gas. The product distribution of each experiment was
analyzed by GC/MS. The results of the thermal isomerization of our model compound
1a are displayed in Table 2. Two general tendencies are evident: 1) the conversion rate
is increased, as expected, by raising the reactor temperature and 2) decreasing by
raising the flow rate. However, product formation occurred only in a limited
temperature range (580 6808). Almost no product formation was observed at
temperatures below 5808, whereas temperatures above 6808 provided numerous low-
boiling side products, e.g., dehydrated 2-phenylbornene and acetophenone. However, a
reactor temperature of 6308 in combination with a flow rate of 1.2 l/h provided the best
results (73% yield of 7a).
1
Examination of the isomerization product 7a by H- and 13C-NMR spectroscopy
indicated that only one diastereoisomer had been formed. The 13C-NMR spectrum
(CDCl3) exhibited a singlet at d(C) 201.1, which is typical for the CˆO C-atom of
aliphatic phenones. As the stereogenic center at C(4) in 1a is not involved in a bond-
cleavage/bond-formation process during the isomerization reaction, the (R)-config-
uration is retained in the product ((R)-configuration at C(1')). The relative

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Helvetica Chimica Acta Vol. 87 (2004)
Table 2. Thermal Isomerization of2-Phenylisoborneol (1a) to (1R,3S)-1-Phenyl-2-(2,2,3-trimethylcyclopentyl)-
ethanone (7a)
Temp. [8]
Flow Rate [l/h]
7a (%)
1a (% )a)
550
580
600
620
630
630
630
650
680
1.2
1.2
1.2
1.2
1.2
0.8
1.4
1.2
1.2
85
6
29
7
4
2
21
48
70
73
62
65
59
36
8
a) Recovered starting material.
configuration at C(3') in the tetrasubstituted cyclopentane ring was established by 1H-
1
NOE studies (CDCl3) on a 600-MHz spectrometer. The H-NMR spectrum of 7a
displayed three singlets for the Me groups on the cyclopentane ring. As displayed in
Scheme 3, irradiation of the signals of the exocyclic methylidene group, which appeared
as the AB part of an ABX system at d(H) 3.03 and 2.73, respectively, produced an NOE
effect for the exo-Me group at C(2') at 0.88 ppm. Irradiation of the X part (HÀC(1')) at
d(H) 1.66 caused an NOE for the signals of the endo-Me group at 0.89 ppm. An NOE
effect was further observed between MeexoÀC(2') and HÀC(3'). These observations
provided evidence that the configuration at C(3') was (S), i.e., trans-1-phenyl-2-(2,2,3-
trimethylcyclopentyl)ethanone (7a) was the exclusive isomerization product.
To gain additional insight into the mechanism of this highly regio- as well as
stereoselective intramolecular H-transfer reaction, we prepared the O-deuterated
isoborneol [O-2H]-1a by repeated treatment of 1a with MeOD/D2O. After DGPTI at
6308, the label was found to be fully incorporated into the exo-position at C(3') of [3-
2H]-7a (Scheme 3)2). The sextet for HÀC(3') of [3-2H]-7a at d(H) 1.66 had vanished
while the 2H-NMR spectrum (CDCl3) showed a broad singlet at the same ppm value. It
is important to state that no reaction or only tar formation occurred, when 1a was
thermolyzed up to 3508 under static conditions in a sealed glass tube.
The above findings are consistent with a reaction pathway involving radical
structures. Due to the required high thermal-energy impact (6308 in the reactor zone),
the weakest single bond (C(1)ÀC(2)) in the molecule is broken homolytically, and this
highly regioselective cleavage leads to a stabilized hydroxy benzyl radical on one side of
the pentacyclus, and a tertiary alkyl radical on the other side. This monocyclic diradical
1
2
)
The deuterium content was determined by H-NMR and MS to be above 80%.

Helvetica Chimica Acta Vol. 87 (2004)
1973
Scheme 3
intermediate C can relax either way, giving back isoborneol 1a by recombination, or
going forward to the energetically more-stable phenone 7a by intramolecular H-
transfer, which is favored by 16.7 kcal molÀ1 according to AM1-calculated DHfo values
of 1a (À29.3 kcal molÀ1) and 7a (À46.0 kcal molÀ1). AM1 Calculations of 1a further
showed that the C(1)ÀC(2) bond is longer (157.6 pm) than the C(2)ÀC(3) bond
(155.9 pm), which is in excellent accordance with X-ray crystallographic analyses of
reported phenylisoborneol derivatives [6]. Contrarily, cleavage of the stronger
C(2)ÀC(3) bond would result in a disfavored diradical intermediate D, containing a
primary alkyl radical, which would afford the sterically encumbered cis-phenyl-
methanone 8 (À 34.4 kcal molÀ1) through an analogous intramolecular H-transfer. The
formation of 8, however, was not observed even at temperatures of up to 6808
(Table 2). The labeling experiment further showed the OHgroup to be the exclusive
H-source for the disproportionation reaction. H-abstraction from C(3), forming
thereby the enol of 7a, which on tautomerization would give 7a, could not be observed.
It is further noteworthy that H-abstraction can be accomplished only under retention of

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Helvetica Chimica Acta Vol. 87 (2004)
the geometry at bridgehead C(1), which explains the unique diastereoselectivity of this
reaction (100% de).
As phenone 7a represents a versatile chiral building block for the construction of a
variety of useful synthetic intermediates, we tried to convert it to a-campholanic acid
(9) by BaeyerÀVilliger oxidation and subsequent hydrolysis of the intermediate phenyl
ester 10 (Scheme 4). In addition, alkyl esters of 9 are reported to smell fruity and floral
[7], which make them interesting for applications in the fragrance industry.
Unfortunately, any attempts to effect regioselective oxidation of 7a failed. Hence,
treatment of 7a with MCPBA (3-chlorobenzenecarboperoxoic acid) and 1 equiv. of
TFA (trifluoroacetic acid) in CH2Cl2 at room temperature [8] yielded both the
expected phenyl ester 10 along with benzoate 10' in comparable amounts. Although
hydrolysis of this mixture with LiOHin MeOH/H 2O [9], leading to (‡)-trans-a-
campholanic acid (9) and (1S,3S)-(2,2,3-trimethylcyclopentyl)methanol (11), was
feasible, this procedure was considered not to be satisfactory due to the lack of
regioselectivity in the BaeyerÀVilliger oxidation.
Scheme 4
a) MCPBA, TFA, CH2Cl2, r.t.; 93%. b) LiOH, MeOH, H2O, r.t.; 91%.
To circumvent this inconvenience, we subjected the freshly prepared para-
substituted isoborneols 1b d to DGPTI at 610 6308, which provided the correspond-
ing phenones 7b d in moderate-to-good yields (Scheme 5). The optimal conditions for
each reaction were determined as described above by means of GC/MS analysis (for
details, see Exper. Part). The CˆO absorptions in the IR spectra of 7b d were shifted
to lower wave numbers with increasing electron density at the aromatic ring. The lowest
value (1677 cmÀ1) was observed in the case of 7c with the p-donating MeO group.
Conversely, the electron-withdrawing F3C group in 7d effected the highest value
(1694 cmÀ1), the CˆO absorption in the case of the s-donating Me group lying in
between (1682 cmÀ1).
The difference of the substituent-controlled electronic properties of the aromatic
rings of 7c and 7d enabled us to perform regioselective BaeyerÀVilliger oxidations, as
shown in Scheme 6. The oxidizing agent, trifluoroperacetic acid, was generated by the
addition of TFA (CF3COOH) to a solution of MCPBA in CH2Cl2 at 08. Application of
this procedure provided, in the case of the electron-rich 7c, the corresponding
methoxyphenyl ester 12 (99%), whereas the electron-deficient 7d afforded the

Helvetica Chimica Acta Vol. 87 (2004)
1975
Scheme 5
cyclopentylmethyl ester 13 (89%). Subsequent hydrolysis proceeded smoothly in both
cases to furnish the desired (‡)-trans-a-campholanic acid (9) and cyclopentylmethanol
11, respectively3), in almost quantitative yields. However, BaeyerÀVilliger oxidation of
substrate 7b under similar conditions led only to a 3 :1 mixture of both possible esters as
a result of predominant migration of the p-tolyl group.
Scheme 6
a) MCPBA, TFA, CH2Cl2, r.t. b) LiOH, MeOH, H2O, r.t. c) H2SO4, H NO, À158. d) CrO3, H2SO4, 08 ! r.t.
3
e) CH2N2, Et2O, r.t.; 96%.
Alternatively, the introduction of electron-withdrawing groups can also be
accomplished on the stage of phenone 7a by electrophilic aromatic substitution, which
has been demonstrated by nitration. The NO2 group of the corresponding electron-
deficient phenone 16 was introduced in the meta-position (nÄ(CˆO) 1695 cmÀ1), and
subsequent BaeyerÀVilliger oxidation followed by hydrolysis of the intermediate ester
3
)
Only the corresponding racemic cis-compound has been reported so far [10].

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Helvetica Chimica Acta Vol. 87 (2004)
led to the desired alcohol 11 (69% over three steps). Oxidation of 11 was achieved
quantitatively with Jones reagent [11] to afford (‡)-trans-a-dihydrocampholytic acid
(14), the normethylene analogue of 9.
The class of enantiomerically pure a-dihydrocampholytic acid derivatives is still
sparsely populated due to the awkward stereocontrol of two stereogenic centers.
Among the four possible diastereoisomers of 14, only cis/trans mixtures have been
reported in the literature, obtained predominantly via nonselective hydrogenation of
unsaturated precursors (for leading references, see [10] and [12 16]). However, the
presented −DGPTI/BaeyerÀVilliger procedure× is limited to the preparation of trans-
configured derivatives of a-campholanic acid (9) and a-dihydrocampholytic acid (14)
due to the stereochemical reasons mentioned above. Attempts to at least partially
epimerize methyl ester 15 to the corresponding cis-compound by treatment with
NaOMe in MeOHwere futile.
2.2.2. DGPTI of2-Vinylisoborneol . In sharp contrast to the isomerization of
phenylisoborneols 1a d, pyrolysis of 2-vinylisoborneol (1e) under similar conditions
provided an isomerization product exhibiting spectral data that showed no evidence for
the expected vinylketone. Instead, an isomeric compound (43% isolated yield)
containing a singlet at d(C) 147.7 and a doublet at 121.6 in its 13C-NMR spectrum
(CDCl3) was observed. Moreover, the upfield-shifted CˆO absorption at d(C) 211.6
indicated the presence of a saturated rather than an a,b-unsaturated ketone, and the
1H-NMR spectrum exhibited a triplet at d(H) 1.06, with a vicinal coupling of 7.3 Hz
typical for an ethyl ketone. These data are consistent with the formation of (R)-1-
(2,2,3-trimethylcyclopent-3-enyl)butan-2-one (17a; Scheme 7)4). In addition, the
presence of a minor amount (ca. 10%) of the isomeric butanone 17b, with an exocyclic
1
CˆC bond, was evident from H- and 13C-NMR analyses.
Interestingly, the isomerization reaction occurred already at a relatively low
temperature (6008). As the ability to stabilize radicals in a-position is decreasing by
passing from phenyl (ca. 16 kcal molÀ1) to vinyl (ca. 14 kcal molÀ1) [19 21], one would
expect a higher temperature (>6308) to be required for the thermal isomerization of 2-
vinylisoborneol (1e) relative to 2-phenylisoborneol (1a; 6308). These observations are
not compatible, however, with a reaction pathway via initial homolysis of the weakest
single bond and subsequent H-transfer. Apparently, the proper arrangement in 1e
allows a concerted retro-ene reaction, having a lower activation energy than a reaction
involving complete dissociation of the weakest single bond. Indeed, our assumption has
firmly been corroborated by theoretical calculations using PBE density-functional
theory5) [22]. All calculated energy values given in Scheme 7 refer to the applied
reactor temperature (6008C ˆ 873 K). Generally, four six-membered transition states
s-trans/cis-E and s-trans/cis-F are possible. The intermediates s-trans- and s-cis-E
implicate HendoÀC(6), whereas s-trans- and s-cis-F implicate HÀCH2ÀC(1). The
energetically most-favored reaction pathway via s-trans-E, with a transoid arrangement
4
)
Compound 17a has previously been prepared by Siewinsky et al. by addition of EtMgBr to a-
campholenonitrile [17][18].
PBE Density-functional theory has been implemented in the computer program written by Laikov [23].
Full geometry optimizations for energy minima and transition states were followed by harmonic
vibrational analysis to get the thermochemical data.
5
)

Helvetica Chimica Acta Vol. 87 (2004)
1977
Scheme 7. Calculated Relative Energies [22] (in parentheses; kcal molÀ1) for Different Thermo-Isomerization
Pathways of 1e
of the hydroxyally moiety (DG=873 ˆ 35.3 kcal molÀ1, cf. Fig. 3) affords enol (E)-17a'
(DDG873 ˆ À7.2 kcal molÀ1).
The tautomerization to ketone 17a is assumed to take place only in the condensed
phase (cooling trap) as an intermolecular process. The activation barrier for an
intramolecular, symmetry-forbidden 1,3-H-shift, however, would be insurmountable
under these conditions. Also, a reaction pathway leading to (Z)-17a' via highly
energetic s-cis-E (DG=873 ˆ 48.4 kcal molÀ1) can be neglected for the same reasons. In
contrast, a pathway via the cisoid transition state s-cis-F (cf. Fig. 3) was found to be
favored over transoid s-trans-F by 17.5 kcal molÀ1. Enol (Z)-17b' is then formed
(DDG873 ˆ À3.9 kcal molÀ1), followed by intermolecular tautomerization to ketone
17b. The ratio for 17a/17b of 10 :1 determined is in quite good agreement with PBE-
calculated DG=873 values for s-trans-E and s-cis-F, which accounts for the predominant

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Helvetica Chimica Acta Vol. 87 (2004)
Fig. 3. DFT-Calculated transition-state structures s-trans-E and s-cis-F (interatomic distances in ä)
formation of 17a (DDG=873 ˆ 2.7 kcal molÀ1 corresponds to ca. 83% of 17a and 17% of
17b, assuming the reaction to occur under kinetic control).
2.2.3. DGPTI of2-Alkylisoborneols . Interestingly, isoborneol substrates such as 1f
and 1g, having an aliphatic substituent at C(2), could not be thermo-isomerized to the
desired monocyclic isopropyl and cyclohexyl ketones, respectively (Scheme 8). At
elevated temperatures (680 7508), isopropyl methyl ketone (18) and 1-cyclohexyl-
ethanone (19) were the only products isolated (<20%) besides many unidentified low-
molecular-weight components (80%) according to GC/MS analysis. Taking into
account the high reactor temperatures, concomitant cleavage of the C(1)ÀC(2) and
C(3)ÀC(4) bonds becomes feasible under formation of the enol forms of 18 or 19, and
a highly reactive 1,4-diyl species undergoing further 1,4-fragmentation. Unfortunately,
neither of these compounds could be isolated or characterized. Apparently, aliphatic
substituents are not capable to sufficiently stabilize C(2) radicals. In other words,
homolytic cleavage of the C(1)ÀC(2) bond requires higher temperatures (>6808) at
which competing homolysis of non-activated single bonds in the molecule can also
occur.
Scheme 8

Helvetica Chimica Acta Vol. 87 (2004)
1979
2.2.4. DGPTI of5,6-Dehydrolisoborneols . In contrast to 2-phenylisoborneol (1a),
DGPTI of its dehydro analogue 6a occurred already at 5208, providing the two products
20 and 21 of different molecular weights in a 2 :1 ratio (Scheme 9). Compounds 21 and
‡
22 exhibited M signals at m/z 228 (18%) and 120 (40%), respectively. The product
mixture revealed a typical smell of acetophenone, and, indeed, co-injection of an
authentic sample proved 20 to be acetophenone. The 13C-NMR spectrum of 21 showed
two signals at d(C) 136.0 and 132.4, and a broad singlet at d(H) 5.95 appeared in the
1H-NMR spectrum. Apart from that, the spectra were very similar to those of phenone
7a. These data were in agreement with the cyclopent-2-enyl phenyl ethanone 21, which,
upon hydrogenation, quantitatively afforded ent-7a. Apart from the optical rotation
power (opposite sign of [a]2D3 ), the spectroscopic data of the latter were identical in all
respects with those recorded for 7a. Even though the reactor temperature was
remarkably low (5208), the structure of 21 could not be rationalized by a concerted
process. Thus, the isomerization reaction is more likely to proceed through diradical
transition structures in analogy to that observed in the case of 7a. Homolytic cleavage
of the C(1)ÀC(2) bond in 6a results in a stabilized diradical intermediate consisting of a
hydroxy benzyl radical and a trisubstituted allyl radical, which, upon intramolecular
disproportionation, leads to 216). Conversely, the formation of acetophenone (20) is
consistent with a concerted retro-DielsÀAlder reaction under loss of trimethylcyclo-
pentadiene. The presence of two competing reaction mechanisms was firmly
established by varying the reactor temperature. Besides the main product 20, only
traces of 21 were detected up to 4508, but the ratio of 21 to 20 increased with increasing
temperature to almost equal amounts (6508).
Scheme 9
a) DGPTI, 4808; 40% (20), 18% (21). b) H2, Pd(C), MeOH, r.t.; 98%.
Although 5,6-dehydro-2-vinylisoborneol (6b) has been reported to be smoothly
converted to the bicyclic ketone 22 (85%) upon treatment with KHin THF at room
temperature [28], its thermochemical behavior has apparently not been investigated so
far. As outlined in Scheme 10, the formation of four different products is possible upon
pyrolysis of 6b, each via a separate mechanism. Only the formation of cyclopentyl vinyl
6
)
Compound 21 can be viewed as a precursor of necrodanes (1,2,2,3,4-pentamethylcyclopentanes), which
are found in the defense spray of Necrodes surinamensis, a silphid beetle from Surinam, and as
constituents of the essential oils of Lavandula luisieri. For leading references, see [24 27]

1980
Helvetica Chimica Acta Vol. 87 (2004)
Scheme 10. Possible Transformations of 6b. Numbers in parentheses refer to DFT-calculated DG=823 values (in
kcal molÀ1).
ketone 25 would require a diradical intermediate, whereas the formation of compounds
22 24 involves concerted reactions leading primarily to the corresponding enol
compounds. A retro-DielsÀAlder pathway could well give methyl vinyl ketone 23 and
trimethylcyclopentadiene, as was observed for DGPTI of the corresponding phenyl
analogue 6a, while a retro-ene process would provide the conjugated diene 24.
Our interest was focused on whether DGPTI of 6b could effect homolysis between
C(1)ÀC(2) and give, at least partially, the monocyclic vinylketone 25 via a diradical
state. However, applying even harsher conditions (> 7008, 0.4 l/h N2 flow) resulted in
the formation of 22 as the sole product. Furthermore, the yield of rearranged 22
reported by Hutchinson et al. [28] could be improved to 93% by carrying out the
pyrolysis at 5508. Excellent yields were also obtained by heating 6b in a sealed glass
tube under static conditions at 2208 (95%), whereas the same transformation under
anionic oxy-Cope conditions, as reported above, provided lower yields (80%). In
addition, DFT calculations referring to a reactor temperature of 5508 (823 K) showed
that the lowest activation barrier was found for a concerted oxy-Cope rearrangement
(DG=823 ˆ 22.3 kcal molÀ1). As depicted in Scheme 11, enol 22' is the actual product of
the gas-phase reaction (DDG823 ˆ À22.4 kcal mol-1). Subsequent intramolecular
Scheme 11. DFT-Calculated Relative DG873 Values (in kcal molÀ1) for the Proposed Transition State G and the
Product 22'

Helvetica Chimica Acta Vol. 87 (2004)
1981
tautomerization providing hexahydroindenone 22 occurs then in the condensed phase
at low temperatures. The DFT-calculated structures of both the oxy-Cope transition
state G and enol 22' are displayed in Fig. 4.
Fig. 4. DFT-Calculated structures oftransition state G and enol 22' (interatomic distances in ä)
Both a retro-DielsÀAlder (DG8=23 ˆ 24.9 kcal molÀ1) and a retro-ene reaction
(DG=823 ˆ 29.5 kcal molÀ1) leading to 23 and 24, respectively, were found to require
higher activation energies. To approximately determine the activation energy for the
homolytic cleavage of the C(1)ÀC(2) bond in 6b to a hydroxyallyl radical on one side
of the chain and a trisubstituted allyl diradical on the other, we used dissociation
energy-values of similar compounds reported in the literature. However, the bond-
dissociation energies are generally reduced with increasing substitution of one or both
of the bond-breaking centers. Thereby, the contribution of p-substituents adjacent to
this center is by far the most important due to resonance-stabilizing effects. Taking an
average, unactivated CÀC single bond (ca. 83 kcal molÀ1) and subtracting the radical-
stabilization-energy values of a hydroxyallyl radical (ca. 15 kcal molÀ1), a trisubstituted
allyl radical (ca. 15 kcal molÀ1), and some ring strain (ca. 5 kcal molÀ1) being released
upon ring opening, the activation energy is estimated to be in the range of 48 kcal
molÀ1. Hence, a diradical-mediated mechanism is energetically clearly disfavored in
comparison to the symmetry-allowed concerted reactions.
Finally, pyrolysis of 5,6-dehydro-2-isopropylisoborneol (6c) in the range of 450
6508 produced isopropyl methyl ketone in moderate yields (30 50%), accompanied by
a large number of low-boiling side products. In contrast to the phenyl group in 6a, the
radical-stabilization energy provided by the i-Pr group is too small to be in accordance
with the formation of a diradical intermediate, but is consistent with a concerted retro-
DielsÀAlder reaction. Apparently, the additional CˆC bond in 5,6-dehydroisoborneol
substrates not only affects the radical-stabilization energy by means of lowering the

1982
Helvetica Chimica Acta Vol. 87 (2004)
activation energy for the intramolecular H-transfer reactions, but also enables
competing concerted pericyclic processes such as retro-DielsÀAlder reactions and
oxy-Cope rearrangements.
3. Conclusions. We have demonstrated that the concept of the −cleavage of the
weakest single bond× can be extended to loco- and stereoselective ring-opening
reactions. Easily available monoterpene substrates were thermally isomerized under
DGPTI conditions to optically pure monocyclic compounds that can be used as chiral
building blocks in terpenoid synthesis or further transformed to valuable odorant
molecules by regioselective BaeyerÀVilliger oxidation. The reaction pathway passes
either through diradical intermediates or concerted processes, depending on the
substrate framework and the nature of the substituents.
The authors are indebted to the Swiss National Science Foundation for financial support and to the
analytical department of our institute for specific NMR measurements and elemental analyses. Thanks are due
to Dr. D. Laikov for DFT calculations and for lively discussions.
Experimental Part
1. General. See [29].
2. Monoterpene Substrates. 2.1. Arylisoborneols 7a 7d. General Procedure (GP 1) for Grignard Addition.
A 0.5m soln. of aryl magnesium bromide was prepared by treating a suspension of Mg (0.843 g, 34.68 mmol) in
anh. THF (63 ml) with the corresponding aryl bromide (31.53 mmol) at r.t. In a separate flask, (‡)-camphor
(4.0 g, 26.27 mmol) was added with stirring to a suspension of CeCl3 (0.8 1.2 equiv.) in anh. THF (100 ml) at r.t.
Stirring was continued for 0.5 2 h, after which the initially yellowish-colored suspension became homogenous
and yogurt-like. To this mixture, the freshly prepared ArMgBr soln. was added by cannula at r.t., while the
temperature rose to 458. Stirring was continued for 0.5 2 h at r.t., and the conversion of the reaction was
monitored by TLC and GC (normally more than 95% consumption after 20 min). The resulting ivory-colored
suspension was then poured into a separatory funnel containing crushed ice, H2O (500 ml), and Et2O (200 ml).
A 10% aq. HCl soln. was added with stirring until the mixture became clear (pH < 3). The org. layer was washed
twice with H2O. The aq. layers were extracted with Et2O (3 Â 50 ml). The combined org. layers were washed
with sat. aq. NaHCO3 and with brine, dried (MgSO4), filtered, and evaporated under reduced pressure.
2.1.1. (1R,2S,4R)-1,7,7-Trimethyl-2-phenylbicyclo[2.2.1]heptan-2-ol (1a). GP 1, with 1.2 equiv. of CeCl3.
The crude product was purified by CC (hexane/AcOEt 30 :1) to give 1a (5.75 g, 95%). Colorless oil. [a]D23
ˆ
À29.6 (c ˆ 0.52, MeOH). IR (film): 3060m, 2958vs, 2871vs, 1495m, 1482s, 1458s, 1389m, 1297m, 1146w, 1111m,
1080m, 1059s, 1016m, 966s, 906m, 860m, 761vs, 703vs. 1H-NMR (300 MHz, CDCl3): 7.54 (A of AA'BB'C, Ho of
Ph); 7.33 (B of AA'BB'C, Hm of Ph); 7.25 (C of AA'BB'C, Hp of Ph); 2.33 (d, 2J(3endo,3exo) ˆ 14.0, HendoÀC(3));
2.19 (dt, 2J(3exo,3endo) ˆ 14.0, 3J(3exo,4) ˆ 4.0, HexoÀC(3)); 1.91 (t, 3J ˆ 4.0, HÀC(4)); 1.75 1.64 (m, OH ,
HexoÀC(5)); 1.28 (s, MeÀC(1)); 1.25 1.11 (m, 2 H); 0.91 (s, Me2C(7)); 0.86 0.79 (m, HendoÀC(6)).
13C-NMR (75 MHz, CDCl3): 146.0 (s, Cipso of Ph); 127.5 (d, Co of Ph); 126.7, 126.6 (2d, Cm/p of Ph); 83.5
(s, C(2)); 53.8 (s, C(1)); 50.4 (s, C(7)); 45.5 (d, C(4)); 45.4 (t, C(3)); 31.1 (t, C(6)); 26.5 (t, C(5)); 21.6
.
.
.
‡
‡
‡
(q, Me2C(7)); 9.7 (q, MeÀC(1)). EI-MS: 230 (2, M ), 212 (100, [M À H2O] ), 196 (2), 153 (4, [M À Ph] ),
120 (8), 105 (12), 95 (20).
2.1.2. (1R,2S,4R)-1,7,7-Trimethyl-2-(4-methylphenyl)bicyclo[2.2.1]heptan-2-ol 1b). GP 1, with 1.2 equiv. of
CeCl3. The crude product was purified by CC (hexane/AcOEt 30 :1) to give 1b (5.91 g, 92%). Colorless oil.
[a]2D3 ˆ À17.4 (c ˆ 0.77, MeOH). IR (film): 3557m, 3473m, 3023m, 2954vs, 1511m, 1481m, 1458vs, 1388s, 1368s,
1
1214m, 1106m, 1063vs, 1017m, 946s, 821s, 806s, 787m. H-NMR (300 MHz, CDCl3): 7.41 (A of AA'BB', Ho of
Ar); 7.33 (B of AA'BB', Hm of Ar); 2.33 (s, 4'-Me); 2.28 (d, 2J(3endo,3exo) ˆ 13.8, HendoÀC(3)); 2.17
(dt, 2J(3exo,3endo) ˆ 13.8, 3J(3exo,4) ˆ 4.0, HexoÀC(3)); 1.87 (t, 3J ˆ 4.0, HÀC(4)); 1.75 1.67 (m, 2 H ); 1.26
(s, MeÀC(1); 1.25 1.09 (m, OH , HexoÀC(5)); 0.90 (s, Me2C(7)); 0.87 0.80 (m, HendoÀC(6)). 13C-NMR
(75 MHz, CDCl3): 143.2 (s, Cp of Ar); 136.2 (s, Cipso of Ar); 128.2, 126.6 (2d, Co/p of Ar); 83.4 (s, C(2)); 53.3
(s, C(1)); 50.3 (s, C(7)); 45.6 (d, C(4)); 45.4 (t, C(3)); 31.2 (t, C(6)); 26.5 (t, C(5)); 21.6 (2q, Me2C(7)); 20.8 (q, 4'-

Helvetica Chimica Acta Vol. 87 (2004)
1983
.
.
‡
‡
Me); 9.8 (q, MeÀC(1)). EI-MS: 244 (1, M ), 226 (100, [M À H2O] ), 198 (1), 172 (2), 156 (2), 136 (3, [M À
.
‡
ArÀ H] ), 120 (9), 108 (5), 95 (2).
2.1.3. (1R,2S,4R)-2-(4-Methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (1c). GP 1, with 1.0 equiv.
of CeCl3. The crude product was crystallized from hexane/AcOEt 40 :1 to afford 1c (6.02 g, 88%). Slightly
reddish solid. M.p. 92 948. [a]2D3 ˆ À19.5 (c ˆ 0.50, MeOH). IR (KBr): 3473vs, 2926vs, 1605s, 1509vs, 1460vs,
1388m, 1369m, 1300s, 1242vs, 1183vs, 1106w, 1062s, 1017s, 976m, 963m, 834s. 1H-NMR (300 MHz, CDCl3): 7.43
(A of AA'BB', 2 H); 6.85 (B of AA'BB', 2 H); 3.80 (s, MeO); 2.27 (d, 2J(3endo,3exo) ˆ 13.8, HendoÀC(3)); 2.16
(dt, 2J(3exo,3endo) ˆ 13.8, 3J(3exo,4) ˆ 4.0, HexoÀC(3)); 1.88 (t, 3J ˆ 4.0, HÀC(4)); 1.80 1.68 (m, OH , HexoÀC(5));
1.26 (s, MeÀC(1); 1.23 1.09 (m, 2 H ); 0.903 (s, MeantiÀC(7)); 0.897 (s, MesynÀC(7)); 0.87 0.80
(m, HendoÀC(6)). 13C-NMR (75 MHz, CDCl3): 158.3 (s, Cp of Ar); 138.3 (s, Cipso of Ar); 127.7 (d, Co of Ar);
112.7 (d, Cm of Ar); 82.2 (s, C(2)); 55.2 (q, MeO); 53.4 (s, C(1)); 50.2 (s, C(7)); 45.5 (d, C(4)); 45.5 (t, C(3)); 31.2
.
‡
(t, C(6)); 26.5 (t, C(5)); 21.6, 21.5 (2q, Me2C(7)); 9.8 (q, MeÀC(1)). EI-MS: 260 (3, M ), 242 (100, [M À
.
.
‡
‡
H2O] ), 153 (4, [M À ArÀ H] ), 134 (8), 109 (6), 95 (4).
2.1.4. (1R,2S,4R)-1,7,7-Trimethyl-2-[4-(trifluormethyl)phenyl]bicyclo[2.2.1]heptan-2-ol (1d). GP 1, with
0.8 equiv. of CeCl3. The crude product was purified by CC (hexane/AcOEt 20 :1) to give 1d (7.68 g, 98%).
Colorless oil. [a]2D3 ˆ À21.2 (c ˆ 2.16, hexane). IR (film): 3605w, 3470m, 3021m, 2959vs, 2879s, 1618s, 1459s,
1408s, 1372s, 1330vs, 1249s, 1168vs, 1128vs, 1071vs, 969s, 852s, 836vs. 1H-NMR (600 MHz, CDCl3): 7.64
(d, 3J(o,m) ˆ 8.5, Ho of Ar); 7.56 (d, 3J(m,o) ˆ 8.5, Hm of Ar); 2.30 (d, 2J(3endo,3exo) ˆ 14.0, HendoÀC(3)); 2.20
(dt, 2J(3exo,3endo) ˆ 14.0, 3J(3exo,4) ˆ 4.1, HexoÀC(3)); 1.93 (t, 3J ˆ 4.1, HÀC(4)); 1.87 (br. s, OH); 1.80 1.73
(m, HexoÀC(5)); 1.27 (s, MeÀC(1)); 1.25 1.18 (m, 2 H); 0.92 (s, MeantiÀC(7)); 0.90 (s, MesynÀC(7)); 0.80 0.74
(m, HendoÀC(6)). 13C-NMR (150 MHz, CDCl3): 150.0 (s, Cipso of Ar); 128.9 (q, 2J(Cp,F) ˆ 32.1, Cp of Ar); 127.1
(d, Co of Ar), 124.3 (q, 3J(Cm,F) ˆ 3.8, Cm of Ar); 124.2 (q, 1J(C,F) ˆ 270.2, F3C); 83.3 (s, C(2)); 53.5 (s, C(1));
50.5 (s, C(7)); 45.6 (t, C(3)); 45.5 (d, C(4)); 31.0 (t, C(6)); 26.4 (t, C(5)); 21.4 (q, Me2C(7)); 9.5 (q, MeÀC(1)).
.
.
‡
‡
‡
EI-MS: 298 (1, M ), 280 (5, [M À H2O] ), 237 (21), 188 (25), 172 (46), 145 (48, (F3C)C6H4 ), 127 (35), 109
(100), 95 (87), 77 (33), 67 (41), 55 (45).
2.2. (1R,2S,4R)-2-Ethenyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (1e). To a stirred suspension of anh.
CeCl3 (4.86 g, 19.7 mmol) in anh. THF (80 ml) was added (‡)-camphor (2.5 g, 16.4 mmol) at r.t. After stirring
for 2 h at r.t., the suspension became homogenous and yogurt-like. To this mixture, a 1m soln. of vinyl magnesium
bromide (32.8 ml, 32.8 mmol) was added at r.t. Workup in the usual fashion followed by CC (hexane/AcOEt
30 :1) provided 1e (2.25 g, 76%). Colorless oil. [a]D23 ˆ À46.3 (c ˆ 1.0, MeOH). IR (film): 3038m, 2960vs, 2871vs,
1495m, 1480s, 1450m, 1389m, 1293m, 1146w, 1111m, 1088m, 1076s, 1021m, 906m, 869m, 761m. 1H-NMR
(300 MHz, CDCl3): 6.03 (dd, 3Jtrans ˆ 17.3, 3Jcis ˆ 10.7, HÀC(1')); 5.23 (dd, 3Jtrans ˆ 17.3, 2J ˆ 1.2, HtransÀC(2')); 5.07
(dd, 3Jcis ˆ 10.7, 2J ˆ 1.2, HcisÀC(2')); 2.01 (dt, 2J(3exo,3endo) ˆ 13.3, 3J(3exo,4) ˆ 4.5, HexoÀC(3)); 1.77 (t, 3J ˆ 4.5,
HÀC(4)); (d, 2J(3endo,3exo) ˆ 13.3, HendoÀC(3)); 1.64 (br. s, OH); 1.37 1.32 (m, 1 H); 1.15 (q, MeÀC(1)); 1.07
0.89 (m, 3 H); 0.87, 0.83 (2q, Me2C(7)). 13C-NMR (75 MHz, CDCl3): 143.7 (d, C(1')); 112.0 (t, C(2')); 81.4
(s, C(2)); 52.5 (s, C(1)); 49.0 (s, C(7)); 45.4 (d, C(4)); 44.6 (t, C(3)); 31.1 (t, C(6)); 27.0 (t, C(5)); 21.2, 20.8
.
‡
(2q, Me2C(7)); 9.6 (q, MeÀC(1)). EI-MS: 180 (4, M ), 110 (12), 95 (100), 77 (45), 55 (12).
2.3. O-Deuteration ofIsoborneol 1a. To a soln. of 1a (1.15 g, 4.99 mmol) in MeOD (5 ml), D2O (0.1 ml) was
added, and the soln. was stirred at 408 for 30 min, after which the solvent was evaporated under reduced
pressure. This procedure was repeated two more times. The O-deuterated phenylisoborneol [O-2H]-1a was
obtained in quant. yield.
2.4. (1S,4R,6S)-6-Bromo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4). A mixture of chlorosulfonic acid
(40 ml) and (‡)-3-endo-bromocamphor (3) (10.0 g, 43.2 mmol) was placed in a three-neck round-bottom flask
and stirred at 458 for 20 min, after which the starting material had been entirely consumed (GC analysis). The
resulting dark suspension was then carefully poured onto ice (500 g). After extraction with Et2O (3 Â 100 ml),
the combined org. layers were washed once each with sat. aq. NaHCO3 soln., H2O, and brine. The org. phase was
dried (MgSO4), filtered, and evaporated under reduced pressure to afford a dark brown solid, which was
recrystallized from hexane to give 4 (4.10 g, 42%). Colorless prisms. M.p. 129 1318. [a]2D3 ˆ À9.4 (c ˆ 1.0,
CH2Cl2). IR (film): 2970vs, 2932vs, 1746vs, 1458s, 1430s, 1324m, 1170m, 1054s, 1010s, 916s, 857m, 793s, 763s,
735m, 635m. 1H-NMR (300 MHz, CDCl3): 4.22 (dd, 3J(6,5exo) ˆ 10.2, 3J(6,5endo) ˆ 3.3, HÀC(6)); 2.84
(dddd, 2J(5exo,5endo) ˆ 15.1, 3J(5exo,6) ˆ 10.2, 3J(5exo,4) ˆ 4.3, 4J(5exo,3endo) ˆ 3.6, HexoÀC(5)); 2.45 (br. td,
2J(3exo,3endo) ˆ 18.5, 3J(3exo,4) ˆ 3.6, HexoÀC(3)); 2.22 (dd, 3J(4,5exo) ˆ 4.3, 3J(4,3exo) ˆ 3.6, HÀC(4)); 2.04
(d, 2J(3endo,3exo) ˆ 18.5, HendoÀC(3)); 1.89 (dd, 2J(5endo,5exo) ˆ 15.1, 3J(5endo,6) ˆ 3.3, HendoÀC(5)); 1.00 (s, Me);
0.97 (s, Me); 0.91 (s, Me). 13C-NMR (75 MHz, CDCl3): 213.9 (s, C(2)); 71.1 (s, C(1)); 50.9 (d, C(4)); 47.8
(s, C(7)); 42.7 (t, C(3)); 42.3 (d, C(6)); 39.9 (t, C(5)); 20.9 (q, Me); 19.2 (q, Me); 7.5 (q, Me). EI-MS: 230 (5,
.
.
‡
‡
M
), 175 (18), 151 (75, [M À HBr] ), 109 (100), 93 (26), 81 (31), 67 (19), 53 (9).

1984
Helvetica Chimica Acta Vol. 87 (2004)
2.5. (1S,4R)-1,7,7-Trimethylbicyclo[2.2.1]hept-5-en-2-one (ˆ( ‡ )-5,6-Dehydrocamphor; 2). A soln. of 4
(4.0 g, 17.32 mmol) and KOH(4.82 g, 86.5 mmol) in a mixture of DMSO (160 ml) and H 2O (24 ml) was heated
at 1208 for 2.5 h under vigorous stirring. The resulting orange soln. was allowed to cool to r.t., and H2O (100 ml)
was added. After extraction with Et2O (3 Â 100 ml) the combined org. layers were washed with brine, dried
(MgSO4), filtered, and evaporated under reduced pressure to afford crude 2 as a highly volatile orange oil.
Purification by CC (pentane/Et2O 20 :1) provided 2 (1.18 g, 45%). Colorless oil. [a]2D3 ˆ ‡718 (c ˆ 0.6, CH2Cl2).
IR (film): 3066w, 2968vs, 2873vs, 1735vs, 1467s, 1447vs, 1380m, 1291m, 1150m, 1111s, 1029s, 982m, 853m.
1H-NMR (300 MHz, CDCl3): 6.48 (dd, 3J(5,6) ˆ 5.4, 3J(5,4) ˆ 2.0, HÀC(5)); 5.58 (d, 3J(6,5) ˆ 5.4, HÀC(6));
2.68 (br. s, HÀC(4)); 2.21 (ddd, 2J(3exo,3endo) ˆ 16.7, 3J(3exo,4) ˆ 3.4, 3J(3exo,5) ˆ 1.0, HexoÀC(3)); 1.93
(d, 2J(3endo,3exo) ˆ 16.7, HendoÀC(3)); 1.21 (s, Me); 1.07 (s, Me); 1.01 (s, Me). 13C-NMR (75 MHz, CDCl3):
216.8 (s, C(2)); 142.6 (d, C(5)); 133.5 (d, C(6)); 65.7 (d, C(4)); 65.2 (s, C(1)); 60.7 (s, C(7)); 48.7 (t, C(3)); 19.6
.
‡
(q, Me); 19.2 (q, Me); 6.8 (q, Me). EI-MS: 150 (12, M ), 108 (100), 93 (75), 77 (26), 65 (18), 53 (14).
2.6. (1S,2R,4R)-1,7,7-Trimethyl-2-phenylbicyclo[2.2.1]hept-5-en-2-ol (6a). To a stirred suspension of anh.
CeCl3 (0.79 g, 3.2 mmol) in anh. THF (30 ml), (‡)-5,6-dehydrocamphor (2; 2.40 g, 16.0 mmol) was added at r.t.
Stirring was continued for 1 h, after which a 1m soln. of PhMgBr (32 ml, 32 mmol) was added at r.t. Workup in
the usual fashion followed by CC (hexane/AcOEt 30 :1) provided 6a (3.51 g, 93%). Slightly yellow oil [a]D23
ˆ
‡93.8 (c ˆ 1.5, CH2Cl2). IR (film): 3448s, 3087w, 3056s, 3025s, 2954vs, 2871vs, 1596m, 1492s, 1470s, 1444vs,
1389vs, 1365s, 1225s, 1154s, 1120s, 1012s, 906s, 755vs, 732vs, 702vs. 1H-NMR (600 MHz, CDCl3): 7.37 (A of
AA'BB'C, Ho of Ph); 7.24 (B of AA'BB'C, Hm of Ph); 7.19 (C of AA'BB'C, Hp of Ph); 6.09 (dd, 3J(5,6) ˆ 5.7,
3J(5,4) ˆ 3.2, HÀC(5)); 5.11 (d, 3J(6,5) ˆ 5.7, HÀC(6)); 2.54 (br. t, 3J(4,5) ˆ 3J(4,3exo) ˆ 3.2, HÀC(4)); 2.36
(dd, 2J(3exo,3endo) ˆ 13.1, 3J(3exo,4) ˆ 3.2, HexoÀC(3)); 2.27 (d, 2J(3endo,3exo) ˆ 13.1, HendoÀC(3)); 1.86 (s, OH); 1.31
(s, MesynÀC(7)); 1.03 (s, MeÀC(1)); 0.96 (s, MeantiÀC(7)). 13C-NMR (150 MHz, CDCl3): 146.9 (s, Cipso of Ph);
139.8 (d, C(5)); 135.7 (d, C(6)); 128.1, 127.1 (2d, Co/m of Ph); 126.4 (d, Cp of Ph); 83.5 (s, C(2)); 61.1, 60.8
.
‡
(2s, C(1,7)); 52.3 (d, C(4)); 42.3 (t, C(3)); 22.6, 21.8 (2q, Me2C(7)); 7.5 (q, MeÀC(1)). EI-MS: 228 (1, M ), 108
(100, retro-DielsÀAlder), 93 (71), 77 (16).
2.7. (1S,2R,4R)-2-Ethenyl-1,7,7-trimethylbicyclo[2.2.1]hept-5-en-2-ol (6b). To a stirred suspension of anh.
CeCl3 (0.36 g, 1.46 mmol) in anh. THF (10 ml) was added 2 (1.10 g, 7.32 mmol) at r.t. Stirring was continued for
30 min, after which a 1m soln. of vinyl magnesium bromide (14.6 ml, 14.6 mmol) was added via syringe at r.t.
Workup in the usual fashion followed by CC (hexane/AcOEt 20 :1) provided 6b (1.25 g, 96%). Colorless oil.
[a]2D3 ˆ ‡69.5 (c ˆ 1.75, CH2Cl2). IR (film): 3598m, 3060w, 3024w, 2965vs, 2872vs, 1452m, 1387m, 1326w, 1214w,
1118w, 1062m, 1009m, 891s, 745m. 1H-NMR (600 MHz, CDCl3): 6.01 (dd, 3J(5,6) ˆ 5.8, 3J(5,4) ˆ 3.2, HÀC(5));
3
5.84 (dd, 3Jtrans ˆ 17.3, Jcis ˆ 10.7, HÀC(1')); 5.62 (d, 3J(6,5) ˆ 5.8, HÀC(6)); 5.15 (dd, 3Jtrans ˆ 17.3, 2J ˆ 1.1,
HtransÀC(2')); 5.00 (dd, 3Jcis ˆ 10.7, 2J ˆ 1.1, HcisÀC(2')); 2.42 (br. t, 3J(4,5) ˆ 3J(4,3exo) ˆ 3.2, HÀC(4)); 2.15
(dd, 2J(3exo,3endo) ˆ 12.7, 3J(3exo,4) ˆ 3.2, HexoÀC(3)); 1.61 (d, 2J(3endo,3exo) ˆ 12.7, HendoÀC(3)); 1.60 (s, OH); 1.19
(s, MesynÀC(7)); 0.94 (s, MeantiÀC(7)); 0.92 (s, MeÀC(1)). 13C-NMR (150 MHz, CDCl3): 146.3 (d, C(1')); 139.8
(d, C(5)); 136.1 (d, C(6)); 111.9 (t, C(2')); 83.4 (s, C(2)); 60.8, 60.1 (2s, C(1,7)); 52.0 (d, C(4)); 41.3 (t, C(3));
.
‡
22.3, 21.8 (2q, Me2C(7)); 7.3 (q, MeÀC(1)). EI-MS: 178 (2, M ), 108 (100, retro-DielsÀAlder), 93 (95), 77 (12),
55 (11).
2.8. (1S,2R,4R)-1,7,7-Trimethyl-2-(1-methylethyl)bicyclo[2.2.1]hept-5-en-2-ol (6c). To a stirred suspension
of anh. CeCl3 (0.17 g, 0.68 mmol) in anh. THF (5 ml) was added 2 (0.52 g, 3.43 mmol) at r.t. Stirring was
continued for 30 min, after which a 2m soln. of i-PrMgCl (3.42 ml, 6.84 mmol) was added via syringe at r.t.
Workup in the usual fashion followed by CC (hexane/AcOEt 30 :1) provided 6c (0.62 g, 93%). Colorless oil.
[a]2D3 ˆ ‡28.1 (c ˆ 1.3, CH2Cl2). IR (film): 3523m, 2956vs, 2874vs, 1473s, 1386s, 1365s, 1267m, 1209m, 1100m,
1
1039m, 1004s, 954w, 926m, 905m, 858w, 742s, 715s, 650m. H-NMR (300 MHz, CDCl3): 5.88 (dd, 3J(5,6) ˆ 5.8,
J ˆ 3.1, HÀC(5)); 5.73 (d, 3J(6,5) ˆ 5.8, HÀC(6)); 2.26 (br. t, J ˆ 3.2, HÀC(4)); 1.92 (dd, 2J(3exo,3endo) ˆ 12.5, J ˆ
3.7, HexoÀC(3)); 1.62 (sept., J ˆ 6.9, Me2CH); 1.36 (s, OH); 1.33 (d, 2J(3endo,3exo) ˆ 12.5, HendoÀC(3)); 1.04
(s, MesynÀC(7)); 0.98 (s, MeantiÀC(7)); 0.83 (s, MeÀC(1)); 0.81, 0.80 (2d, J ˆ 6.9, Me2CH). 13C-NMR (75 MHz,
CDCl3): 138.8 (d, C(5)); 135.9 (d, C(6)); 84.9 (s, C(2)); 61.1, 60.1 (2s, C(1,7)); 50.9 (d, C(4)); 40.4 (t, C(3)); 38.0
.
‡
(d, Me2CH); 22.3, 21.4 (2q, Me2C(7)); 18.0, 17.7 (2q, Me2CH); 9.7 (q, MeÀC(1)). EI-MS: 194 (2, M ), 151 (2),
121 (3), 108 (100, retro-DielsÀAlder), 93 (81), 77 (5).
3. Thermal Isomerization Reactions and Derivatizations. 3.1. General Procedure (GP 2) for DGPTI of
1a 1e, and 6a and 6b. The thermo-isomerization device consisted of an electrically heatable tube furnace (1 m),
a condenser unit with a cooling trap at the outlet side, and a Kugelrohr oven as the evaporation unit at the inlet
side. A quartz tube (110-cm long, 2.5 cm i.d.), which fitted into the furnace, was connected to a trap (cooled with
liquid N2) on one side and to a bulb placed in the Kugelrohr oven on the other. The starting material (typically
2 g) was placed in the bulb equipped with a capillary inlet device for the inert gas (N2) flow and a magnetic

Helvetica Chimica Acta Vol. 87 (2004)
1985
stirrer. After evacuation of the apparatus with a high-vacuum oil pump, the starting material was directly
distilled through the preheated reactor tube (1 3 g/h). After all of the starting material had been distilled, the
apparatus was vented, and the frozen products were transferred to a bulb using Et2O as solvent. The resulting
soln. was dried (MgSO4) and evaporated under reduced pressure. The following parameters are typical for
DGPTI of isoborneol and dehydroisoborneol substrates 1a 1e, and 6a and 6b, respectively: i) the Kugelrohr
oven was heated to 80 1308; ii) a flow of N2 was adjusted from 0.8 1.4 l/h; iii) the reactor tube was heated up to
450 7508; iv) the high vacuum was adjusted at 2 4 Â 10À2 mbar.
3.1.1. 2-[(1R,3S)-(2,2,3-Trimethylcyclopent-1-yl)]-1-phenylethan-1-one (7a). Following GP 2, 1a (2.0 g,
8.68 mmol) was thermo-isomerized at 6308. The dark-yellow crude product was purified by CC (hexane/AcOEt
20 :1) to give 7a (1.46 g, 73%). Slightly yellow oil. [a]2D3 ˆ ‡54.7 (c ˆ 0.6, MeOH). IR (film): 3060w, 3027w,
2958vs, 2871s, 1687vs, 1598m, 1580m, 1448s, 1366m, 1285m, 1215m, 1180m, 1016m, 1002m, 752s, 690s. 1H-NMR
(600 MHz, CDCl3): 7.95 (dd, 3J(o,m) ˆ 8.1, 4J(o,p) ˆ 1.4, Ho of Ph); 7.54 (tt, 3J(p,m) ˆ 7.4, 4J(p,o) ˆ 1.4, Hp of
Ph); 7.45 (t, J ˆ 8.1, Hm of Ph); 3.03 (A of ABX, 2JAB ˆ 16.2, 3J ˆ 4.0, HaÀC(2)); 2.73 (B of ABX, 2JAB ˆ 16.2, 3J ˆ
10.4, HbÀC(2)); 2.20 (mc, HÀC(1')); 1.93 (mc, HendoÀC(5')); 1.85 (mc, HexoÀC(4')); 1.66 (sext., 3J ˆ 7.1,
HÀC(3')); 1.25 1.20 (m, HendoÀC(4'), HexoÀC(5')); 0.89 (s, MeendoÀC(2')); 0.88 (s, MeexoÀC(2')); 0.86
(d, 3J ˆ 7.1, Me ÀC(3')). 13C-NMR (150 MHz, CDCl3): 201.1 (s, C(1)); 137.6 (s, Cipso of Ph); 133.0 (d, Cp of
Ph); 128.7 (d, Cm of Ph); 128.3 (d, Co of Ph); 44.3 (d, C(1')); 43.7 (d, C(3')); 42.4 (s, C(2')); 40.7 (t, C(2)); 31.6
(t, C(4')); 29.7 (t, C(5')); 24.4 (q, MeexoÀC(2')); 23.8 (q, MeendoÀC(2')); 16.5 (q, MeÀC(3')). EI-MS: 230 (12,
.
.
.
‡
‡
‡
M
), 221 (2), 187 (1), 173 (45), 145 (7), 120 (82, [M À COPh] ), 105 (100, [M À PhAc] ), 95 (23), 77 (30), 69
(11). Anal. calc. for C16H22O (230.35): C 83.43, H9.63; found: C 83.31, H9.62.
3.1.2. 1-(4-Methylphenyl)-2-((1R,3S)-2,2,3-trimethylcyclopent-1-yl)ethan-1-one (7b). Following GP 2, 1b
(1.25 g, 5.11 mmol) was thermo-isomerized at 6208. The orange crude product was purified by CC (hexane/
AcOEt 30 :1) to give 7b (0.56 g, 45%). Colorless oil. [a]2D3 ˆ ‡53.2 (c ˆ 0.6, hexane). IR (film): 3031m, 2958vs,
2872vs, 1682vs, 1608vs, 1451s, 1366s, 1289vs, 1224s, 1181vs, 1016m, 806s. 1H-NMR (300 MHz, CDCl3): 7.85 (A of
AA'BB', Ho of Ar); 7.25 (B of AA'BB', Hm of Ar); 3.00 (A of ABX, 2JAB ˆ 15.4, 3J ˆ 4.0, HaÀC(2)); 2.70 (B of
2
ABX, JAB ˆ 15.4, 3J ˆ 10.4, HbÀC(2)); 2.41 (s, p-Me); 2.18 (mc, HÀC(1')); 1.95 1.80 (m, HexoÀC(4'),
HendoÀC(5')); 1.65 (sext., 3J ˆ 7.1, H ÀC(3')); 1.28 1.14 (m, HendoÀC(4'), HexoÀC(5')); 0.89 (s, MeendoÀC(2'));
0.87 (s, MeexoÀC(2')); 0.86 (d, 3J ˆ 7.0, MeÀC(3')). 13C-NMR (75 MHz, CDCl3): 200.5 (s, C(1)); 143.4 (s, Cp of
Ar); 134.9 (s, Cipso of Ar); 129.1 (d, Cm of Ar); 128.1 (d, Co of Ar); 44.2 (d, C(1')); 43.4 (d, C(3')); 42.1 (s, C(2'));
40.3 (t, C(2)); 31.3 (t, C(4')); 29.4 (t, C(5')); 24.1 (q, MeexoÀC(2')); 23.5 (q, MeendoÀC(2')); 21.4 (q, p-Me); 16.2
.
.
.
‡
‡
‡
(q, MeÀC(3')). EI-MS: 244 (4, M ), 187 (12), 173 (2), 134 (91, ArAc ), 119 (100, COAr ), 91 (25).
3.1.3. 1-(4-Methoxyphenyl)-2-[(1R,3S)-2,2,3-trimethylcyclopent-1-yl)]ethan-1-one (7c). Following GP 2, 1c
(1.86 g, 7.14 mmol) was thermo-isomerized at 6108. The dark-yellow crude product was purified by CC (hexane/
AcOEt 30 :1) to give 7c (1.15 g, 62%). Yellow oil. [a]2D3 ˆ ‡50.0 (c ˆ 0.32, hexane). IR (film): 2966s, 2872s,
1677vs, 1601vs, 1510vs, 1418s, 1365s, 1259vs, 1170vs, 1032s, 829s. 1H-NMR (300 MHz, CDCl3): 7.94 (A of AA'BB',
Ho of Ph); 6.93 (B of AA'BB', Hm of Ph); 3.86 (s, MeO); 2.97 (A of ABX, 2JAB ˆ 15.3, 3J ˆ 4.0, HaÀC(2)); 2.67 (B
2
of ABX, JAB ˆ 15.3, 3J ˆ 10.4, HbÀC(2)); 2.18 (mc, HÀC(1')); 1.95 1.80 (m, HexoÀC(4'), HendoÀC(5')); 1.65
(sext., 3J ˆ 7.1, H ÀC(3')); 1.28 1.14 (m, HendoÀC(4'), HexoÀC(5')); 0.89 (s, MeendoÀC(2')); 0.87
(s, MeexoÀC(2')); 0.86 (d, 3J ˆ 7.0, MeÀC(3')). 13C-NMR (75 MHz, CDCl3): 199.4 (s, C(1)); 163.2 (s, Cp of
Ar); 130.5 (s, Cipso of Ar); 130.2 (d, Co of Ar); 113.5 (d, Cm of Ar); 55.3 (q, MeO); 44.3 (d, C(1')); 43.4 (d, C(3'));
42.1 (s, C(2')); 40.0 (t, C(2)); 31.3 (t, C(4')); 29.4 (t, C(5')); 24.1 (q, MeexoÀC(2')); 23.5 (q, MeendoÀC(2')); 16.2
.
.
‡
‡
(q, MeÀC(3')). EI-MS: 260 (5, M ), 203 (10), 189 (7), 163 (1), 150 (100), 135 (90), 110 (7, [M À ArAc À H] ),
92 (9), 77 (12), 69 (3), 55 (4).
3.1.4. 1-[(4-Trifluoromethyl)phenyl]-2-[(1R,3S)-1-(2,2,3-trimethylcyclopent-1-yl)]ethan-1-one (7d). Fol-
lowing GP 2, 1d (1.41 g, 4.73 mmol) was thermo-isomerized at 6108. The dark-yellow crude product was
purified by CC (hexane/AcOEt 25 :1) to give 7d (1.0 g, 71%). Colorless oil. [a]2D3 ˆ ‡40.2 (c ˆ 0.6, hexane). IR
(film): 2961vs, 2874s, 1694vs, 1512m, 1470m, 1410s, 1367m, 1325vs, 1289s, 1214m, 1170vs, 1133vs, 1110s, 1067vs,
1016s, 994m, 857m, 825m. 1H-NMR (300 MHz, CDCl3): 8.05 (d, 3J(o,m) ˆ 8.2, Ho of Ar); 7.72 (d, 3J(m,o) ˆ 8.2,
2
3
2
3
Hm of Ar); 3.06 (A of ABX, JAB ˆ 15.9, J ˆ 4.1, HaÀC(2)); 2.75 (B of ABX, JAB ˆ 15.9, J ˆ 10.2, HbÀC(2));
2.18 (mc, HÀC(1')); 1.98 1.82 (m, HexoÀC(4'), HendoÀC(5')); 1.67 (sext., 3J ˆ 7.2, H ÀC(3')); 1.27 1.14
(m, HendoÀC(4'), HexoÀC(5')); 0.89 (s, MeendoÀC(2')); 0.88 (s, MeexoÀC(2')); 0.87 (d, 3J ˆ 7.2, MeÀC(3')).
13C-NMR (75 MHz, CDCl3): 199.7 (s, C(1)); 140.0 (s, Cipso of Ar); 134.0 (q, 2J(Cp,F) ˆ 32.6, Cp of Ar); 128.6
(d, Co of Ar); 125.4 (q, 3J(Cm,F) ˆ 3.5, Cm of Ar); 123.5 (q, 1J(C,F) ˆ 271.2, F3C); 44.0 (d, C(1')); 43.4 (d, C(3'));
42.1 (s, C(2')); 40.7 (t, C(2)); 31.2 (t, C(4')); 29.4 (t, C(5')); 24.1 (q, MeexoÀC(2')); 23.4 (q, MeendoÀC(2')); 16.1
.
‡
(q, MeÀC(3')). EI-MS: 298 (4, M ), 279 (5), 241 (88), 213 (8), 188 (81), 173 (100), 145 (95), 125 (16), (22,

1986
Helvetica Chimica Acta Vol. 87 (2004)
.
.
.
‡
‡
‡
M
), 155 (8), 138 (24), 127 (19), 111 (25, [M À COAr‡ H] )), 110 (76, [M À ArAc] ), 95 (98), 84 (37), 69
(79), 55 (68).
3.1.5. 1-[(R)-(2,2,3-Trimethylcyclopent-3-en-1-yl)]butan-2-one (17a) and 1-[(R)-(2,2-dimethyl-3-methyl-
idenecyclopent-1-yl)]butan-2-one (17b). Following GP 2, 1e (1.25 g, 6.93 mmol) was thermo-isomerized at 6008.
The yellow crude product was purified by CC (hexane/AcOEt 60 :1) to give 17a,b (0.54 g, 43%; 17a/17b 10 :1) as
a colorless oil. The presence of a minor amount of the isomeric butanone 17b was evident from 1H- and
13C-NMR analyses.
Data of 17a. IR (film): 3038w, 2962vs, 2876vs, 1713vs, 1462s, 1440s, 1412s, 1376s, 1364s, 1271m, 1160m, 1114s,
1032m, 988m. 1H-NMR (300 MHz, CDCl3): 5.22 (s, HÀC(4')); 2.53 2.31 (m, 5 H); 2.30 2.19 (m, 1 H); 1.84
1.75 (m, 1 H); 1.60 (mc, MeÀC(3')); 1.06 (t, 3J(4,3) ˆ 7.3, Me(4)); 0.99, 0.77 (2s, Me2C(2')). 13C-NMR (75 MHz,
CDCl3): 211.6 (s, C(2)); 147.7 (s, C(3')); 121.6 (d, C(4')); 46.6 (s, C(2')); 45.4 (d, C(1')); 43.3 (t, C(1)); 36.1
.
‡
(t, C(3)); 35.6 (t, C(1)); 25.4, 19.8 (2q, Me2C(2')); 12.4 (q, MeÀC(3')); 7.7 (q, Me(4)). EI-MS: 180 (2, M ), 108
.
‡
(100, [M À C4H8O] ), 93 (61), 77 (6), 57 (26).
Data of 17b. 13C-NMR (75 MHz, CDCl3): 211.1 (s, C(2)); 161.1 (s, C(3')); 103.3 (t, CH2C(3')); 46.8
(s, C(2')); 43.6 (d, C(1')); 43.0 (t, C(1)); 36.2 (t, C(4')); 30.3 (t, C(3)); 28.3 (t, C(5')); 26.4, 24.0, 23.4 (3q). EI-MS:
.
.
‡
‡
180 (1, M ), 123 (3), 108 (100, [M À C4H8O] ), 93 (54), 81 (10), 67 (7), 57 (49).
3.1.6. 1-Phenyl-2-((1R,4R)-4,5,5-trimethylcyclopent-2-en-1-yl)ethan-1-one (21). Following GP 2, 6a (1.45 g,
6.35 mmol) was thermo-isomerized at 5208. The yellow crude product was purified by CC (hexane/AcOEt 40 :1)
to give a first fraction of nonpolar, volatile side products (0.2 g), followed by 21 (0.26 g, 18%) as a colorless oil,
and acetophenone (20) (0.31 g, 40%). [a]D ˆ À194.2 (c ˆ 1.2, CH2Cl2). IR (film): 3043w, 2961vs, 2870vs, 1686vs,
1596s, 1448vs, 1385m, 1363s, 1316m, 1282s, 1218s, 1180m, 1002s, 917w, 760vs, 690vs. 1H-NMR (600 MHz, CDCl3):
7.95 (A of AA'BB'C, Ho of Ph); 7.55 (C of AA'BB'C, Hp of Ph); 7.45 (B of AA'BB'C, Hm of Ph); 5.95
3
(br. s, HÀC(2'), HÀC(3')); 3.05 (A of ABX, 2JAB ˆ 15.8, J ˆ 4.7, HaÀC(2)); 2.92 (dd, 3J ˆ 10.0, 4.7, HÀC(1'));
2
2.81 (B of ABX, JAB ˆ 15.8, 3J ˆ 10.0, HbÀC(2)); 2.37 (q, 3J ˆ 7.2, HÀC(4')); 0.98, 0.97 (2s, Me2C(5')); 0.91
(d, 3J ˆ 7.4, MeÀC(4')). 13C-NMR (150 MHz, CDCl3): 200.6 (s, C(1)); 137.6 (s, Cipso of Ph); 136.0, 132.4
(2d, C(2',3')); 133.1 (d, Cp of Ph); 128.8 (d, Cm of Ph); 128.3 (d, Co of Ph); 50.4 (d, C(1')); 49.3 (d, C(4')); 42.9
.
‡
(s, C(5')); 38.8 (t, C(2)); 24.6, 24.0 (2q, Me2C(5')); 14.1 (q, MeÀC(4')). EI-MS: 228 (5, M ), 213 (2), 157 (3),
.
‡
108 (63, [M À PhAc] ), 105 (100), 93 (22), 77 (34).
3.1.7. (3aR,7aR)-3,3a,4,6,7,7a-Hexahydro-2,3,3-trimethylinden-5(5H)-one (22). a) Following GP 2, 6b
(0.74 g, 4.15 mmol) was thermo-isomerized at 5508. The temp. of the evaporation unit was adjusted to 808 to
prevent concerted [3,3]-oxy-Cope rearrangements, which may already take place under static conditions above
1208. The yellow crude product was purified by CC (hexane/AcOEt 20 :1) to give 22 (0.69 g, 93%) as a colorless
oil.
b) Alternatively, 6b (0.10 g, 0.56 mmol) was added to a suspension of KH(2.80 mmol) in anh. THF (2 ml) at
r.t. The mixture was stirred for 30 min at r.t., cooled in an ice bath, and then carefully treated with EtOH(1 ml)
via rapid injection. H2O (5 ml) was added, and the resulting slurry was extracted with Et2O (3 Â 10 ml). The
combined org. layers were washed with sat. aq. NH4Cl soln. and brine, dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by CC (hexane/AcOEt 20 :1) to give 22 (80 mg, 80%).
Colorless oil. [a]D23 ˆ À126.7 (c ˆ 1.6, CH2Cl2). IR (film): 3030s, 2958vs, 1718vs, 1461vs, 1436vs, 1385s, 1376s,
1328s, 1269s, 1184vs, 1146s, 1083m, 1040m, 919m, 850s, 822s. 1H-NMR (600 MHz, CDCl3): 5.17 (s, HÀC(1));
2.97 2.92 (m, HÀC(7a)); 2.38 (dd, 3J(4a,4b) ˆ 13.2, 3J(4a,3a) ˆ 8.6, HaÀC(4)); 2.35 2.27 (m, HÀC(3a),
HbÀC(4), HaÀC(6)); 2.22 2.16 (m, HbÀC(6)); 2.01 (dq, 3J(7a,7b) ˆ 13.8, J ˆ 5.5, HaÀC(7)); 1.69 1.63
(m, HbÀC(7)); 1.62 (mc, MeÀC(2)); 1.02 (s, MeexoÀC(3)); 0.93 (s, MeendoÀC(3)). 13C-NMR (150 MHz,
CDCl3): 214.9 (s, C(5)); 147.4 (s, C(2)); 125.6 (d, C(1)); 48.7 (s, C(3)); 47.3 (d, C(3a)); 41.2 (d, C(7a)); 39.8
(t, C(4)); 37.9 (t, C(6)); 28.0 (q, MeexoÀC(3)); 26.5 (t, C(7)); 22.7 (q, MeendoÀC(3)); 12.6 (q, MeÀC(2)). EI-MS:
.
.
‡
‡
178 (23, M ), 163 (100, [M À Me] ), 135 (7), 121 (69), 107 (24), 93 (23), 79 (8), 55 (11).
3.2. 4-Methoxyphenyl (1R,3S)-(2,2,3-Trimethylcyclopent-1-yl)acetate (12). Phenone 7c (0.34 g, 1.31 mmol)
was dissolved in anh. CH2Cl2 (7 ml), and MCPBA (80 85%, 0.59 g, 3.40 mmol) was added. The suspension was
cooled to 08, and TFA (0.1 ml, 1.31 mmol) was added dropwise over 15 min. The reaction flask protected from
light was stirred over night at r.t., whereupon the ketone was completely consumed (GC analysis). The mixture
was diluted with CH2Cl2 (50 ml), washed once each with 10% aq. Na2SO3 soln., sat. aq. K2CO3 soln., and H2O.
The org. phase was dried (MgSO4) and evaporated. The residue was taken up in hexane and filtered over a short
pad of silica gel using hexane/AcOEt 50 :1 to give 12 (0.36 g, 99%). Colorless oil. [a]2D3 ˆ ‡27.5 (c ˆ 1.0,
MeOH). IR (CHCl 3): 2962s, 2874m, 1747s, 1506vs, 1467m, 1368w, 1290w, 1249s, 1195vs, 1145s, 1103m, 1036m.
1H-NMR (300 MHz, CDCl3): 6.98 (A of AA'BB', Ho of Ar); 6.88 (B of AA'BB', Hm of Ar); 3.79 (s, MeO); 2.59
2
2
(A of ABX, JAB ˆ 14.5, 3J ˆ 4.6, HaÀC(2)); 2.30 (B of ABX, JAB ˆ 14.5, 3J ˆ 10.3, HbÀC(2)); 2.15

Helvetica Chimica Acta Vol. 87 (2004)
1987
(mc, HÀC(1')); 2.06 1.95 (m, HendoÀC(5')); 1.92 1.84 (m, HexoÀC(4')); 1.66 (sext., 3J ˆ 7.2, HÀC(3')); 1.43
1.19 (m, HendoÀC(4'), HexoÀC(5')); 0.89 (s, MeendoÀC(2')); 0.87 (s, MeexoÀC(2')). 13C-NMR (75 MHz, CDCl3):
172.8 (s, C(1)); 157.1 (s, Cp of Ar); 144.2 (s, Cipso of Ar); 122.2 (d, Co of Ar); 114.3 (d, Cm of Ar); 55.5 (q, MeO);
44.8 (d, C(1')); 43.4 (d, C(3')); 42.1 (s, C(2')); 36.5 (t, C(2)); 31.2 (t, C(4')); 29.1 (t, C(5')); 23.8 (q, MeexoÀC(2'));
.
‡
23.4 (q, MeendoÀC(2')); 15.9 (q, MeÀC(3')). EI-MS: 276 (3, M ), 219 (1), 153 (1), 135 (1), 124 (100), 109 (14,
.
‡
[M À ArAc] ), 81 (3), 69 (10), 55 (7).
3.3. (1R,3S)-(2,2,3-Trimethylcyclopent-1-yl)acetic Acid (ˆ( ‡ )-trans-a-Campholanic Acid; 9). To a stirred
soln. of 12 (1.27 g, 4.60 mmol) in MeOH(10 ml) at 0 8 was added sat. aq. LiOH(10 ml). The mixture became
immediately dark and cloudy. After stirring for 15 min at r.t., H2O was added, and the soln. was treated with
10% aq. HCl (pH < 3). The resulting mixture was extracted with sat. aq. NaHCO3 soln. (3Â). The aq. layer was
acidified again and extracted with Et2O (3Â). The combined org. layers were washed with brine, dried
(MgSO4), and evaporated to yield 9 (0.76 g, 97%) as a colorless oil. An anal. sample was purified by bulb-to-
bulb distillation. [a]2D3 ˆ ‡40.6 (c ˆ 0.85, hexane). IR (CHCl3): 3517vw, 2961vs, 2874vs, 2680m, 1704vs, 1470m,
1452m, 1412s, 1389m, 1368m, 1296vs, 1230m, 1178w, 1136w. 1H-NMR (300 MHz, CDCl3): 2.43 (A of ABX,
2
2JAB ˆ 14.1, 3J ˆ 3.5, HaÀC(2)); 2.12 (B of ABX, JAB ˆ 14.1, 3J ˆ 10.4, HbÀC(2)); 2.06 1.81 (mc, HÀC(1'),
HexoÀC(4'), HendoÀC(5')); 1.62 (sext., 3J ˆ 7.1, H ÀC(3')); 1.31 1.17 (m, HendoÀC(4'), HexoÀC(5')); 0.86 (d, 3J ˆ
6.9, MeÀC(3')); 0.84 (s, MeendoÀC(2')); 0.81 (s, MeexoÀC(2')). 13C-NMR (75 MHz, CDCl3): 180.6 (s, C(1)); 44.5
(d, C(1')); 43.3 (d, C(3')); 42.0 (s, C(2')); 36.2 (t, C(2)); 31.1 (t, C(4')); 29.1 (t, C(5')); 23.7 (q, MeexoÀC(2')); 23.3
.
.
‡
‡
(q, MeendoÀC(2')); 16.0 (q, MeÀC(3')). EI-MS: 170 (10, M ), 127 (11), 114 (37), 110 (26, [M À AcOH À H] ),
95 (42), 84 (67), 69 (100), 55 (23). Anal. calc. for C10H18O2 (170.25): C 70.55, H10.66; found: C 70.42, H9.53.
3.4. [(1S,3S)-(2,2,3-Trimethylcyclopent-1-yl)]methyl 4-(Trifluoromethyl)benzoate (13). Phenone 7d (0.30 g,
1.0 mmol) was dissolved in anh. CH2Cl2 (5 ml), and MCPBA (80 85%, 0.45 g, 2.6 mmol) was added. The
suspension was cooled to 08, and TFA (77 ml, 1.0 mmol) was added dropwise over 15 min. The mixture,
protected from light, was stirred for 10 d at r.t. Workup as described above, followed by filtration over a short
pad of silica gel with hexane/AcOEt 50 :1, provided 13 (0.28 g, 89%). Colorless oil. [a]2D3 ˆ ‡27.7 (c ˆ 1.0,
hexane). IR (film): 2961s, 2874m, 1725vs, 1469w, 1412m, 1326vs, 1276vs, 1170vs, 1067vs, 1018s, 863m, 776m,
705m. 1H-NMR (300 MHz, CDCl3): 8.14 (d, 3J(o,m) ˆ 8.1, Ho of Ar); 7.70 (d, 3J(m,o) ˆ 8.1, Hm of Ar); 4.39 (A of
2
2
ABX, JAB ˆ 10.9, 3J ˆ 6.5, HaÀC(2)); 4.23 (B of ABX, JAB ˆ 10.9, 3J ˆ 7.5, HbÀC(2)); 2.08 (mc, HÀC(1'));
1.99 1.83 (m, HexoÀC(4'), HendoÀC(5')); 1.68 (sext., 3J ˆ 7.1, H ÀC(3')); 1.35 1.19 (m, HendoÀC(4'),
HexoÀC(5')); 0.96 (s, MeendoÀC(2')); 0.92 (s, MeexoÀC(2')); 0.89 (d, 3J ˆ 7.1, Me ÀC(3')). 13C-NMR (75 MHz,
CDCl3): 165.4 (s, C(1)); 134.4 (s, Cipso of Ar); 133.7 (q, 2J(Cp,F) ˆ 32.2, Cp of Ar); 129.8 (d, Co of Ar); 125.3
(q, 3J(Cm,F) ˆ 3.5, Cm of Ar); 123.7 (q, 1J(C,F) ˆ 271.2, F3C); 67.5 (t, C(2)); 47.3 (d, C(1')); 44.1 (d, C(3')); 41.7
(s, C(2')); 31.4 (t, C(4')); 26.8 (t, C(5')); 24.5 (q, MeexoÀC(2')); 23.6 (q, MeendoÀC(2')); 15.2 (q, MeÀC(3')). EI-
.
.
‡
‡
MS: 314 (1, M ), 295 (6), 258 (3), 231 (3), 211 (1), 173 (100, [COAr ‡ H] ), 145 (43), 124 (40), 109 (56), 95
(18), 82 (42), 69 (43), 55 (16).
3.5. [(1S,3S)-2,2,3-Trimethylcyclopent-1-yl]methanol (11). To a stirred soln. of 13 (1.40 g, 4.45 mmol) in
MeOH(10 ml) was added at 0 8 sat. aq. LiOHsoln. (10 ml). The mixture became immediately dark and cloudy.
After stirring for 30 min at r.t., 2n NaOHsoln. (10 ml) was added, and the mixture was extracted with Et 2O
(3Â). The combined org. layers were washed with brine, dried (MgSO4), and evaporated to afford 11 (0.62 g,
98%). Colorless oil. [a]2D3 ˆ ‡49.9 (c ˆ 0.85, hexane). IR (CHCl3): 3623m, 3469w, 2961vs, 2874vs, 1681s, 1598w,
1581vw, 1469s, 1450s, 1388m, 1367s, 1285m, 1217m, 1181m, 1022s. 1H-NMR (300 MHz, CDCl3): 3.71 (A of ABX,
2
2JAB ˆ 10.4, 3J ˆ 5.7, HaÀC(1)); 3.44 (B of ABX, JAB ˆ 10.4, 3J ˆ 8.2, HbÀC(1)); 1.91 1.73 (m, HÀC(1'),
HexoÀC(4'), HendoÀC(5')); 1.65 (sext., 3J ˆ 7.0, H ÀC(3')); 1.53 (br. s, OH ); 1.46 1.16 (m, HendoÀC(4'),
HexoÀC(5')); 0.87 (s, MeendoÀC(2')); 0.85 (d, 3J ˆ 7.0, MeÀC(3')); 0.85 (s, MeexoÀC(2')). 13C-NMR (75 MHz,
CDCl3): 65.0 (t, C(1)); 50.9 (d, C(1')); 44.0 (d, C(3')); 41.5 (s, C(2')); 31.5 (t, C(4')); 26.7 (t, C(5')); 24.2
.
.
‡
‡
(q, MeexoÀC(2')); 23.4 (q, MeendoÀC(2')); 15.1 (q, MeÀC(3')). EI-MS: 142 (2, M ), 124 (6, [M À H2O] ), 109
(78), 99 (14), 95 (10), 84 (33), 69 (100), 55 (30).
3.6. (1S,3S)-2,2,3-Trimethylcyclopentanecarboxylic Acid (ˆ(‡)-trans-a-Dihydrocampholytic Acid; 14).
Jones reagent, prepared by dissolving CrO3 (1.13 g, 11.30 mmol) in H2O (3.5 ml) and H2SO4 (1 ml), was added
dropwise to a soln. of 11 (0.5 g, 3.52 mmol) in acetone (25 ml) at 08. After stirring for 30 min at r.t., H2O (20 ml)
and Et2O (30 ml) were added. The mixture was extracted with 2n NaOHsoln. (3 Â 20 ml), and the aq. layer was
acidified with 10% aq. HCl to pH 3. The aq. phase was extracted with Et2O (2 Â 30 ml), and the combined org.
extracts were dried (MgSO4) and evaporated. The residual oil was filtered through a short pad of silica gel with
hexane/AcOEt 50 :1 to provide 14 (0.54 g, 99%). Colorless oil. [a]2D3 ˆ ‡51.2 (c ˆ 1.0, hexane). IR (film):
1
2963vs, 2875vs, 2748s, 2668s, 1700vs, 1471s, 1420s, 1369s, 1291s, 1239vs, 1190s, 941s, 713w. H-NMR (600 MHz,
CDCl3): 2.53 (dd, 3J ˆ 8.4, 6.0, HÀC(1)); 1.97 1.89 (m, HexoÀC(4), HexoÀC(5)); 1.88 1.79 (m, HÀC(3),

1988
Helvetica Chimica Acta Vol. 87 (2004)
HendoÀC(5)); 1.35 1.21 (m, HendoÀC(4)); 0.98 (s, MeendoÀC(2)); 0.94 (s, MeexoÀC(2)); 0.86 (d, 3J ˆ 7.0,
MeÀC(3)). 13C-NMR (150 MHz, CDCl3): 182.6 (s, CO2H); 54.9 (d, C(1)); 44.7 (s, C(2)); 43.5 (d, C(3)); 32.1
.
‡
(t, C(4)); 25.8 (t, C(5)); 24.5 (q, MeexoÀC(2)); 24.1 (q, MeendoÀC(2)); 14.9 (q, MeÀC(3)). EI-MS: 156 (6, M ),
.
‡
138 (4), 123 (4, [M À CO2 ‡ H] ), 113 (6), 101 (10), 96 (12), 84 (100), 69 (70), 55 (19).
3.7. Methyl (1S,3S)-2,2,3-Trimethylcyclopentanecarboxylate (15). A soln. of 14 (0.20 g, 1.28 mmol) in Et2O
(5 ml) was treated with a 0.5m soln. of CH2N2 in Et2O (7.68 ml, 3.84 mmol) at 08. The mixture was allowed to
warm to r.t. within 30 min, whereupon the solvent was evaporated under reduced pressure to give 15 (0.21 g,
96%). Colorless oil. [a]2D3 ˆ ‡68.0 (c ˆ 1.0, hexane). IR (film): 2962vs, 2875vs, 1733vs, 1455s, 1435s, 1389m,
1369s, 1357s, 1295m, 1258s, 1216vs, 1199vs, 1162vs, 105m, 1037m, 918m, 735s. 1H-NMR (600 MHz, CDCl3): 3.65
(s, MeO); 2.52 (dd, 3J ˆ 8.4, 5.9, HÀC(1)); 1.97 1.88 (m, HexoÀC(4), HexoÀC(5)); 1.86 1.77 (m, HÀC(3),
HendoÀC(5)); 1.31 1.25 (m, HendoÀC(4)); 0.91 (s, MeendoÀC(2)); 0.89 (s, MeexoÀC(2)); 0.85 (d, 3J ˆ 6.9,
MeÀC(3)). 13C-NMR (150 MHz, CDCl3): 176.6 (s, MeOOC); 54.9 (d, C(1)); 51.3 (s, MeO); 44.5 (s, C(2));
43.4 (d, C(3)); 32.2 (t, C(4)); 25.9 (t, C(5)); 24.5 (q, MeexoÀC(2)); 24.1 (q, MeendoÀC(2)); 14.7 (q, MeÀC(3)).
.
.
‡
‡
EI-MS: 170 (22, M ), 155 (8), 138 (24), 127 (19), 111 (25, [M À CO2Me ‡ H] ), 95 (88), 87 (88), 84 (100), 69
(92), 55 (56).
3.8. 1-(3-Nitrophenyl)-2-[(1R,3S)-2,2,3-trimethylcyclopent-1-yl]ethan-1-one (16). A round-bottom flask
containing H2SO4 (0.6 ml) was cooled to À158, and phenone 7a (0.53 g, 2.28 mmol) was added dropwise. Then, a
3 :2 mixture of H2SO4/HNO3 (0.5 ml) was added at such a rate that the temp. of the mixture remained below
À58. Stirring was continued for 15 min at 08, and the contents of the flask were poured onto ice. The yellow
mixture was extracted with Et2O (2 Â 30 ml), and the combined org. extracts were washed with sat. aq. NaHCO3
soln. and brine, dried (MgSO4), and evaporated. The residual oil was filtered through a short pad of silica gel
with hexane/AcOEt 50 :1 to provide 16 (0.49 g, 78%). Yellow oil. [a]2D3 ˆ ‡43.5 (c ˆ 1.0, hexane). IR (film):
3086w, 2959vs, 2872s, 1695vs, 1613s, 1534s, 1471m, 1439m, 1406m, 1351vs, 1294m, 1212s, 1086m, 1001m, 920w,
810m, 735s, 676s. 1H-NMR (300 MHz, CDCl3): 8.76 (t, 4J ˆ 1.8, arom. H); 8.41 (ddd, 3J ˆ 8.2, 4J ˆ 2.2, 1.1,
arom. H); 8.28 (ddd, 3J ˆ 7.8, 4J ˆ 1.5, 1.2, arom. H); 7.68 (t, 3J ˆ 8.0, arom. H); 3.08 (A of ABX, 2JAB ˆ 16.1, 3J ˆ
2
3
4.0, HaÀC(2)); 2.79 (B of ABX, JAB ˆ 16.1, J ˆ 10.1, HbÀC(2)); 2.18 (mc, HÀC(1')); 1.92 (mc, HendoÀC(5'));
1.86 (mc , HexoÀC(4')); 1.65 (sext., 3J ˆ 7.1, H ÀC(3')); 1.26 1.19 (m, HendoÀC(4'), HexoÀC(5')); 0.91
(s, MeendoÀC(2')); 0.90 (s, MeexoÀC(2')); 0.87 (d, 3J ˆ 7.1, Me ÀC(3')). 13C-NMR (150 MHz, CDCl3): 198.3
(s, C(1)); 148.4 (s, CÀNO2); 138.5 (s, Cipso of Ar); 133.5 (d); 129.7 (d); 127.0 (d); 122.9 (d); 43.9 (d, C(1')); 43.4
(d, C(3')); 42.1 (s, C(2')); 40.7 (t, C(2)); 31.2 (t, C(4')); 29.5 (t, C(5')); 24.1 (q, MeexoÀC(2')); 23.5
.
‡
(q, MeendoÀC(2')); 16.1 (q, MeÀC(3')). EI-MS: 275 (2, M ), 218 (100), 150 (42), 95 (39), 69 (36), 55 (12).
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Received February 13, 2004