A Straightforward Synthesis of Trideuterated α-Terpinene for Mechanistic Studies

Article abstract of DOI:10.1002/ejoc.202000684

Regiospecifically trideuterated (2,6,6-²H₃)-α-terpinene was prepared in six steps and with a deuterium incorporation of >99 % in 24 % yield from 1,4-cyclohexanedione monoethylene ketal. The synthetic procedure involved twofold cross-coupling reactions of alkylcuprates (lithium dimethylcuprate and chloromagnesium cyano(isopropyl)cuprate, respectively) with enol triflates to introduce the alkyl substituents on the 1,3-cyclohexadiene backbone. By changing the alkylcuprates, the synthetic approach could serve as a prototype for the synthesis of various 1,4-dialkyl-substituted 1,3-cyclohexadiene derivatives, which could be deuterium-labeled as well, for example for mechanistic studies.

Full text of DOI:10.1002/ejoc.202000684

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: A Straightforward Synthesis of Trideuterated α-Terpinene for
Mechanistic Studies
Authors: Nico Mitschke, Jens Christoffers, and Heinz Wilkes
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000684
Link to VoR: https://doi.org/10.1002/ejoc.202000684
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000684
A Straightforward Synthesis of Trideuterated α-Terpinene for Mechanistic
Studies
Nico Mitschke, Jens Christoffers,* Heinz Wilkes*
N. Mitschke, Prof. Dr. H. Wilkes
Institut für Chemie und Biologie des Meeres (ICBM), Carl von Ossietzky Universität
Oldenburg, 26111 Oldenburg (Germany)
E-Mail: heinz.wilkes@uni-oldenburg.de
Homepage: https://uol.de/icbm/ogc/
Prof. Dr. J. Christoffers
Institut für Chemie, Carl von Ossietzky Universität Oldenburg, 26111 Oldenburg
(Germany)
2
Abstract: Regiospecifically trideuterated (2,6,6- H )-α-terpinene was prepared in six
3
steps and with a deuterium incorporation of >99% in 24% yield from 1,4-
cyclohexanedione monoethylene ketal. The synthetic procedure involved twofold
cross-coupling reactions of alkylcuprates (lithium dimethylcuprate and
chloromagnesium cyano(isopropyl)cuprate, respectively) with enol triflates to introduce
the alkyl substituents on the 1,3-cyclohexadiene backbone. By changing the
alkylcuprates, the synthetic approach could serve as a prototype for the synthesis of
various 1,4-dialkyl substituted 1,3-cyclohexadiene derivatives, which could be
deuterium labeled as well, for example for mechanistic studies.
2
Graphical Abstract: Trideuterated (2,6,6- H
3
)-α-terpinene was prepared in six steps
from 1,4-cyclohexanedione monoethylene ketal. The key step of the synthesis was the
twofold cross-coupling of alkylcuprates (lithium dimethylcuprate and chloromagnesium
cyano(isopropyl)cuprate, respectively) with enol triflates.
Keywords: Hydrocarbons, Terpenes, Deuteration, Cross-coupling, Biodegradation
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
Introduction
The mechanisms of chemical and biological processes can be uniquely investigated
using deuterium labeling, which enables the position specific incorporation of defined
[
1]
additional masses into an organic compound. While the constitution of deuterated
compounds is essentially the same, certain physico-chemical properties as well as the
biological activities may change more or less significantly depending among others on
the extent and the position of deuterium incorporation.[2–4] Today, deuterium labeling
[
5]
has many applications in nearly all disciplines in life sciences. A prominent example
is the deuterated drug Austedo (deutetrabenazine) for the treatment of Huntington’s
disease-related movement disorders, recently approved by the US Food and Drug
Administration (FDA).[6]
Moreover, deuterium-labeled compounds are often used for the investigation of
enzymatic reactions in biochemical pathways. Excellent reviews on various aspects of
terpene biosynthesis have highlighted the utility of deuterium labeling in the elucidation
of enzymatic reaction mechanisms.[7–9] For example, deuterium labeling experiments
have been used to elucidate the biosynthetic pathway and establish syn-configuration
of cyclic ether formation in the biosynthesis of the monoterpene 1,8-cineole
(
eucalyptol) in the herb Salvia officinalis[10] and the Gram-positive bacterium
Streptomyces clavuligerus.[11] Likewise, syn-addition has been implicated in the
mechanism of abiotic cyclization of nerol to eucalyptol inside a supramolecular catalyst
on the basis of a deuterium-labeling experiment.[12] Other studies utilizing deuterium
labeling have addressed open issues of sesquiterpene[13–17] and diterpene[18,19]
biosynthesis. However, deuterium labeling also provides important insights into key
reactions of biodegradation pathways. For example, the stereochemistry of the initial
activation reaction of a hydrocarbon-transforming enzyme was previously elucidated
using regio- and stereospecifically deuterium-labeled n-hexanes.[20] Also other
examples, like the elucidation of the anaerobic degradation mechanism of
triethanolamine by a homoacetogenic bacterium emphazise the importance of
deuterium-labeled compounds for the characterization of biochemical pathways.[21]
Based on cultivation studies it has been shown that the denitrifying
betaproteobacterium “Aromatoleum aromaticum” pCyN1 is capable to grow on
different hydrocarbon substrates, such as aromatic (i.e. p-cymene, 1) and non-
aromatic (i.e. α-terpinene, 6a) monoterpenes under anoxic conditions (Scheme 1).[22]
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
More recently, metabolite studies revealed that the pathway of the anaerobic
degradation of p-cymene (1) starts with methyl-group hydroxylation (product 2,
Scheme 1, step a). After subsequent oxidation and thioesterification (steps b–d), the
reductive dearomatization (step e), yielding dienoyl-CoA 5, is catalyzed by a class I
benzoyl-CoA reductase (BCR). After further functional group interconversions (steps f,
m, n) the ring is cleaved to furnish 3-isopropylpimeloyl-CoA (11, step o).[23,24] Further
investigations showed that the disproportionation of dienoyl-CoA 14 to benzoyl-CoA
1
6 and enoyl-CoA 15 is catalyzed by a tungsten-containing class II BCR under artificial
conditions (Scheme 2, eq. 1) as well as by Ferroglobus placidus cell extracts by a so
far unknown enzyme.[25,26] Latest investigations in our laboratories on methylated
extracts of bacterial cultures of strain pCyN1 grown on α-terpinene (6a) led to the
identification of four compounds, namely 4-isopropyl-1,5-cyclohexadiene-1-carbonyl-
CoA
isopropylcyclohexane-1-carbonyl-CoA (13) and 3-isopropylpimeloyl-CoA (11)
unpublished results; Rabus, Wilkes, Christoffers and co-workers). The presence of
(9b),
4-isopropyl-1-cyclohexene-1-carbonyl-CoA
(10a),
2-hydroxy-4-
(
these compounds suggest a degradation pathway of α-terpinene (6a) that is similar to
the known degradation pathway of p-cymene (1).[23,24] In addition, p-isopropylbenzoyl-
CoA (4b) was abundant in the culture extracts (unpublished results; Rabus, Wilkes,
Christoffers and co-workers), which is not necessarily expected to occur as an
intermediate during anaerobic degradation of α-terpinene (6a). Based on these
findings and taking into account the possibility of a disproportionation reaction, a
pathway for the degradation of α-terpinene (6a) is proposed (Scheme 1, steps e–p),
including a disproportionation of 4-isopropyl-1,3-cyclohexadiene-1-carbonyl-CoA (9b)
to p-isopropylbenzoyl-CoA (4b) and 4-isopropyl-1-cyclohexene-1-carbonyl-CoA (10a)
(
Scheme 2, eq. 2). On the stage of these intermediates, the proposed pathway for the
degradation of α-terpinene (6a) is supposed to converge with the pathway of p-cymene
1) degradation.
(
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
Scheme 1. Proposed pathways for the anaerobic degradation of p-cymene (1) and α-terpinene (6a) by strain pCyN1. The red arrows
represent the proposed disproportionation reaction of dienoyl-CoA 9b to p-isopropylbenzoyl-CoA (4b) and enoyl-CoA 10a, converging
with the pathway of p-cymene (1) degradation.
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
Scheme 2. Disproportionation of dienoyl-CoA 14 to enoyl-CoA 15 and benzoyl-CoA
6 (eq. 1), dienoyl-CoA 9b to enoyl-CoA 10a and 4-isopropylbenzoyl-CoA (4b) (eq. 2),
dienoyl-CoA-d 9c to enoyl-CoA-d 10b and 4-isopropylbenzoyl-CoA-d (4c) (eq. 3)
and dienoyl-CoA-d 9d to 4-isopropylbenzoyl-CoA-d (4d) and either enoyl-CoA-d 10c
eq. 4) or enoyl-CoA-d 10d (eq. 5).
1
6
8
4
3
2
4
(
4
As outlined above, the use of deuterated compounds could provide valuable insights
into the reaction mechanisms of enzymes. Following this concept, we envisioned
highly regiospecifically deuterated α-terpinene to be a perfect substrate for
investigating the mechanisms of its degradation by the bacterial strain pCyN1. If the
proposed disproportionation mechanism takes places in a classical manner, formally
D
2
(Scheme 1, eq. 3) or HD (in case of eq. 4 and eq. 5) is abstracted from one molecule
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
of 4-isopropyl-1,3-cyclohexadiene-1-carbonyl-CoA (9c or 9d) to introduce the double
bond under formation of the aromatic system. The same two deuterium atoms (or one
hydrogen atom and one deuterium atom in case of eq. 4 and eq. 5) are subsequently
used for the hydrogenation of the double bond of a second molecule of 4-isopropyl-
1
,3-cyclohexadiene-1-carbonyl-CoA (9c or 9d). The resulting, specifically deuterium-
labeled, 4-isopropyl-1-cyclohexene-1-carbonyl-CoAs (10b, 10c or 10d) could be easily
distinguished from a product that would not be formed by a disproportionation reaction
according to their mass spectra using GC-MS after hydrolysis and methylation with
diazomethane. The expected outcome of such an experiment would provide direct
evidence for or against the proposed disproportionation even in whole cell
experiments. However, it is clear that the elucidation of the molecular mechanism of
this reaction would require access to the substrate enzyme complex.
A literature survey yielded only one reported access to deuterated α-terpinene,
involving an ene reaction of liquid sulfur dioxide with α-terpinene (6a) accompanied
with hydrogen–deuterium exchange at allylic carbon atoms.[27] However, we were not
able to reproduce the reported results. Furthermore, considering the safety concerns
and instrumental effort for performing reactions with liquid sulfur dioxide, we wished to
have available a safer and easier access to a specifically deuterated α-terpinene.
Therefore, the objective of this study was the development of a facile and reliable
synthetic procedure to obtain regiospecifically deuterated α-terpinene.
Results and Discussion
The retrosynthetic analysis of deuterated α-terpinene is based upon twofold coupling
of an alkylcuprate (methyl and isopropyl, respectively) and an enol triflate (17 and 22,
respectively) as outlined in Scheme 3. Initially, we envisioned that starting the
synthesis from 1,4-cyclohexanedione (20a) would be ideal since hydrogen–deuterium
exchange in α-position of a carbonyl group is feasible by the α-acidity of this position.
To protect the second carbonyl functionality during the first triflate formation and in the
first cross-coupling reaction a 1,3-dioxolane would be a perfect choice. Since the
isomer with conjugated double bonds should be thermodynamically favoured, it is very
likely that the double bonds would arrange as the 1,3-diene 17 in the second triflate-
forming reaction from compound 18.
6
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
2
Scheme 3. Retrosynthetic analysis of hexadeuterated (2,3,5,5,6,6- H
6
)-α-terpinene
6
b.
To proof our synthetic strategy we first carried it out without incorporation of deuterium,
starting from commercially available 1,4-cyclohexanedione monoethylene ketal 21a
that was converted into the corresponding enol triflate 22a using phenyl triflimide and
LiHMDS (Scheme 4).[28,29] Our initial attempts included the introduction of the methyl
group at first, followed by the introduction of the isopropyl group. Unfortunately, some
resulting synthetic intermediates (the non-deuterated analogues of compounds 17b
and 18b) turned out to be very volatile and relatively unstable. Therefore, we changed
our strategy and introduced the isopropyl group in a cross-coupling reaction of the enol
triflate 22a with chloromagnesium cyano(isopropyl)cuprate first. Attempts using lithium
diisopropylcuprate were less successful. The deprotection was performed with
pTsOHH O and the resulting β,γ-unsaturated ketone 18a was converted directly
2
without storage into the corresponding enol triflate 17a, because the double bond of
ketone 18a readily isomerized to the α,β-conjugated system. After some
experimentation, the reaction conditions for forming the enol triflate 17a were optimized
to shorter reaction times, which had the additional advantage that the previously
observed formation of the aromatic side product by oxidation was significantly reduced.
Finally, the cross-coupling of the enol triflate 17a with lithium dimethylcuprate, applying
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
standard conditions[30] but changing the solvent to diethyl ether, furnished α-terpinene
a in excellent yield.
6
Scheme 4. Synthesis of non-deuterated α-terpinene 6a. Reagents and conditions: (a)
1
1
.1 equiv. LiHMDS, 1.1 equiv. PhNTf
2
, THF, –78 to 23 °C, 14 h; (b) 8.5 equiv. iPrMgCl,
0 equiv. CuCN, Et O, –78 °C, 14 h; (c) 0.1 equiv. pTsOHH
2
2
O, acetone, 23 °C, 25 h;
(d) 1.1 equiv. LiHMDS, 1.1 equiv. PhNTf
2
, THF, –78 to 23 °C, 2 ¼ h; (e) 4.9 equiv.
MeLi, 3.4 equiv. CuI, Et O, –15 °C, 14 h.
2
2
Next, attempts were made on the synthesis of a hexadeuterated (2,3,5,5,6,6- H
6
)-α-
terpinene (6b), starting with a literature-known deuteration of 1,4-cyclohexanedione
20a) using PCl and D
O.[31] The subsequent protection with ethylene glycol was
performed following a slighty modified procedure, reported previously in the literature,
including the four times repeated addition and removal of D O by azeotropic distillation
(
5
2
2
from the reaction mixture.[32] As one could assume, the separation of the mono- and
the diprotected 1,4-cyclohexanedione required a lot of effort. At this stage we initially
recognized the loss of deuterium which was mainly due to column chromatography but
also occurred upon storage. Therefore, we changed our strategy to the synthesis of a
2
trideuterated (2,6,6- H
3
)-α-terpinene (Scheme 5, 6c), which should provide us the
same information in a biological experiment (cf. Scheme 2, eq. 4 and eq. 5). As a great
advantage, this opened the possibility to start with commercially available 1,4-
cyclohexanedione monoethylene ketal 21a. To avoid cleavage of the ketal, the
deuteration reaction was changed to basic conditions using K
2
CO
3
, following a
8
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
modified procedure which has already been reported.[33] As outlined above, twofold
cross-coupling reactions of the triflates 22c and 17d with chloromagnesium
cyano(isopropyl)cuprate and lithium dimethylcuprate, respectively, furnished the
targeted trideuterated α-terpinene 6c with a deuterium incorporation >99%, according
to NMR (no residual proton signals were detected at deuterated positions).
2
Scheme 5. Synthesis of trideuterated (2,6,6- H
3
)-α-terpinene 6c. Reagents and
conditions: (a) 0.5 equiv. K
LiHMDS, 1.1 equiv. PhNTf , THF, –78 to 23 °C, 5 h; (c) i: 3.2 equiv. iPrMgCl, 5.0 equiv.
CuCN, Et O, –78 to 0 °C, 16 h; (d) 0.5 equiv. pTsOHH O, acetone/H O 10:1, 23 °C,
3 h; (e) 1.1 equiv. LiHMDS, 1.1 equiv. PhNTf
2
CO
3 2
, D O, 130 °C, 16 h, one repetition; (b) 1.1 equiv.
2
2
2
2
2
2
, THF, –78 °C to 23 °C, 3 h; (f) 6.1 equiv.
MeLi, 3.6 equiv. CuI, Et O, –15 °C, 16 h.
2
Conclusion
9
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
In the course of our studies on the elucidation of anaerobic degradation pathways of
monoterpenes in the denitrifying betaproteobacterium “A. aromaticum” pCyN1, we
suggest the use of deuterated α-terpinene as a model substrate. Therefore, we
developed a facile and reliable synthetic approach to the α-terpinene scaffold, which
opens the possibility of deuterium incorporation. Following this approach, trideuterated
2
(
2,6,6- H
3
)-α-terpinene 6c was prepared in 24% yield (31% brsm) and with a deuterium
incorporation >99% over six steps starting from 1,4-cyclohexanedione monoethylene
ketal 21a. The synthetic procedure involved twofold cross-coupling reactions of
dialkylcuprates or alkylcyanocuprates with the enol triflates 22c and 17d to introduce
the alkyl substituents of the 1,3-cyclohexadiene backbone. In general, this approach
offers the possibility to adopt the synthetic procedure in the synthesis of various 1,4-
dialkylsubstituted 1,3-cyclohexadiene derivatives by changing the corresponding
alkylcuprates. In particular, these derivatives could be as well synthesized with a highly
and well-defined deuterium incorporation, using them for example in mechanistic
studies.
Experimental Section
General: Unless otherwise noted, all synthetic transformations were performed under
inert conditions (nitrogen atmosphere, exclusion of air and moisture) using anhydrous
solvents. Preparative column chromatography was carried out using Merck SiO
2
(40–
6
3 μm, type 60 A) with hexanes (mixture of isomers, bp. 64–71 °C), pentane, tert-butyl
methyl ether (MTBE) and diethyl ether (Et O) as eluents. TLC was performed on
2
aluminum plates coated with SiO F254. GC-MS analyses were performed on a
2
Shimadzu GCMS-QP2020 using a Macherey-Nagel OPTIMA 5 HT fused silica
capillary column (30 m length, 0.25 mm internal diameter, 0.25 μm film thickness).
Helium was used as carrier gas. The GC oven temperature was programmed from 50
–1
°
C (2 min hold time) to 250 °C at a rate of 30 K min (7 min hold time). The MS was
operated in EI mode (70 eV) at a source temperature of 230 °C and a transfer line
temperature of 280 °C. The mass range was 50–600 Dalton at a scan cycle time of 0.2
1
13
s. H and C NMR spectra were recorded on a Bruker Avance DRX 300 instrument.
Multiplicities of carbon signals were determined with DEPT experiments. HRMS
spectra of products were obtained with a Waters Q-TOF Premier (ESI) or Thermo
Scientific DFS (EI) spectrometer. IR spectra were recorded on a Shimadzu IRSpirit
1
0
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
spectrometer equipped with a diamond ATR unit. All starting materials were
commercially available.
1
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
1
,4-Dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (22a). According to a
slightly modified procedure reported previously in the literature,[28] LiHMDS (1.3 mol/L
solution in THF, 16.3 mL, 21.1 mmol, 1.1 equiv.) was added dropwise over a period of
1
1
5 min to a solution of ketone 21a (3.00 g, 19.2 mmol) and PhNTf
2
(7.55 g, 21.1 mmol,
.1 equiv.) in THF (80 mL) at –78 °C. After stirring for 1 h at this temperature, the
reaction mixture was warmed to ambient temperature and stirring was continued for
1
1
3 h. The reaction mixture was diluted with H
2
O (75 mL), extracted with MTBE (3 
00 mL), washed with H O (250 mL) and brine (250 mL), dried over MgSO
2
4
and
filtered. The solvent was evaporated to yield the title compound 22a as a slightly
yellowish liquid (5.54 g, 19.2 mmol, 100%) which was used without further purification
1
in the next step. H NMR (300 MHz, CDCl
3
): δ = 1.90 (t, J = 6.5 Hz, 2H), 2.40–2.41 (m,
1
3
1
2
H), 2.52–2.56 (m, 2H), 3.99 (s, 4H), 5.65–5.67 (m, 1H) ppm. C{ H} NMR (75 MHz,
CDCl ): δ = 26.54 (CH ), 31.16 (CH ), 34.31 (CH ), 64.84 (2  CH ), 106.28 (C), 115.95
CH), 118.66 (q, J = 318.3 Hz, CF ), 148.33 (C) ppm. All data were in accordance with
the literature.[34]
3
2
2
2
2
(
3
8
-Isopropyl-1,4-dioxaspiro[4.5]dec-7-ene (19a). According to a slightly modified
procedure reported previously in the literature,[35] iPrMgCl (2.0 mol/L solution in THF,
7.2 mL, 94.4 mmol, 8.5 equiv.) was added dropwise over a period of 35 min to a
suspension of CuCN (9.94 g, 111 mmol, 10 equiv.) in Et O (100 mL) at –78 °C. The
reaction mixture was warmed to 0 °C, stirred for 15 min at this temperature and cooled
again to –78 °C. Then, a solution of triflate 22a (3.20 g, 11.1 mmol) in 50 mL Et O was
added dropwise over a period of 40 min. After stirring at –78 °C for 14 h the reaction
mixture was diluted with saturated, aqueous NH Cl solution (150 mL) and filtered
through a plug of SiO (2 cm, rinsed with MTBE). The organic layer was separated and
the aqueous layer extracted with MTBE (3  150 mL). The combined organic layers
were washed with H O (150 mL) and brine (150 mL), dried over MgSO , filtered and
evaporated. The crude product was submitted to column chromatography (SiO
hexanes/MTBE, 9:1, R = 0.28) to furnish the title compound 19a (1.34 g, 7.34 mmol,
4
2
2
4
2
2
4
2
,
f
1
6
1
6%) as a colorless liquid. H NMR (300 MHz, CDCl ): δ = 1.01 (d, J = 6.8 Hz, 6H),
3
.75 (t, J = 6.5 Hz, 2H), 2.17–2.26 (m, 5H), 3.98 (s, 4H), 5.28–5.33 (m, 1H) ppm.
13
1
C{ H} NMR (75 MHz, CDCl
3 3
): δ = 21.52 (2  CH ), 25.38 (CH
2
), 31.49 (CH ), 34.66
2
1
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
(CH), 35.82 (CH
2 2
), 64.52 (2  CH ), 108.45 (C), 115.71 (CH), 143.20 (C) ppm. All data
were in accordance with the literature.[36]
4
2
-Isopropyl-3-cyclohexen-1-one (18a). pTsOHH O (117 mg, 0.615 mmol, 0.1
equiv.) was added to a solution of ketal 19a (1.12 g, 6.14 mmol) in acetone (20 mL).
After stirring for 27 h at ambient temperature in the dark, NaHCO
was added, the resulting suspension was filtered (rinsed with Et
The crude product was submitted to column chromatography (SiO
= 0.48) to furnish the title compound 18a (557 mg, 4.03 mmol, 66%, based on 88%
3
(7.40 g, 88.1 mmol)
2
O) and evaporated.
2
, pentane/Et O, 4:1,
2
R
f
1
purity established by H NMR) as a colorless liquid. The title compound was used in
1
the next step without further purification. H NMR (300 MHz, CDCl
3
): δ = 1.03 (d, J =
13
1
6
.8 Hz, 6H), 2.26–2.50 (m, 5H), 2.83–2.87 (m, 2H), 5.44–5.46 (m, 1H) ppm. C{ H}
NMR (75 MHz, CDCl ): δ = 21.28 (2  CH ), 26.47 (CH ), 34.88 (CH), 39.04 (CH ),
9.78 (CH ), 115.59 (CH), 144.74 (C), 211.66 (C) ppm. All data were in accordance
with the literature.[37]
3
3
2
2
3
2
4
-Isopropyl-1,3-cyclohexadiene-1-yl trifluoromethanesulfonate (17a). According
to a slightly modified procedure reported previously in the literature,[28] LiHMDS (1.3
mol/L solution in THF, 3.8 mL, 4.9 mmol, 1.1 equiv.) was added dropwise over a period
of 15 min to a solution of ketone 18a (614 mg, 4.44 mmol) and PhNTf (1.75 g, 4.89
2
mmol, 1.1 equiv.) in THF (30 mL) at –78 °C. After stirring for 15 min at this temperature,
the reaction mixture was warmed to ambient temperature and stirring was continued
for 2 h. The reaction mixture was diluted with H
mL), washed with H O and brine (both 50 mL), dried over MgSO
evaporated. The crude product was submitted to column chromatography (SiO
pentane, R = 0.21) to furnish the title compound 17a (889 mg, 3.29 mmol, 74%) as a
colorless liquid. H NMR (300 MHz, CDCl
H), 2.50–2.56 (m, 2H), 5.57 (d, J = 6.1 Hz, 1H), 5.88 (d, J = 6.2 Hz, 1H) ppm. C{ H}
NMR (75 MHz, CDCl ): δ = 21.10 (2  CH ), 26.39 (CH ), 26.53 (CH ), 34.47 (CH),
13.59 (CH), 115.47 (CH), 118.74 (q, J = 318.5 Hz, CF ), 146.34 (C), 146.86 (C) ppm.
IR (ATR): ν = 2966 (w), 2877 (w), 2836 (w), 1670 (w), 1607 (w), 1467 (w), 1417 (s),
386 (w), 1369 (w), 1247 (m), 1203 (vs), 1139 (s), 1082 (s), 1051 (w), 1013 (w), 979
m), 879 (s), 853 (s), 833 (s), 774 (w), 763 (w), 746 (w), 677 (w), 611 (s), 510 (m) cm–
2
O (25 mL), extracted with Et
2
O (3  30
2
4
, filtered and
2
,
f
1
3
): δ = 1.04 (d, J = 6.8 Hz, 6H), 2.26–2.41 (m,
13
1
3
3
3
2
2
1
3
̃
1
(
1.
HRMS (EI): calcd. 270.0532 (for C10
S ), found 270.0527 [M ]; C10
+
+
H
F
O S
13 3
H F O
3
13
3
3
1
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
+
(
(
(
270.27). GC-MS (EI, 70 eV): m/z (%) 270 (18) [M ], 255 (3), 137 (17), 121 (6), 109
20), 95 (100), 93 (10), 91 (10), 81 (18), 79 (15), 77 (15), 69 (23), 67 (27), 65 (10), 55
25), 53 (13).
α-Terpinene (6a). According to a procedure reported previously in the literature,[30]
MeLi (1.6 mol/L solution in Et O, 2.3 mL, 3.7 mmol, 5.0 equiv.) was added dropwise
over a period of 5 min to a suspension of CuI (480 mg, 2.52 mmol, 3.4 equiv) in 5 mL
Et O at 0 °C. After stirring for 5 min, a solution of triflate 17a (200 mg, 0.74 mmol) in 3
mL Et O was added dropwise over a period of 5 min at 0 °C, followed by stirring for 14
h at –15 °C. The reaction mixture was diluted with pentane (5 mL), filtered through a
plug of SiO (2 cm, rinsed with pentane) and evaporated. The crude product was
submitted to column chromatography (SiO impregnated with 8 wt% AgNO
,[38,39]
pentane) to furnish the title compound 6a (102 mg, 0.75 mmol, quant., based on 89%
2
2
2
2
2
3
1
1
purity established by H NMR) as a colorless liquid. H NMR (300 MHz, CDCl
3
): δ =
1
5
.03 (d, J = 6.8 Hz, 6H), 1.77 (s, 3H), 2.03–2.17 (m, 4H), 2.28 (hept, J = 6.8 Hz, 1H),
13
1
.58–5.64 (m, 2H) ppm. C{ H} NMR (75 MHz, CDCl
3
): δ = 21.35 (2  CH ), 23.09
3
3
(CH ), 25.42 (CH
2
), 29.14 (CH
2
), 34.64 (CH), 116.50 (CH), 119.61 (CH), 133.37 (C),
13
[40]
1
42.68 (C) ppm. C Data were in accordance with the literature.
2
(
7,7,9,9- H
4
)-1,4-Dioxaspiro[4.5]decan-8-one (21b). According to a slightly modified
CO (1.33 g, 9.61 mmol, 0.5 equiv.)
was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (21a, 3.00 g, 19.2 mmol) in
O (25 mL) and the mixture was stirred at 130 °C over night. The mixture was
extracted with abs. Et O (4  25 mL), dried over MgSO , filtered and evaporated. The
procedure reported previously in the literature,[33]
K
2
3
D
2
2
4
procedure described above was repeated once to furnish the title compound 21b (2.77
g, 17.3 mmol, 90%) as a slightly brownish solid which was used in the next step without
1
further purification. Mp. = 71–72 °C. H NMR (300 MHz, CDCl
3
): δ = 2.00 (s, 4H), 4.03
), 37.57 (pent, J = 19.9
= 2959 (w),
13
1
(
s, 4H) ppm. C{ H} NMR (75 MHz, CDCl
3
): δ = 33.77 (2  CH
2
2
Hz, 2  C H
2
), 64.66 (2  CH
2
), 107.14 (C), 210.61 (C) ppm. IR (ATR): ν
̃
2
886 (m), 2227 (w), 1706 (vs), 1476 (w), 1436 (m), 1357 (w), 1342 (w), 1277 (m), 1226
w), 1206 (w), 1177 (m), 1124 (m), 1070 (s), 1051 (m), 1029 (m), 1009 (s), 974 (w),
(
–1
9
47 (m), 891 (w), 841 (s), 769 (w), 759 (w), 713 (m), 643 (m) cm . HRMS (ESI, pos.
1
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
2H
LiO +
), found 167.1195 [M + Li ]; C
+
H
8 8
2H
mode): calcd. 167.1192 (for C
H
8 8
4
3
4
O
3
+
(
160.21). GC-MS (EI, 70 eV): m/z (%) 160 (2) [M ], 102 (41), 101 (100), 100 (20), 86
(7), 71 (4), 58 (19), 57 (20), 56 (10).
2
(
7,7,9- H
3
)-1,4-Dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (22c).
According to the procedure reported above for the non-deuterated compound 22a,
LiHMDS (1.3 mol/L solution in THF, 13.2 mL, 17.2 mmol, 1.1 equiv.), ketone 21b (2.50
g, 15.6 mmol) and PhNTf
mL) to furnish the title compound 22c after column chromatography (SiO
hexanes/MTBE, 3:2, R = 0.32) as a slightly yellowish liquid (3.34 g, 11.5 mmol, 73%).
1H NMR (300 MHz, CDCl
NMR (75 MHz, CDCl
4.82 (2  CH
CF ), 148.20 (C) ppm. IR (ATR): ν
344 (w), 1309 (w), 1282 (w), 1247 (m), 1202 (vs), 1137 (s), 1126 (s), 1069 (s), 1036
s), 999 (s), 947 (m), 870 (s), 853 (m), 836 (s), 810 (s), 769 (w), 743 (w), 723 (w), 701
2
(6.13 g, 17.2 mmol, 1.1 equiv.) were converted in THF (70
2
,
f
13
1
3
): δ = 1.89 (s, 2H), 2.40 (s, 2H), 3.98 (s, 4H) ppm. C{ H}
2
3
): δ = 25.88 (pent, J = 20.0 Hz, C H
2
), 30.96 (CH
2
), 34.17 (CH ),
2
2
6
2
), 106.25 (C), 115.79 (t, J = 24.0 Hz, C H), 118.63 (q, J = 318.2 Hz,
3
̃
= 2966 (w), 2889 (w), 1676 (w), 1414 (s), 1362 (w),
1
(
–1
(
w), 677 (w), 659 (w), 609 (s), 570 (m), 517 (m) cm . HRMS (ESI, pos. mode): calcd.
2H
S ), found 314.0353 [M + Na ], C
+
+
H
9 8
2H
O S (291.26).
3
14.0360 (for C
H
9 8
3
3
F NaO
5
3
F
3
5
GC-MS (EI, 70 eV): m/z (%) 159 (9), 158 (100), 142 (2), 130 (8), 128 (7), 114 (22), 101
(5), 86 (39), 74 (9), 70 (14), 69 (23), 58 (16), 57 (9), 56 (58).
2
(
7,7,9- H
3
)-8-Isopropyl-1,4-dioxaspiro[4.5]dec-7-ene (19d). According to the
procedure reported above for the non-deuterated compound 19a, iPrMgCl (2.0 mol/L
solution in THF, 22.0 mL, 43.9 mmol, 3.2 equiv.), CuCN (6.15 g, 68.7 mmol, 5 equiv.)
and triflate 22c (4.00 g, 13.7 mmol) were converted in Et O (100 mL) to furnish the title
2
compound 19d (1.51 g, 8.14 mmol, 59%, 74% brsm) after column chromatography
1
(SiO
2
, hexanes/MTBE, 9:1 to 1:1, R
f
= 0.22) as a colorless liquid. H NMR (300 MHz,
3
CDCl ): δ = 1.01 (d, J = 6.9 Hz, 6H), 1.74 (s, 2H), 2.21 (hept, J = 6.9 Hz, 1H), 2.25 (s,
1
3
1
2
H), 3.98 (s, 4H) ppm. C{ H} NMR (75 MHz, CDCl
3
): δ = 21.37 (2  CH
), 64.38 (2  CH
= 2957 (m), 2927 (w), 2873
3
), 24.55 (pent,
2
J = 19.2 Hz, C H
2
), 31.20 (CH
2
), 34.47 (CH), 35.58 (CH
2
2
), 108.31 (C),
2
1
15.37 (t, J = 23.5 Hz, C H), 142.83 (C) ppm. IR (ATR): ν
̃
(m), 2252 (w), 2190 (w), 2094 (w), 1467 (w), 1424 (w), 1360 (m), 1342 (w), 1306 (w),
1
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
1
8
C
273 (w), 1253 (w), 1124 (s), 1060 (s), 1036 (m), 994 (w), 964 (w), 946 (m), 861 (m),
–1
41 (m), 814 (m), 761 (w), 661 (w), 533 (w) cm . HRMS (EI): calcd. 185.1490 (for
152H
+
), found 185.1491 [M ]; C11
+
H
152H
O (185.28). GC-MS (EI, 70 eV): m/z
11
H
3
O
2
3
2
+
(
%) 185 (16) [M ], 170 (8), 155 (2), 142 (3), 140 (3); 126 (2), 99 (3), 98 (3), 87 (9), 86
100), 68 (3), 57 (3), 56 (3).
(
2
(
3,5,5- H
3
)-4-Isopropyl-3-cyclohexen-1-one (18d). According to the procedure
O (590 mg, 3.11
mmol, 0.5 equiv.) and ketal 19d (1.15 g, 6.21 mmol) were converted in a mixture of
reported above for the non-deuterated compound 18a, pTsOHH
2
2
acetone (20 mL) and H O (2 mL) to furnish the title compound 18d (678 mg, 4.80 mmol,
1
7
7%, based on 91% purity established by H NMR) after column chromatography
(SiO
2
, pentane/Et
2
O, 2:1, R
f
= 0.39) as a colorless liquid. The title compound was used
1
in the next step without further purification. H NMR (300 MHz, CDCl
3
): δ = 1.04 (d, J
13
1
=
6.9 Hz, 6H), 2.31 (hept, J = 6.9 Hz, 1H), 2.46 (s, 2H), 2.85 (s, 2H) ppm. C{ H} NMR
2
(
75 MHz, CDCl
3
): δ = 21.06 (2  CH
3
), 25.61 (pent, J = 19.5 Hz, C H
2
), 34.61 (CH),
2
3
8.65 (CH
2
), 39.45 (CH
2
), 115.17 (t, J = 23.9 Hz, C H), 144.30 (C), 211.29 (C) ppm.
IR (ATR): ν
363 (w), 1292 (w), 1269 (w), 1252 (w), 1233 (w), 1203 (w), 1124 (w), 1099 (w), 1074
w), 1064 (w), 1031 (w), 929 (w), 881 (w), 861 (w), 837 (w), 819 (w), 700 (w), 687 (w),
̃ = 2960 (m), 2932 (w), 2872 (w), 1717 (vs), 1467 (w), 1404 (w), 1383 (w),
1
(
–1
112H
+
6
69 (w), 523 (w) cm . HRMS (EI): calcd. 141.1227 (for C
9
H
3
O ), found 141.1220
+
112H
+
[
M ]; C
9
H
3
O (141.23). GC-MS (EI, 70 eV): m/z (%) 141 (43) [M ], 126 (5), 111 (2),
9
5
9 (35), 98 (19), 84 (100), 83 (36), 82 (29), 70 (13), 69 (14), 68 (16), 67 (7), 57 (12),
6 (14), 55 (10).
1
6
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
2
(
3,5,5- H
3
)-4-Isopropyl-1,3-cyclohexadiene-1-yl trifluoromethanesulfonate (17d).
According to the procedure reported above for the non-deuterated compound 17a,
LiHMDS (1.3 mol/L solution in THF, 2.10 mL, 2.73 mmol, 1.1 equiv.), ketone 18d (350
mg, 2.48 mmol) and PhNTf
2
(975 mg, 2.73 mmol, 1.1 equiv.) were converted in THF
(15 mL) to furnish the title compound 17d (558 mg, 2.04 mmol, 82%, based on 95%
1
purity established by H NMR) after column chromatography (SiO
2
, pentane, R = 0.24)
f
1
as a colorless liquid. H NMR (300 MHz, CDCl
3
): δ = 1.04 (d, J = 6.8 Hz, 6H), 2.32
1
3
1
(
hept, J = 6.9 Hz, 1H), 2.51 (s, 2H), 5.88 (s, 1H) ppm. C{ H} NMR (75 MHz, CDCl
3
):
), 34.39 (CH), 113.33
), 146.10 (C), 146.89
= 2966 (w), 2876 (w), 1659 (w), 1467 (w), 1417 (s), 1386 (w),
367 (w), 1354 (w), 1299 (w), 1246 (m), 1202 (vs), 1139 (s), 1090 (s), 1070 (w), 1056
2
δ = 21.02 (2  CH
3
), 25.79 (pent, J = 19.6 Hz, C H
2
), 26.19 (CH
2
2
(
t, J = 24.5 Hz, C H), 115.37 (CH), 118.74 (q, J = 318.6 Hz, CF
3
(C) ppm. IR (ATR): ν
̃
1
(m), 1036 (w), 963 (m), 893 (s), 877 (m), 841 (s), 821 (s), 769 (w), 737 (w), 719 (w),
–1
6
83 (w), 663 (w), 609 (s), 580 (w), 561 (w), 507 (m) cm . HRMS (EI): calcd. 273.0720
102H
S ), found 273.0719 [M ]; C10
+
+
H
102H
O S (273.28). GC-MS (EI, 70
(for C10H
3 3
F O
3
3
F
3
3
+
eV): m/z (%) 273 (20) [M ], 140 (22), 123 (7), 112 (22), 98 (100), 97 (22), 96 (17), 83
(15), 82 (13), 70 (15), 69 (40), 68 (11), 57 (16), 56 (11), 55 (11).
2
(
2,6,6- H
3
)-α-Terpinene (6c). According to the procedure reported above for the non-
O, 30.7 mL, 49.1 mmol, 6.1
equiv.), CuI (5.54 g, 29.1 mmol, 3.6 equiv.) and triflate 17d (2.20 g, 8.06 mmol) were
deuterated compound, MeLi (1.6 mol/L solution in Et
2
converted in Et
2
O (75 mL) to furnish the title compound 6c (1.14 g, 8.19 mmol, quant.)
1
after column chromatography (SiO
300 MHz, CDCl
2
, pentane, R
f
= 0.51) as a colorless liquid. H NMR
(
3
): δ = 1.02 (d, J = 6.9 Hz, 6H), 1.77 (s, 3H), 2.07 (s, 2H), 2.28 (hept,
13
1
J = 6.9 Hz, 1H), 5.62 (s, 1H) ppm. C{ H} NMR (75 MHz, CDCl
3
): δ = 21.31 (2  CH ),
3
2
2
2
3.07 (CH
3
), 24.61 (pent, J = 19.1 Hz, C H
2
), 28.92 (CH
2
), 34.54 (CH), 116.24 (t, J =
2
3.6 Hz, C H), 119.52 (CH), 133.25 (C), 142.35 (C) ppm. IR (ATR): ν
̃
= 3030 (w), 2959
(
m), 2922 (w), 2870 (w), 2819 (w), 2266 (w), 2247 (w), 2186 (w), 2084 (w), 1646 (w),
447 (w), 1429 (w), 1380 (w), 1362 (w), 1303 (w), 1260 (w), 1134 (w), 1096 (w), 1074
w), 1030 (w), 977 (w), 947 (w), 874 (w), 854 (w), 841 (w), 806 (w), 709 (w), 680 (w),
1
(
–1
6
61 (w), 654 (w), 560 (w), 550 (w), 510 (w) cm . HRMS (EI): calcd. 139.1435 (for
132H +
), found 139.1435 [M ]; C10
+
H
132H
(139.26). GC-MS (EI, 70 eV): m/z (%)
10
C H
3
3
1
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000684
+
1
8
39 (49) [M ], 124 (100), 110 (8), 109 (12), 108 (12), 96 (52), 95 (38), 94 (30), 93 (23),
2 (14), 81 (17), 80 (15), 79 (18), 78 (12), 67 (5), 66 (5), 52 (6).
Acknowledgment
This work was generously supported by the Deutsche Forschungsgemeinschaft (GRK
2
226). MTBE was obtained as a generous gift from Evonik Industries, Marl, Germany.
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2
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