Electrochemical phenylselenoetherification as a key step in the synthesis of (±)-curcumene ether

Article abstract of DOI:10.1002/hlca.201200610

Two variants of a new pathway for the synthesis of (±)-curcumene ether are described. The key steps in these procedures are intramolecular cyclizations of 6-methyl-2-(4-methylphenyl)hept-6-en-2-ol and 2-methyl-6-(4-methylphenyl)hept-6-en-2-ol by means of an electrochemically generated phenylselenyl cation. This synthetic approach provides significantly better yields than the previously reported protocols. Copyright

Full text of DOI:10.1002/hlca.201200610

Helvetica Chimica Acta – Vol. 96 (2013)
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Electrochemical Phenylselenoetherification as a Key Step in the Synthesis of
(ꢀ)-Curcumene Ether
by Dragana Stevanovic´ a), Anka Pejovic´ a), Ivan S. Damljanovic´ a), Mirjana D. Vukic´evic´ b), Georgi
Dobrikovc), Vladimir Dimitrovc), Marija S. Denic´ d), Niko S. Radulovic´*d), and Rastko D. Vukic´evic´*a)
a
´
) Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovica 12, RS-34000
Kragujevac (phone: þ 38134300286; fax: þ 38134335040; e-mail: vuk@kg.ac.rs)
b
´
) Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, S. Markovica 69,
RS-34000 Kragujevac
c) Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Bl. 9,
Acad. G. Bonchev Str., BG-1113 Sofia
) Department of Chemistry, Faculty of Science and Mathematics, University of Nis, Visegradska 33,
d
ˇ
ˇ
ˇ
RS-18000 Nis (phone: þ 381628049210; fax: þ 38118533014; e-mail: nikoradulovic@yahoo.com)
Two variants of a new pathway for the synthesis of (ꢀ)-curcumene ether are described. The key steps
in these procedures are intramolecular cyclizations of 6-methyl-2-(4-methylphenyl)hept-6-en-2-ol and 2-
methyl-6-(4-methylphenyl)hept-6-en-2-ol by means of an electrochemically generated phenylselenyl
cation. This synthetic approach provides significantly better yields than the previously reported
protocols.
Introduction. – Tetrahydropyrans widely occur in nature, often as the core
structural fragment of numerous natural products with antibacterial, antifungal,
antiviral, neurotoxic, cytotoxic activities, etc. [1]. Many reactions have been applied in
the synthesis of these compounds, among which intramolecular cyclizations of the
corresponding unsaturated alcohols, by means of diverse electrophilic reagents, are of
special importance. Over several decades, electrophilic Se reagents, particularly
phenylselenyl halides, have been proven to be quite useful for this purpose [2].
Important advantages of the use of electrophilic Se reagents in these syntheses over
other related ones are mild reaction conditions and an easy removal of the Se unit from
organic molecules. This removal can be performed in an oxidative manner (by means of
H2O2), introducing, thus, a C¼C bond or by hydrogenolysis (effected by Ra-Ni) [2].
As depicted in Scheme 1, two types of unsaturated alcohols, i.e., those containing
hex-5-en-1-ol and pent-4-en-1-ol systems, can serve as substrates in the synthesis of
tetrahydropyran derivatives by the reaction with phenylselenyl halides. Alkenols of the
first type undergo the cyclization to give only tetrahydropyrans, whereas the second
ones might also afford tetrahydrofurans. Since the reaction obeys Markovnikovꢀs rule,
when planning this synthesis, the electronic and steric nature of olefinic C-atoms (or to
be more exact those of the intermediary Se cation) must be taken into account.
However, the (steric) nature of the carbinol C-atom of the substrate also plays a certain
role and must be considered too [2][3].
In continuation of our work on the functionalization of unsaturated compounds by
means of electrochemically generated phenylselenyl cation from diphenyl diselenide
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Scheme 1. Cyclo-etherification via a Phenylselenyl Cation
[3], we decided to utilize phenylselenoetherification in the synthesis of a naturally
occurring tetrahydropyran, curcumene ether (1), isolated from a plant species Thuja
orientalis [4]. To the best of our knowledge, to date four reports on the synthesis of (ꢀ)-
1 appeared in the literature [5][6], among which the first one [5a] could not be
reproduced in other laboratories [7]. Key steps of two of the three further syntheses of
this compound were the cyclizations of 2-methyl-6-(4-methylphenyl)heptane-2,6-diol
[5b] and 2-methyl-6-(4-methylphenyl)-3-phenylthiohept-6-en-2-ol [5c] by treatment
with HCOOH and CF3COOH, respectively, leading to (ꢀ)-1. The most recently
reported synthesis of (ꢀ)-1 was achieved in nine steps (7% overall yield) utilizing an
intramolecular Heck reaction to generate the stereogenic quaternary center [5d]. A 13-
step synthesis of (þ)-1 (involving a resolution of cinenic acid) in an overall yield of 3%
was also recently reported [6].
Results and Discussion. – A retrosynthetic analysis of (ꢀ)-1 (Scheme 2), with
Markovnikovꢀs rule in mind, points to four unsaturated alcohols as the possible starting
materials, two of which, i.e., 3 and 5, possess a hex-5-en-1-ol system, whereas the other
two, i.e., 3a and 5a, contain a pent-4-en-1-ol scaffold. They are expected to undergo
cyclization by means of an electrochemically generated phenylselenyl cation to give b-
(phenylseleno)tetrahydropyrans 2, 4, 2a, and 4a, respectively, which could be reduced
by Raney-Ni to furnish the target molecule. However, we have previously shown that
phenylselenoetherification of tertiary pent-4-en-1-ols with a terminally disubstituted
C¼C bond does not obey Markovnikovꢀs rule and gives derivatives of tetrahydrofuran,
or their mixtures with tetrahydropyran derivatives [3c]. Therefore, we abandoned
alcohols 3a and 5a as possible substrates for the construction of the skeleton of (ꢀ)-1,
and focused our attention on the optimization of synthetic protocols using alkenols 3
and 5.
It is apparent that alcohol 6-methyl-2-(4-methylphenyl)hept-6-en-2-ol (3) can be
easily obtained from the reaction of 6-methylhept-6-en-2-one (6), a commercially
available material, and the Grignard reagent obtained from p-halogenotoluenes
(Scheme 3). Thus, we started with the reaction of Mg mesh with p-iodotoluene (7) in
anhydrous ether, and adding dropwise 6 to the formed p-tolylmagnesium iodide (8)
solution [8]. Alcohol 3 was obtained in a yield of 75%.
The key step of the present synthesis of (ꢀ)-1, i.e., the construction of the
curcumene ether skeleton, was performed by electrolysis of alcohol 3 in an MeCN

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Scheme 2. Retrosynthetic Analysis of (ꢀ)-1
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Scheme 3. Synthesis of (ꢀ)-1 Based on Alcohol 3
solution of LiBr containing Ph2Se2 (in a 3/Ph2Se2 ratio of 1:0.5). As it is known, in this
process bromides serve as mediators [3]. The easy oxidation of bromides at the anode
provides in situ generation of PhSeBr or PhSeþ cation (in the subsequent homogenous

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reaction of liberated Br2 with Ph2Se2) capable of reacting with the p-electronic system
of 3. Two diastereoisomeric ethers, cis-2 and trans-2 (i.e., (R*,S*) and (R*,R*), resp.),
were obtained in the overall yield of 61%, and in the cis-2/trans-2 ratio of 1:1.9 (as
estimated by 1H-NMR spectroscopy). The stereoselectivity of this step does not affect
the final outcome of the synthesis, since the stereogenic center carrying the Se
substituent will be lost during the hydrogenolysis. However, we were able to isolate
pure samples of these compounds by column chromatography (SiO2; hexane/CH2Cl2
2 :1 (v/v)), and their structures were confirmed by spectral analysis. A crucial
information which enabled the assignment of the selenoethersꢀ configurations came
from a conformational analysis of the two compounds and 1. Molecular modeling at
semiempirical level revealed that, in all three cases, the chair conformer with an axial p-
tolyl group was by far prevailing in the conformational equilibria. The Me group
geminal to p-tolyl moiety orients the aromatic core in such a way so that it exerts a
shielding magnetic anisotropy effect on the other axial substituent. This is quite clear
from the upfield shift of the 1H-NMR signals of the axial Me group in trans-2 or axial
CH2 group of PhSeCH2 in cis-2, when compared with the those of the respective
counterpart or with the corresponding chemical shifts of 1. These assignments were also
confirmed by a careful inspection of the cross-peaks in the NOESY spectra of trans-2.
Reduction of the mixture cis-2/trans-2, using a flow reactor (ThalesNano H-cubeTM
)
with the Raney-Ni catalyst cartridge, afforded the target molecule (ꢀ)-1 in 95% yield.
Thus, the overall yield of this synthesis, based on the most expensive starting material 6,
was 43%.
The alternative route to (ꢀ)-1 that makes use of the electrochemically generated
PhSeþ cation starts with 2-methyl-6-(4-methylphenyl)hept-6-en-2-ol (5). However, this
alcohol could not be synthesized in such a short way as alcohol 3, since the
corresponding ketone or another substrate suitable for this purpose is not commercially
available. A possible retrosynthesis of 5 is depicted in Scheme 4, and leads to 5-(4-
methylphenyl)-5-oxopentanoic acid (10), a compound not available commercially, but
well described in the literature [9]. AWittig olefination of the corresponding ethyl ester
11 and a subsequent MeMgCl addition to the obtained ethyl 5-(4-methylphenyl)hex-5-
enoate (9) should yield alcohol 5.
Scheme 4. Retrosynthetic Analysis of Alcohol 5
We started the synthesis by a FriedelꢁCrafts acylation of toluene (12) with glutaric
anhydride (13; Scheme 5) [9]. The obtained keto acid 10 (80%) was esterified with
EtOH in the presence of p-toluenesulfonic acid as the catalyst [10] to give the keto ester
11 (98%). Wittig olefination [11] of 11 gave ethyl 5-(4-methylphenyl)hex-5-enoate (9)
in a yield of 93%, which, in a subsequent Grignard reaction, was transformed to alcohol

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5 (89%). Cyclo-etherification of this alcohol was performed under the same conditions
as for alcohol 3 and gave b-phenylseleno ether 4 in a yield of 59%. Finally, reduction of
4 using the flow reactor with a Raney-Ni catalyst cartridge gave the target (ꢀ)-
curcumene ether ((ꢀ)-1) in a yield of 92%. Thus, the overall yield of (ꢀ)-1 achieved in
this synthesis was 35%.
Scheme 5. Synthesis of (ꢀ)-1 Based on Alcohol 5
Conclusions. – In conclusion, we optimized two new multistep approaches for the
synthesis of (ꢀ)-curcumene ether ((ꢀ)-1) leading to 43 and 35% overall yields,
respectively. The key step of these protocols, i.e., the construction of the heterocyclic
skeleton from aliphatic substrates, involved the cyclization of 6-methyl-2-(4-methyl-
phenyl)hept-6-en-2-ol (3) and 2-methyl-6-(4-methylphenyl)hept-6-en-2-ol (5) by the
electrochemically generated PhSeþ cation (electrochemical phenylselenoetherifica-
tion).
Financial support from the Ministry of Education, Science and Technological Development of the
Republic of Serbia (Grant No. 172034) is gratefully acknowledged.
Experimental Part
General. All the reagents and solvents were obtained from commercial sources (Aldrich, USA;
Merck, Germany; Fluka, Germany) and used as received, except that the solvents were purified by
distillation or dried when necessary. The electrolysis experiments were performed with a Uniwatt, Beha
Labor-Netzgerꢀt (NG 394) power supply, and an undivided electrolytic cell (a cylindrical glass vessel)
equipped with a magnetic stirrer, a graphite stick (˘ 5 mm) as an anode, and a Cu spiral (˘ 10 mm) as a
cathode. Column chromatography (CC): Merck silica gel (SiO2; 70 – 230 mesh). TLC: silica gel 60 on Al
plates; layer thickness, 0.2 mm (Merck, Germany). M.p. (uncorrected): Mel-Temp cap. melting-points
apparatus, model 1001. IR Spectra: Perkin-Elmer Spectrum One FT-IR spectrometer using KBr disks. 1H-
and 13C-NMR spectra: in CDCl3; Varian Gemini 2000 (1H: 200 and 13C: 50 MHz), Bruker AC 250 E (1H:
250 and 13C: 62.9 MHz), or Bruker Avance II þ 600 (1H: 600.13 and 13C: 150.92 MHz) spectrometers;
chemical shifts in d [ppm], relative to TMS and/or residual solvent H-atoms as internal standards (d 7.26
(1H) and 77 for (13C)). GC/MS: Hewlett-Packard 6890N gas chromatograph equipped with a fused silica
cap. column DB-5 (5% phenylmethylsiloxane, 30 m ꢂ 0.25 mm, film thickness 0.25 mm, Agilent
Technologies, USA) and coupled with a 5975B mass-selective detector from the same company. The
injector and interface were operated at 2508 and 3008, resp. Oven temp. was raised from 70 – 2908 at a
heating rate of 58/min and then isothermally held for 10 min. As a carrier gas, He at 1.0 ml/min was used.
The samples, as solns. in Et2O (1 mg/ml), were injected in a pulsed split mode (the flow was 1.5 ml/min for
the first 0.5 min, and then, it was set to 1.0 ml/min throughout the remainder of the analysis; split ratio,
40 :1). MS conditions: ionization voltage, 70 eV; acquisition mass range, 35 – 500; scan time, 0.32 s.
Elemental analyses: Carlo Erba 1106 microanalyser; results in agreement with the calculated values.

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Preparation of 6-Methyl-2-(4-methylphenyl)hept-6-en-2-ol (3) [8]. 4-Iodotoluene (7; 3.05 g,
14 mmol) was added dropwise with stirring during 0.5 h to a refluxing slurry of Mg mesh (0.37 g,
15.4 mmol) and anh. Et2O (50 ml), activated with a few small crystals of I2. The mixture (which became
slightly cloudy after a few min) was stirred for an additional h at reflux, cooled to r.t., and 6-methylhept-6-
en-2-one (6; 0.88 g, 7 mmol) was added dropwise during 0.5 h. After stirring for additional 2 h under
reflux, sat. aq. NH4Cl (20 ml) was added, and the resulting mixture was extracted with Et2O (3 ꢂ 30 ml).
The org. layers were combined, dried (MgSO4), and concentrated under reduced pressure. The resulting
yellow oil was purified by ꢃdry flashꢀ CC (hexane/Et2O 95 :5 ! 85 :15 (v/v)) to yield 3 (1.14 g, 75%). Clear
colorless oil. IR (KBr): 3411, 3025, 2970, 2941, 1649, 1513, 1452, 1373, 1102, 886, 816, 724. 1H-NMR
(200 MHz, CDCl3): 7.36 – 7.25 (AA’ of AA’BB’, 2 arom. H); 7.19 – 7.08 (BB’ of AA’BB’, 2 arom. H); 4.70 –
4.63 (m, 1 H of ¼CH2); 4.63 – 4.57 (m, 1 H of ¼CH2); 2.33 (s, MeAr); 1.95 (br. t, J ¼ 7.4, ¼CCH2CH2);
1.81 – 1.67 (m, ArC(Me)(OH)CH2)); 1.63 (s, MeC¼); 1.54 (s, ArC(OH)Me); 1.50 – 1.21 (m,
CH2CH2CH2). 13C-NMR (50 MHz, CDCl3): 145.5, 144.9 (C¼CH2, 1 arom. C); 136.0 (1 arom. C);
128.8 (2 arom. CH); 124.6 (2 arom. CH); 110.0 (C¼CH2); 74.5 (C(OH)); 43.7, 37.8 (CH2CH2CH2); 30.2,
22.2, 21.8 (C(OH)(Me)CH2CH2CH2C(¼CH2)Me); 20.9 (MeAr). EI-MS (70 eV): 218 (1.3, Mþ), 200 (3.1,
[M ꢁ H2O]þ), 185 (1.9), 172 (1), 147 (1.6), 145 (7.2), 135 (100), 132 (15.5), 119 (19.5), 105 (4.6), 91
(11.2), 77 (2.9), 69 (4.2), 55 (4.2), 43 (52). Anal. calc. for C15H22O (218.33): C 82.52, H 10.16; found: C
82.49, H 10.15.
Electrochemical Phenylselenoetherification of 3 [3c]. A soln. of 3 (0.218 g, 1 mmol), Ph2Se2 (156 mg,
0.5 mmol), and LiBr (210 mg, 1 mmol) in MeCN (10 ml) was placed in a cell supplied with an ice-
acetone-salt bath (ꢁ10 to ꢁ 58) and electrolyzed at constant current (100 mA, 2 F/mol). The solvent was
distilled off, the residue was extracted several times with Et2O, and the obtained soln. was dried
(Na2SO4). The solvent was evaporated, and the residue was purified by CC (SiO2; hexane/CH2Cl2 1:1 (v/
v)) to afford a mixture of cis- and trans-tetrahydro-2,6-dimethyl-2-(4-methylphenyl)-6-[(phenylselanyl)-
methyl]-2H-pyran (cis-2/trans-2; 0.228 g, 0.61 mmol, 61%), a pale yellow oil, which was used in the next
step of the synthesis. The anal. samples of cis- and trans-2 were obtained from 100 mg (0.268 mmol) of
this mixture by CC (silica gel (10 g); hexane/CH2Cl2 2 :1 (v/v)). The first fraction gave 45 mg of pure
trans-2 (a pale yellow oil), the second one gave 30 mg of the mixture of two isomers, whereas the third
fraction gave 23 mg of pure cis-2 (a pale yellow oil).
Data of cis-2: IR (KBr): 3436, 3056, 2972, 2934, 1637, 1579, 1512, 1478, 1372, 1203, 1073, 1041, 1023,
974, 817, 735, 691. 1H-NMR (250 MHz, CDCl3): 7.59 – 7.38 (overlapped m, 2 arom. H of PhSe); 7.36 – 7.14
(overlapped m, 3 arom. H of PhSe); 7.12 – 7.04 (overlapped m, 4 arom. H of Ar); 2.87 (d, 2J(H,H) ¼ 11.6,
2J(Se,H) ¼ 7.7, 1 H, SeCH2); 2.79 (d, 2J(H,H) ¼ 11.6, 2J(Se,H) ¼ 7.0, 1 H, SeCH2); 2.37 (s, MeAr); 2.09 –
2.04 (m, 1 H); 1.97 – 1.51 (overlapped m, 5 H); 1.47 (s, Me); 1.40 (s, Me). 13C-NMR (62.9 MHz, CDCl3):
145.8 (arom. C); 135.9 (arom. C); 132.0 (arom. C of PhSe); 131.6 (2 arom. CH of PhSe); 128.8, 128.6,
126.1, 125.3 (4 arom. CH of Ar; 3 arom. CH of PhSe); 77.1, 74.5 (COC); 40.7, 34.5, 33.7, 32.9, 28.9 (Me,
CCH2CH2CH2CCH2Se); 21.0 (MeAr); 16.8 (Me). EI-MS (70 eV): 374 (0.1, Mþ), 313 (0.1), 288 (0.1), 273
(0.1), 248 (0.1), 232 (0.1), 216 (0.3), 203 (100), 185 (30), 171 (0.7), 157 (4.6), 145 (19.2), 129 (5.9), 119
(45.4), 105 (13.4), 91 (22.9), 77 (5.8), 69 (35.7), 55 (5.5), 41 (11.8). Anal. calc. for C21H26OSe (373.39): C
67.55, H 7.02; found: C 67.59, H 6.98.
Data of trans-2: IR (KBr): 3436, 3055, 2972, 2936, 1616, 1579, 1512, 1478, 1223, 1074, 1006, 817, 735,
1
691. H-NMR (200 MHz, CDCl3): 7.61 – 7.49 (overlapped m, 2 arom. H); 7.41 – 7.31 (overlapped m, 3
2
2
arom. H); 7.21 – 7.07 (overlapped m, 4 arom. H); 3.19 (d, J(H,H) ¼ 11.6, J(Se,H) ¼ 8.0, 1 H, SeCH2);
3.07 (d, 2J(H,H) ¼ 11.6, 2J(Se,H) ¼ 7.2, 1 H, SeCH2); 2.45 – 2.34 (m, 1 H); 2.32 (s, MeAr); 1.90 – 1.36
(overlapped m, 5 H); 1.34 (s, Me); 0.84 (s, Me). 13C-NMR (50 MHz, CDCl3): 144.5 (arom. C); 135.8
(arom. C); 132.2 (2 arom. CH of PhSe); 131.5 (arom. C of PhSe); 128.8, 128.4, 126.2, 125.9 (4 arom. CH of
Ar; 3 arom. CH of PhSe); 77.2, 74.5 (COC); 44.1, 35.4, 34.4, 33.3, 26.0 (Me, CCH2CH2CH2CCH2Se); 21.0
(MeAr); 17.0 (Me). MS: identical to that of cis-2. Anal. calc. for C21H26OSe (373.39): C 67.55, H 7.02;
found: C 67.58, H 7.05.
Preparation of (ꢀ)-Curcumene Ether (¼ 3,4,5,6-Tetrahydro-2,2,6-trimethyl-6-(4-methylphenyl)-2H-
pyran; (ꢀ)-1): Reduction of cis- and trans-2. The reaction was carried out using an H-cube hydrogenation
reactor (Thalesnano) in continuous-flow mode, and Raney-Ni (CarCartTM cartridge) was used as a
catalyst. To prime the system, the catalyst bed was washed continuously with THF (10 ml) at a flow rate

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of 1 ml/min. The pressure was adjusted to full H2 mode, and the temp. was set at 258. The mixture cis-2/
trans-2 (200 mg, 0.536 mmol) was dissolved in THF (30 ml) and allowed to flow through the H-cube at
1 ml/min. The collected soln. was concentrated under reduced pressure to afford 1 (111 mg, 95%).
1
Colorless oil. IR (KBr): 2956, 2924, 2853, 1462, 1378, 1365, 1273, 1224, 1119, 1078, 987, 820. H-NMR
(200 MHz, CDCl3): 7.41 – 7.30 (AA’ of AA’BB’, 2 arom. H); 7.15 – 7.06 (BB’ of AA’BB’, 2 arom. H); 2.32
(s, MeAr); 2.31 – 2.20 (m, 1 H); 1.33 – 1.84 (overlapped m, 5 H); 1.39 (s, Me); 1.25 (s, Me); 0.78 (s, Me);
1H-NMR data are consistent with those reported in [6]. 13C-NMR (50 MHz, CDCl3): 145.5 (arom. C);
135.6 (arom. C); 128.4 (2 arom. CH); 125.7 (2 arom. CH); 73.9, 72.5 (COC); 36.8, 34.8, 34.1, 32.0, 28.3
(MeCCH2CH2CH2CMe); 21.0 (MeAr); 17.1 (Me). EI-MS (70 eV): 203 (100, [M ꢁ Me]þ), 185 (22.5), 170
(0.1), 157 (1.6), 145 (44.8), 135 (48.1), 119 (72.3), 105 (13.1), 91 (22.6), 77 (4.2), 69 (22.5), 56 (4.9), 43
(22.4). Anal. calc. for C15H22O (218.33): C 82.52, H 10.16; found: C 82.55, H 10.14.
Preparation of 5-(4-Methylphenyl)-5-oxopentanoic Acid (10). Compound 10 was synthesized
according to the procedure described in [9] in 80% yield. White solid. M.p. 145 – 1478 (146 – 1488 [9]). IR
(KBr): 3447, 3100, 2967, 1698, 1676, 1607, 1451, 1409, 1287, 1233, 1193, 1185, 1074, 909, 819, 749, 676. The
1H- and 13C-NMR: identical to those reported in [9].
Preparation of Ethyl 5-(4-Methylphenyl)-5-oxopentanoate (11). Ester 11 was synthesized from 10 by
a modified literature procedure [10] as follows: a 100-ml, single-necked, round-bottomed flask equipped
with a magnetic stirring bar, a DeanꢁStark trap filled with dry toluene, and a H2O-cooled condenser is
charged with 10 (412 mg, 2 mmol), dry toluene (30 ml), abs. EtOH (30 ml), and TsOH · H2O (150 mg).
The mixture was refluxed for 8 h. The solvents were distilled off, and the residue was treated with a
NaOH soln. (20 ml, 2 mol/dm3). The mixture was extracted with Et2O, org. layers were washed with H2O
and brine, dried (Na2SO4), and filtered off. The solvent was evaporated in vacuo, and the residue was
subjected to CC (SiO2 (5 g); hexane/AcOEt 9 :1 (v/v)) to give 11 (459 mg, 98%). Colorless crystals. M.p.
39 – 408 ([12]: 39 – 408). IR: identical to that reported in [5a]. 1H-NMR (600 MHz, CDCl3): 7.90 – 7.84 (m,
HꢁC(2’), Hꢁ(6’)); 7.29 – 7.23 (m, HꢁC(3’), HꢁC(5’)); 4.14 (q, J ¼ 7.2, MeCH2O); 3.03 (t, J ¼ 7.3,
ArCOCH2); 2.43 (t, J ¼ 7.3, CH2COOEt); 2.41 (s, MeAr), 2.06 (quint., J ¼ 7.3, CH2CH2CH2), 1.26 (t,
J ¼ 7.2, MeCH2O). 13C-NMR (151 MHz, CDCl3): 199.1 (ArCO); 173.3 (COOEt); 143.8 (C(4’)); 134.3
(C(1’)); 129.2 (C(3’), C(5’)); 128.1 (C(2’), C(6’)); 60.3 (MeCH2O); 37.3 (ArCOCH2); 33.4 (CH2COOEt);
21.6 (MeAr); 19.4 (CH2CH2CH2); 14.2 (MeCH2O).
Preparation of Ethyl 5-(4-Methylphenyl)hex-5-enoate (9). Wittig olefination of 11 was performed as
t
described in [11]: solid BuOK (0.60 g, 5.34 mmol) was added to a suspension of MePPh3Br (2.00 g,
5.72 mmol) in dry toluene (35 ml) at 08, and the mixture was stirred for 20 min at this temp. The soln. of
11 (1.00 g, 4.27 mmol) in dry toluene (15 ml) was added at once. The mixture was stirred for 1.5 h at r.t.
Workup: aq. NH4Cl at r.t., extraction with Et2O. The org. phase was washed with brine and dried
(Na2SO4). After evaporation, the crude product was purified by CC (SiO2 (70 g); 1. petroleum ether
(PE), and 2. PE/MeOtBu 10 :1 (v/v)) to yield 9 (0.85 g, 86%). Pale-yellow oil. 1H-NMR (600 MHz,
CDCl3): 7.32 – 7.28 (m, HꢁC(2’), HꢁC(6’)); 7.15 – 7.11 (m, HꢁC(3’), HꢁC(5’)); 5.27 (br. d, J ¼ 1.3,
C¼CHAHB, cis to Ar); 5.02 (br. d, J ¼ 1.3, C¼CHAHB, trans to Ar); 4.11 (q, J ¼ 7.1, MeCH2O); 2.56 – 2.51
(m, ArC(¼CH2)CH2); 2.43 (s, MeAr); 2.33 – 2.28 (m, CH2COOEt); 1.81 – 1.75 (m, CH2CH2CH2); 1.25 (t,
J ¼ 7.1, MeCH2O). 13C-NMR (151 MHz, CDCl3): 173.6 (COOEt); 147.2 (C¼CH2); 137.8 (C(1’)); 137.2
(C(4’)); 129.0 (C(3’), C(5’)); 125.9 (C(2’), C(6’)); 112.1 (C¼CH2); 60.2 (MeCH2O); 34.5
(ArC(¼CH2)CH2); 33.6 (CH2COOEt); 23.4 (MeAr); 21.1 (CH2CH2CH2); 14.2 (MeCH2O). CI-MS:
233 (13, [M þ 1]þ), 203 (16, [M ꢁ Et]þ), 189 (100, [M ꢁ Et ꢁ Me]þ). Anal. calc. for C15H20O2 (232.32): C
77.55, H 8.68; found: C 77.50, H 8.73.
Preparation of 2-Methyl-6-(4-methylphenyl)hept-6-en-2-ol (5). MeMgCl in THF (4.59 ml of 3 mol/
dm3 soln., 13.77 mmol) was added to a soln. of 9 (0.80 g, 3.44 mmol) in dry THF at 08, and the mixture
was stirred for 1 h at 08, and additional 2 h at r.t. Workup: aq. NH4Cl at 08, extraction with 3 ꢂ 50 ml Et2O.
The org. phase was washed with H2O and dried (Na2SO4). After evaporation, the crude product was
purified by CC (SiO2 (70 g); 1. PE/MeOtBu 10 :1 and 2. PE/MeOtBu 4 :1 (each v/v)) to yield pure 5
(0.67 g, 89%). Pale-yellow oil. IR (KBr): 3365, 3083, 3025, 2968, 2942, 2869, 1626, 1513, 1465, 1377, 1365,
1189, 1148, 1132, 941, 890, 823, 890, 734. 1H-NMR (600 MHz, CDCl3): 7.32 – 7.28 (m, HꢁC(2’), HꢁC(6’));
7.15 – 7.11 (m, HꢁC(3’), HꢁC(5’)); 5.25 (br. d, J ¼ 1.5, C¼CHAHB, cis to Ar); 5.02 (br. q, J ¼ 1.3,
C¼CHAHB, trans to Ar); 2.52 – 2.46 (m, C(¼CH2)CH2); 2.34 (s, MeAr); 1.48 – 1.55 (m,

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Helvetica Chimica Acta – Vol. 96 (2013)
CH2CH2C(Me)2OH); 1.17 (s, 2 Me). 13C-NMR (151 MHz, CDCl3): 148.1 (C¼CH2); 138.2 (C(1’)); 137.0
(C(4’)); 129.0 (C(3’), C(5’)); 125.9 (C(2’), C(6’)); 111.6 (C¼CH2); 70.9 (C(Me)2OH); 43.4
(CH2C(Me)2OH); 35.7 (C(¼CH2)CH2); 29.2 (C(Me)2OH); 23.0 (CH2CH2CH2); 21.1 (MeAr). ESI-
MS: 241 (100, [M þ Na]þ). Anal. calc. for C15H22O (218.33): C 82.52, H 10.16; found: C 82.46, H 10.20.
Electrochemical Phenylselenoetherification of 5 to Yield 3,4,5,6-Tetrahydro-2,2-dimethyl-6-(4-
methylphenyl)-6-[(phenylselanyl)methyl]-2H-pyran (4) [3c]. The electrochemical phenylselenoetherifi-
cation of 5 was performed as described for 3. From 0.218 g (1 mmol) of 5, 0.220 g (0.59 mmol) of 4 (a
pale-yellow oil) was obtained (59%). IR (KBr): 3055, 3023, 2970, 2937, 2869, 1579, 1510, 1459, 1380, 1364,
1226, 1073, 1032, 1022, 980, 816, 733, 690. 1H-NMR (200 MHz, CDCl3): 7.43 – 7.33 (overlapped m, 4 arom.
H); 7.18 – 7.05 (overlapped m, 5 arom. H); 3.37 (d, 2J(H,H) ¼ 11.6, 2J(Se,H) ¼ 8.7, 1 H, SeCH2); 3.06 (dd,
2
2J(H,H) ¼ 11.6, J(Se,H) ¼ 7.5, 1 H, SeCH2); 2.43 (br. dt, J ¼ 13.6, 4.1, 1 H); 2.32 (s, MeAr); 2.10 – 1.89
(m, 1 H); 1.79 – 1.60 (overlapped m, 2 H); 1.53 – 1.35 (overlapped m, 2 H); 1.24 (s, Me); 0.73 (s, Me).
13C-NMR (50 MHz, CDCl3): 142.4 (arom. C); 136.5 (arom. C); 132.3 (2 arom. CH of PhSe); 132.0 (arom.
C of PhSe); 128.6, 128.5, 126.6 (4 arom. CH of Tol; 2 arom. CH of PhSe); 126.2 (arom. CH of PhSe); 76.1,
73.3 (COC); 46.2, 36.6, 32.0, 30.4, 27.6 (MeCCH2CH2CH2CCH2Se); 21.0 (MeAr); 16.9 (Me). Anal. calc.
for C21H26OSe (373.39): C 67.55, H 7.02; found: C 67.50, H, 7.01.
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Received November 12, 2012