Aldols by Michael addition: Application of the retro-Michael addition to the slow release of enones

Article abstract of DOI:10.1002/hlca.200590252

The reversibility of Michael additions was exploited to create Michael adduct profragrances of several enones. Some of them proved to exhibit interesting properties. The synthesis of aldols (3-hydroxy ketones) by Michael addition also opens a ready access

Full text of DOI:10.1002/hlca.200590252

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Aldols by Michael Addition: Application of the retro-Michael Addition to the
Slow Release of Enones
by Charles Fehr* and José Galindo
Firmenich SA, Corporate R&D Division, P. O. Box 239, CH-Geneva 8
(phone: +41227803638; fax: +41227803334; e-mail: charles.fehr@firmenich.com)
Dedicated to Dr. Ferdinand Näf on the occasion of his 65th birthday
The reversibility of Michael additions was exploited to create Michael adduct profragrances of several
enones. Some of them proved to exhibit interesting properties. The synthesis of aldols (3-hydroxy ketones)
by Michael addition also opens a ready access to 1,3-diketones.
Introduction. – Time-delayed fragrance-delivery systems have been developed to
render possible the perception of a fragrance which, on its own, would be evanescent,
over a long period of time. One distinguishes between physical delivery systems (e.g.
micro-encapsulated perfumes [1]) and chemical delivery systems, in which an odorless
‘profragrance’ (or ‘properfume’) liberates the fragrance molecule by means of a chem-
ical reaction [2–9]. The chemical approach is of course limited to compounds possess-
ing an agreeable odor (fresh, clean) and having a low threshold value (cost, effi-
ciency)1)2). We herein report on a new chemical delivery system, based on retro-
Michael reactions [8]3) and on an alternative method for the formation of aldols (and
1,3-diketones) from enones [10][11].
In 1998, Procter & Gamble [6] submitted a patent covering the release properties of
all possible aldehydic or ketonic fragrance compounds bound to an amine (or poly-
amine). Among all these ‘Schiff bases’, the most efficient delivery systems were in
fact those derived from enones (damascones, carvone). More recently, a similar patent
has been published by BASF [7], indicating that this area represents a hot topic.
Based on earlier work in our laboratory, we hypothesized that the properfumes
derived from enones were in fact not Schiff bases but b-amino ketones derived from
Michael additions. We examined the possibility of other Michael adducts between
the damascones and various O- and S-nucleophiles. The damascones were chosen as
the first targets, because they represent good Michael acceptors, possess a fresh
fruity-flowery odor which is perceived as agreeable even in the absence of other per-
fume components, and have very low threshold values [12].
1
)
Digeranyl succinate represents the first commercialized Firmenich properfume (liberating geraniol); see
[3].
Geranyl 2-phenyl-2-oxoacetate represents the first photolabile properfume (liberating citral); see [4].
For an extension of this work to polymer-bound Michael adducts, see the accompanying publication [9].
2
3
)
)
© 2005 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 88 (2005)
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In addition, we knew from our earlier work [13] that benzyl alcohol (BnOH) readily
adds to a-damascone (1) under basic conditions (Scheme 1; 1,1,3,3-tetramethylguani-
dine=TMG). The Michael adduct 2 served as intermediate for the conversion of
(R)-a-damascone ((R)-1) into (R)-a-ionone ((R)-3) without any racemization.
Scheme 1
a) BnOH, TMG (0.2 equiv.), 208.
From results of that same work, we could assume that hydrogenolysis of benzyl
ether 2 should afford hydroxy ketone 4 (Scheme 2). The perspective of a simple proto-
col to access aldols (and 1,3-diketones) from enones, especially in cases where applica-
tion of the aldol reaction would have been problematic (conservation of enantiomer
purity, macrocyclic 3-hydroxy ketones, etc.), represented an interesting challenge4)5).
We expected that the corresponding esters, e.g., benzoate 5, would represent good can-
didates for the slow release of a-damascone (1) in typical applications of functional per-
fumery.
Results. – Following our own procedure [13], we treated (Æ)-1 with excess BnOH in
the presence of 20 mol-% of TMG and allowed the solution to stand for 24–48 h
(Scheme 2). The volatile portion (1, TMG, and BnOH) of the equilibrium mixture
(2/1 ca. 70 :30) was separated from 2 by bulb-to-bulb distillation and then equilibrated
at r.t. for 24 h. Re-distillation and re-equilibration gave benzyloxy ketone 2 in 92%
yield. Hydrogenolytic cleavage of the benzyl group with Pd/C and TsOH·H2O as cat-
alysts afforded hydroxy ketone 46) in 83% yield. Acylation with benzoyl chloride fur-
nished benzoate 5 (Et3N; cat. N,N-dimethylpyridin-4-amine (DMAP); 73%).
Whereas benzoate 5 proved to be an excellent properfume, releasing a-damascone
(1) of intense odor strength over a period of at least one week [8], the benzyloxy ketone
2 was stable in the absence of base, and did not undergo the retro-Michael reaction. As
we had found that the Michael addition of BnOH was reversible in the presence of
TMG, we prepared ether 6 linked to an amine. Here, due to a lower conversion and
an increased thermal instability, the yield was only 33%, but ether 6 indeed slowly
released a-damascone over time.
Although 2 was stable in the presence of weak bases (anilines, tertiary amines), it
underwent rapid elimination in the presence of TMG or 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU). Indeed, DBU also showed approximately the same catalytic activity
4
)
)
)
For other Michael additions of O-nucleophiles, see [10].
For aldols from epoxy alcohols, see [11a]; for aldols from epoxy ketones, see [11b].
For an alternative preparation by reduction of 8, see [14]; the reported H-NMR data are, however, not
5
6
1
identical with ours.

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Scheme 2
a) ROH, TMG (0.2 equiv.), 208. b) H2, 10% Pd/C, cat. TsOH·H2O, EtOH, 208. c) PhCOCl (1.6 equiv.),
Et3N (1.4 equiv.), cat. DMAP, 0–208.
for Michael additions as TMG. Very recently, an independent report on DBU-catalyzed
Michael additions has been published [10b].
Oxo ester 7 is an interesting properfume, as it represents a Michael adduct capable
of releasing a-damascone (1) but is also a photolabile system prone to undergo Norrish-
II cleavage to generate the diketone 8 (Scheme 3) [4]. Under the usual conditions of
application (softener at pH 3, weak light source), a-damascone (1) was formed, and
the photolytic path could not be ascertained.
Scheme 3
a) PhCOCOCl (1.3 equiv.), Et3N (1.83 equiv.), CH2Cl2, 0–208.
The excellent releasing properties of benzoate 5, derived from a-damascone (1),
prompted us to prepare benzoate 12, derived from d-damascone (9; Scheme 4). The
Michael addition worked very well, affording benzyl ether 10 as a mixture of two dia-
steroisomers (ca. 1:1) in 88% yield. However, hydrogenolysis of 10 in the presence of
10% Pd/C and catalytic amounts of TsOH·H2O occurred with concomitant hydrogen-
ation of the C=C bond. Omitting TsOH·H2O even led to complete hydrogenation of

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Scheme 4
a) BnOH, TMG (0.2 equiv.), 208. b) DDQ (1.2 equiv.), CH2Cl2, H2O, 208. c) PhCOCl (1.6 equiv.), Et3N (1.4
equiv.), cat. DMAP, 0–208.
10 without any debenzylation7). However, debenzylation was readily achieved with 2,3-
dichloro-5,6-dicyanoquinone (DDQ=4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-
dicarbonitrile) [15], affording hydroxy ketone 11 in 90% yield8). Profragrance 12,
obtained by esterification of 11, proved to be as efficient as benzoate 5.
We next explored the thio-Michael adducts of a- and d-damascone with the odorless
dodecane-1-thiol (Scheme 5). These additions were very rapid in the presence of only 1
mol-% of DBU. Michael adducts 13 and 14 showed excellent releasing properties, were
stable upon storage, and their preparations were straightforward. We also prepared the
corresponding sulfoxide 15 and sulfone 16. Whereas both 15 and 16 showed excellent
releasing properties, sulfoxide 15 was too unstable for application in a softener9).
The herein described synthesis of aldols was extended to the synthesis of 1,3-dike-
tones. ‘Ketodamascone’ 8 (Scheme 6), in solution predominantly enolized according to
NMR, possesses interesting odor properties [14]. As we were interested in the odor of
its enantiomers and have ready access to the enantiomers of a-damascone by enantio-
selective protonation [13][17], we decided to convert both (À)-(S)- and (+)-(R)-1 into
the target compounds (À)-(S)-8 and (+)-(R)-8. This was accomplished in three straight-
forward steps (Michael addition, hydrogenolysis, Jones oxidation [18]) without any rac-
emization. The olfactive evaluation showed that (À)-(S)-8 contributes almost exclu-
sively to the appreciated character of racemic ‘ketodamascone’ 8.
Finally, we applied the herein outlined reaction sequence to the synthesis of cyclo-
dodecane-1,3-dione 20 (Scheme 7), which we required in another project. The known
syntheses of diketone 20 are either less efficient [19a,b] or give rise to a mixture of
the isomeric 1,2- and 1,3-diones [19c]. The Michael addition of BnOH to enone 17
7
)
)
)
We thank Dr. M. Marty, Firmenich SA, for performing this study.
8
9
For an alternative synthesis of crude 11 (no spectral data were given), see [16].
Possibly, the thioethers were oxidized to the sulfoxides in air (e.g., 14 to 15) and the sulfoxides then under-
went elimination (via an enol or by Ei elimination). It should be noted that all Michael adducts eliminate
rapidly under basic conditions (e.g., in detergents) but are inappropriate for slow release. We have not tried
to quantify this release process.

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Scheme 5
a) Dodecane-1-thiol (1.0 equiv.), DBU (1 mol-%), THF, 258. b) NaIO4 (1.04 equiv.), MeOH, EtOH, 208. c)
KHSO5 (4.9 equiv.), MeOH, H2O, 0 – 408.
Scheme 6
a) BnOH, TMG (0.2 equiv.), 208. b) H2, 10% Pd/C, cat. TsOH·H2O, EtOH, 208. c) Jones oxidation.
worked as expected, affording crude benzyloxy ketone 18 in 80% yield (in addition to
recovered 17). Hydrogenolysis of 18 and oxidation of the resultant hydroxy ketone 19
furnished diketone 20 (in part enolized) in 79% yield. It should be noted that the prep-
aration of macrocyclic hydroxy ketone 19 by intramolecular aldolization would cer-
tainly be more difficult.
Conclusions. – The preparation of aldols (3-hydroxy ketones) from enones by
BnOH Michael addition/debenzylation was applied to the synthesis of properfumes,
e.g., 5 and 12, and to 1,3-diketones, e.g., (À)-(S)-8 and 20. On the other hand, Michael
adducts derived from thiols are readily accessible and also represent excellent proper-
fumes for applications in functional perfumery, as exemplified by dodecylthioketones
13 and 14.

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3133
Scheme 7
a) BnOH, TMG (0.2 equiv.), 208. b) H2, 10% Pd/C, EtOH, 208. c) Jones oxidation.
Experimental Part
General. Bulb-to-bulb distillation: Büchi-GKR-51 glass-oven; b.p. correspond to the oven temp. TLC: silica
gel F-254 plates (Merck); detection with EtOH/anisaldehyde/H2SO4 18 :1:1. Column chromatography: silica gel
60 (Merck; 0.063–0.2 mm, 70–230 mesh, ASTM); FC=flash chromatography. GC: Varian instrument, model
3500; capillary columns: DB1 30 W (15 m×0.319 mm), DB-WAX 15W (15 m×0.32 mm); chiral capillary col-
umn: CP-Chirasil-DEX CB (25 m×0.25 mm; Chrompack), carrier gas He at 0.63 bar. Optical rotations: 1-ml
cell, Perkin-Elmer-241 polarimeter. 1H- and 13C-NMR: Bruker WH 400 (400 and 100 MHz, resp.). MS: Hewlett
Packard MSD 5972 automated GC/MS instrument, electron energy 70 eV.
(Æ)-3-Hydroxy-1-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-1-one ((Æ)-4; diast. ca. 1:1). A suspension of
benzyl ether 2 [13] (69.0 g, 230 mmol), TsOH·H2O (3.3 g), and 10% Pd/C (1.5 g) in EtOH (250 ml) was shaken
in an H2 atmosphere. After uptake of 5.75 l (90 min), the mixture was filtered over Celite, treated with 10% aq.
K2CO3 soln. (100 ml), and evaporated. The residue was extracted with Et2O, and the extract washed with H2O
and sat. aq. NaCl soln., dried (Na2SO4), and evaporated: 43.8 g (92% pure; 83% of (Æ)-4). 1H-NMR (2 diast.;
1:1): 0.92, 0.92, 0.93 (3s, 6 H); 1.12–1.23 (m, 1 H); 1.17–1.19 (d, J=6, 3 H); 1.60 (split s, 3 H); 1.64–1.77 (m, 1
H); 1.96–2.20 (m, 2 H); 2.42–2.80 (m, 2 H); 2.72 (br. s, 1 H); 3.25–3.43 (br. d, 1 H, OH); 4.20 (m, 1 H); 5.62 (br.
m, 1 H). 13C-NMR (2 diast.; 1:1): 215.8, 215.3 (2s); 129.9, 129.7 (2s); 123.9, 123.8 (2d); 63.9 (d); 63.8, 63.5 (2d);
53.3 (t); 32.5 (s); 30.8, 30.7 (2t); 28.0 (q); 27.8, 27.7 (2q); 23.4 (q); 22.6 (t); 22.2 (q). MS (both diast.): 210 (33), 123
(100), 109 (30), 87 (84), 81 (52), 43 (57).
(Æ)-1-Methyl-3-oxo-3-(2,6,6-trimethylcyclohex-2-en-1-yl)propyl Benzoate ((Æ)-5; diast. ca. 1:1). A soln. of
4 (4.00 g, 92% pure, 17.5 mmol), Et3N (2.30 g (3.20 ml), 22.85 mmol), and DMAP (400 mg) in CH2Cl2 (100 ml)
was treated at r.t. with benzoyl chloride (2.94 g, 2.43 ml, 20.94 mmol). The soln. was stirred for 65 h, treated with
5% HCl soln., and extracted with Et2O (2×). The extract was washed with H2O, sat. aq. NaHCO3 soln., and sat.
aq. NaCl soln., dried (Na2SO4), and concentrated at 50–608/0.03 mbar. The oil (5.84 g) was purified by FC, (SiO2
(90 g), cyclohexane/AcOEt 97:3). 4.25 g (73%) of (Æ)-5. 1H-NMR (2 diast.; 1:1): 0.92, 0.93, 0.94 (3s, 6 H); 1.12–
1.23 (m, 1 H); 1.39–1.42 (2d, J=6, 3 H); 1.59 (s, 3 H); 1.65–1.80 (m, 1 H); 1.95–2.20 (m, 2 H); 2.60–2.83 (m, 1
H); 2.72–2.74 (2s, 1 H); 3.02–3.20 (m, 1 H); 5.50–5.63 (m, 2 H), 7.36–7.45 (m, 2 H), 7.48–7.57 (m, 1 H), 7.96–
8.04 (m, 2 H). 13C-NMR (2 diast.; 1:1): 210.1 (s); 165.7 (s); 132.8 (d); 130.5 (s); 129.9 (s); 129.5 (2d); 128.2 (2d);
123.8 (d); 67.4, 67.6 (2d); 63.6, 63.8 (2d); 51.1 (t); 32.5 (s); 30.7, 30.8 (2t); 27.9 (q); 27.8 (q); 23.5 (q); 22.6 (t); 20.1,
20.1 (2q). MS: 192 (52), 123 (22), 105 (100), 81 (13), 77 (20), 69 (45).
(Æ)-3-[2-(Dimethylamino)ethoxy]-1-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-1-one ((Æ)-6; diast. ca. 1:1).
A soln. of a-damascone (1; 6.44 g; 33.5 mmol), 2-(dimethylamino)ethanol (26.83 g, 30.25 ml, 301 mmol), and
TMG (0.77 g, 6.70 mmol) was stirred at r.t. for 15 h (GC control: 4% conversion). Heating at 708 for 15 h
gave a 70% conversion. The flask was equipped with a distillation still, and excess 2-(dimethylamino)ethanol
was distilled at ca. 608/10 to 2 mbar. Unreacted 1 (3.74 g, 58%), due to some retro-Michael reaction during
workup, was recovered by extraction (Et2O, 5% HCl soln.) and washing (H2O, then sat. aq. NaCl soln.). The
aq. phases were basified (aq. NaOH) and extracted with Et2O (2×), the combined org. phases were washed
with H2O and sat. aq. NaCl soln.), dried (Na2SO4), and evaporated. Bulb-to-bulb distillation (100–1258/0.05
mbar) afforded 3.14 g (33%) of 7. 1H-NMR: 0.90, 0.92, 0.93 (3s, 6 H); 1.10–1.20 (m, 1 H); 1.15–1.18 (2d,
J=6, 3 H); 1.58 (s, 3 H); 1.65–1.77 (m, 1 H); 1.95–2.20 (m, 2 H); 2.23 (s, 6 H); 2.37–2.56 (m, 3 H); 2.70–
2.75 (br. m, 1 H); 2.82–3.00 (m, 1 H); 3.40–3.50 (m, 1 H); 3.55–3.64 (m, 1 H); 3.86–3.99 (m, 1 H); 5.58 (br.
m, 1 H). 13C-NMR: 211.7–212.0 (s); 130.2 (s); 123.6 (d); 71.8, 71.4 (2d); 66.9, 66.8 (2t); 64.1, 64.0 (2d); 59.2
(t); 52.6, 52.4 (2t); 45.9 (2q); 32.4 (s); 30.9, 30.7 (2t); 28.0 (q); 27.9 (q); 23.5, 23.4 (2q); 22.7 (t); 19.8, 19.6
(2q). MS: 281 (3, M+), 192 (2), 123 (7), 73 (17), 72 (17), 58 (100).

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(Æ)-1-Methyl-3-oxo-3-(2,6,6-trimethylcyclohex-2-en-1-yl)propyl Oxophenylacetate ((Æ)-7; diast. ca. 1 :1). A
soln. of phenylglyoxylic acid (=oxophenylacetic acid; 2.57 g, 17.1 mmol) and DMF (5 drops) in CH2Cl2 (40 ml)
was treated at 358 with oxalyl chloride (3.47 g, 2.35 ml, 27.4 mmol) in CH2Cl2 (6 ml). After the exothermic reac-
tion and gas evolution, the yellow soln. was evaporated under N2 (removal of excess oxalyl chloride), the residue
dissolved in CH2Cl2 (10 ml), and the soln. added at 08 to a soln. of 4 (3.00 g, 92% pure, 13.1 mmol) and Et3N (2.43
g, 3.40 ml, 24.0 mmol) in CH2Cl2 (15 ml). The mixture was allowed to reach r.t. (15 min), treated with 5% HCl
soln., and extracted with Et2O (2×), the extract washed with H2O, 5% NaOH soln., and sat. aq. NaCl soln., dried
(Na2SO4), and evaporated, and the residue (4.95 g) purified by FC (SiO2 (50 g), cyclohexane/AcOEt 95 :5): 3.93
g (88%) of (Æ)-7. 1H-NMR: 0.82, 0.85, 0.90, 0.91 (4s, 6 H); 1.08–1.20 (m, 1 H); 1.42–1.43 (2d, J=6, 3 H); 1.51–
1.54 (2 split s, 3 H); 1.59–1.78 (m, 1 H); 1.96–2.18 (m, 2 H); 2.56–2.81 (m, 1 H); 2.70 (s, 1 H); 2.96–3.19 (m, 1
H); 5.53–5.62 (m, 1 H); 5.62–5.75 (m, 1 H); 7.45–7.54 (m, 2 H); 7.60–7.68 (m, 1 H); 7.96–8.04 (m, 2 H). 13C-
NMR: 209.8 (s); 186.8, 186.6 (2s); 163.4, 163.3 (2s); 134.8 (d); 132.4 (s); 129.8 (2d); 129.8, 129.7 (2s); 128.9 (2d);
123.9 (d); 68.3–69.2 (d); 63.8, 63.6 (2d); 50.6, 50.5 (2t); 32.5, 32.4 (2s); 30.7 (t); 27.9, 27.8 (2q); 27.7 (q); 23.4, 23.3
(2q); 22.6 (t); 19.8 (q). MS: 191 (49), 135 (15), 123 (72), 105 (100), 81 (23), 77 (28), 69 (62).
(Æ)-trans-3-(Benzyloxy)-1-(2,6,6-trimethylcyclohex-3-en-1-yl)butan-1-one ((Æ)-10; diast. ca. 1 :1). A soln.
of (Æ)-d-damascone (9; 500 g, 2.46 mol), BnOH (798.1 g, 7.39 mol), and TMG (57.4 g, 0.49 mol) was stirred
at 408 for 21 h (GC control: 78% conversion). The volatiles were separated from 10 by distillation (bath
temp. 50–708/0.2 mbar) furnishing 867 g of distillate (containing at least 150 g (30%) of 9) and 480 g of residue.
Bulb-to-bulb distillation of a sample (10.6 g) at 1258/0.05 mbar afforded 10.1 g of pure 10 (58%). 1H-NMR: 0.87
(split d, J=6, 3 H); 0.91–1.03 (4s, 6 H); 1.24 (d, J=6, 3 H); 1.69 (dd, J=16, 4, 1 H); 1.97 (br. d, J=16, 1 H);
2.23–2.26 (2d, J=9, 1 H); 2.52 (m, 1 H); 2.38–3.03 (m, 2 H); 4.12 (m, 1 H); 4.49 (m, 1 H); 4.55 (m, 1 H);
5.45 (br. d, J=9, 1 H); 5.53 (m, 1 H); 7.21–7.35 (m, 5 H). 13C-NMR: 212.9–213.2 (s); 138.7 (s); 124.0–131.9
(5d); 71.1, 71.0 (2t); 70.7 (d); 63.3, 63.2 (2d); 54.9, 54.8 (2t); 41.8, 41.7 (2t); 33.2, 33.0 (2s); 31.6, 31.5 (2d);
29.8 (q); 20.8 (q); 19.9 (2q). MS: 300 (2, M+), 209 (11), 194 (21), 123 (53), 91 (100), 87 (22).
(Æ)-trans-3-Hydroxy-1-(2,6,6-trimethylcyclohex-3-en-1-yl)butan-1-one ((Æ)-11; diast. ca. 1:1). A soln. of 10
(10.0 g, 33.3 mmol) in CH2Cl2 (180 ml) was treated under stirring at r.t. with H2O (20 ml) and DDQ (9.10 g, 40.0
mmol). The mixture turned red, and gradually an orange precipitate formed. After 6 h, the mixture was filtered
over Celite, the filtrate washed with sat. aq. NaHCO3 soln. and sat. aq. NaCl soln. (2×), dried (Na2SO4), and
evaporated, and the residue (9.75 g) purified by FC (SiO2 (300 g), cyclohexane/AcOEt 95 :5): 6.29 g (90%) of
(Æ)-11. 1H-NMR: 0.89–0.92 (2d, J=6, 3 H); 0.95 (s, 3 H); 0.97–1.00 (2s, 3 H); 1.18–1.20 (2d, J=6, 3 H);
1.71 (dd, J=16, 4, 1 H); 1.96 (br. d, J=16, 1 H); 2.24–2.25 (2d, J=9, 1 H); 2.52 (m, 1 H); 2.41–2.80 (m, 2
H); 3.10–3.80 (br. m, 1 H); 4.24 (m, 1 H); 5.46 (br. d, J=9, 1 H); 5.55 (m, 1 H). 13C-NMR: 216.7–217.1 (s);
131.6, 131.7 (2d); 124.2, 124.3 (2d); 63.3–63.6 (2d); 55.6, 55.4 (2t); 41.7 (t); 33.2 (s); 31.7, 31.6 (2d); 29.8 (q);
22.2, 22.1 (2q); 20.7 (q); 19.9, 19.8 (q). MS: 210 (15, M+), 192 (11), 166 (9), 135 (9), 123 (100), 109 (27), 107
(48), 87 (60), 81 (56), 69 (63), 43 (60).
(Æ)-trans-1-Methyl-3-oxo-3-(2,6,6-trimethylcyclohex-3-en-1-yl)propyl Benzoate ((Æ)-12; diast. ca. 1:1). A
soln. of 11 (25.9 g, 124 mmol), Et3N (16.26 g, 22.40 ml, 161 mmol), and DMAP (2 g) in CH2Cl2 (200 ml) was
treated at r.t. with benzoyl chloride (19.04 g, 15.7 ml, 136 mmol). The mixture was stirred for 15 h, treated
with 5% HCl soln., and extracted with Et2O (2×). The extract was washed with H2O, sat. aq. NaHCO3 soln.,
and sat. aq. NaCl soln., dried (Na2SO4), and concentrated at 65–758/0.01 mbar, and the oil (32.0 g) purified
by FC (SiO2 (500 g), cyclohexane/AcOEt 95 :5): 29.6 g (76%) of (Æ)-12. 1H-NMR: 0.88–0.92 (2d, 3 H);
0.93–1.05 (4s, 6 H); 1.40–1.44 (2d, 3 H); 1.65–1.75 (m, 1 H); 1.95–2.02 (2 br. m, 1 H); 2.22–2.30 (m, 1 H);
2.52 (m, 1 H); 2.60–2.83 (m, 1 H); 2.95–3.20 (m, 1 H); 5.40–5.61 (m, 3 H), 7.38–7.45 (m, 2 H); 7.50–7.56
(m, 1 H); 7.96–8.04 (m, 2 H). 13C-NMR: 211.5, 211.3 (2s); 165.7 (s); 132.8 (d); 131.8, 131.7 (2d); 130.6, 130.5
(2s); 129.5 (2d); 128.3 (2d); 124.2, 124.1 (2d); 67.4, 67.2 (2d); 62.9–63.1 (d); 53.3 (t); 41.7 (t); 33.1 (s); 31.6
(d); 29.8 (q); 20.7 (q); 20.1 (q); 19.9 (q). MS: 192 (42), 122 (33), 105 (90), 77 (45), 69 (100).
(Æ)-3-(Dodecylthio)-1-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-1-one ((Æ)-13). A mixture of a-damascone
(1, 12.00 g, 62.5 mmol) and DBU (95 mg, 0.625 mmol) was treated under water cooling at 25–358 with dodec-
ane-1-thiol (12.63 g, 14.95 ml, 62.5 mmol). After 45 min at 258, the mixture was treated with aq. H2SO4 soln.
(from conc. H2SO4 (34 mg, 0.35 mmol) and H2O (12 ml)) and extracted with AcOEt (12 ml) and the extract
washed with H2O, sat. aq. NaHCO3 soln., and 10% aq. NaCl soln., and concentrated at 758/0.01 mbar: 24.35 g
1
(99%) of crude 13. H-NMR: 0.88 (t, J=7, 3 H); 0.91 (s, 3 H); 0.93 (s, 3 H); 1.17 (m, 1 H); 1.20–1.33 (m, 19
H); 1.36 (m, 2 H); 1.57 (m, 2 H); 1.60 (br. s, 3 H); 1.73 (m, 1 H); 1.96–2.18 (m, 2 H); 2.52 (m, 2 H); 2.53–
2.94 (m, 2 H); 2.71 (br. s, 1 H); 3.27 (m, 1 H); 5.58 (m, 1 H). 13C-NMR: 211.2, 211.1 (2s); 130.0 (s); 123.7 (d);
63.7, 63.6 (2d); 53.4, 53.1 (2t); 34.3, 34.2 (2d); 32.5, 32.4 (2s); 31.9–29.0 (several t); 27.9 (q); 27.8 (q); 23.5
(q); 22.7 (t); 21.6 (q); 14.1 (q).

Helvetica Chimica Acta – Vol. 88 (2005)
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(Æ)-trans-3-(Dodecylthio)-1-(2,6,6-trimethylcyclohex-3-en-1-yl)butan-1-one ((Æ)-14; diast. ca. 1:1). As
described for (Æ)-13, with d-damascone (9; 12.00 g, 62.5 mmol), DBU (95 mg, 0.625 mmol) and dodecane-1-
thiol (12.63 g, 14.95 ml, 62.5 mmol): 23.83 g (97%) of crude 14. 1H-NMR: 0.84–0.92 (m, 6 H); 0.93–1.02 (4s,
6 H); 1.26 (m, 16 H); 1.29 (m, 3 H); 1.36 (m, 2 H); 1.58 (m, 2 H); 1.69 (m, 1 H); 1.96 (2 br. m, 1 H); 2.22 (m,
1 H); 2.50 (m, 3.5 H); 2.70 (m, 1 H); 2.90 (m, 0.5 H); 3.30 (m, 1 H); 5.43 (m, 1 H); 5.53 (m, 1 H). 13C-NMR:
212.5, 212.4 (2s); 131.9, 131.8 (2d); 124.2, 124.1 (2d); 62.9–63.0 (d); 55.3, 55.2 (2t); 41.7 (t); 34.1 (d); 33.2,
33.0 (2s); 31.9 (t); 31.8, 31.6 (2d); 30.9 (t); 29.8 (q); 29.0–29.8 (several t); 22.7 (t); 21.8, 21.6 (2q); 20.7 (q);
19.9 (q); 14.1 (q).
(Æ)-trans-3-(Dodecylsulfinyl)-1-(2,6,6-trimethylcyclohex-3-en-1-yl)butan-1-one ((Æ)-15; diast. ca. 1:1). A
soln. of 11 (2.00 g, 5.10 mmol) in MeOH (20 ml) was added at 08 to a soln. of NaIO4 (1.14 g, 5.30 mmol) in H2O
(11 ml). For solubility reasons, the temperature was brought to r.t., and EtOH (30 ml) was added. The suspen-
sion was stirred for 15 h and then extracted (Et2O/sat. aq. NaCl soln.). The org. phase was washed with aq.
NaHSO3 soln., H2O, sat. aq. NaHCO3 soln., and sat. aq. NaCl soln., dried (Na2SO4), and evaporated, and the
residue (16.2 g) subjected to FC (SiO2 (40 g), cyclohexane/AcOEt 7:3, then 1:1): 803 mg (38%) of 15.
In another experiment, oxidation with H2O2/AcOH was less satisfactory, and one diastereoisomer decom-
posed during purification. 1H-NMR: 0.85–0.94 (m, 6 H); 0.95–1.03 (4s, 6 H); 1.25 (m, 19 H); 1.45 (m, 2 H);
1.65–1.83 (m, 3H); 1.97 (2 br. m, 1 H); 2.28 (m, 1 H); 2.46–2.62 (m, 2.5 H); 2.67 (m, 1 H); 2.78 (m, 0.5 H);
2.98 (m, 0.5 H); 3.15–3.27 (m, 1.5 H); 5.45 (m, 1 H); 5.54 (m, 1 H). 13C-NMR: 211.9, 211.8 (2s); 131.6, 131.5
(2d); 124.4, 124.2 (2d); 62.9–63.0 (d); 49.0–49.3 (t); 48.0 (d); 41.6 (t); 33.2 (s); 31.9 (t); 31. 8 (d); 29.8 (q);
29.0–29.8 (several t); 23.2 (t); 22.7 (t); 21.8, 21.6 (2q); 20.7 (q); 19.9 (q); 14.1 (q); 10.4, 10.3 (2q).
(Æ)-trans-3-(Dodecylsulfonyl)-1-(2,6,6-trimethylcyclohex-3-en-1-yl)butan-1-one ((Æ)-16; diast. ca. 1:1). A
soln. of KHSO5 (10.9 g, 86.5% pure, 62.1 mmol) in H2O (50 ml) was added under ice cooling to a soln. of 14
(5.00 g, 12.7 mmol) in MeOH (100 ml). The temp. was allowed to attain 408. The suspension was stirred for 2
h, and sulfone 16 was extracted (Et2O/aq. NaCl soln.). The org. phase was washed with H2O, sat. aq.
NaHCO3 soln., and sat. aq. NaCl soln., dried (Na2SO4), and evaporated, and the residue (4.32 g) subjected to
FC (SiO2 (130 g), cyclohexane/AcOEt 95 :5): 2.59 g (48%) of 16. 1H-NMR: 0.84–0.92 (m, 6 H); 0.95–1.02
(3s, 6 H); 1.26 (m, 16 H); 1.38 (m, 3 H); 1.43 (m, 2 H); 1.72 (m, 1 H); 1.85 (m, 2 H); 1.98 (2 br. m, 1 H); 2.29
(m, 1 H); 2.52 (m, 1 H); 2.60 (m, 0.5 H); 2.83 (m, 0.5 H); 2.95 (t, J=8, 2 H); 3.12 (m, 0.5 H); 3.35 (m, 0.5 H);
3.63 (m, 1 H); 5.46 (m, 1 H); 5.55 (m, 1 H). 13C-NMR: 210.8, 210.6 (2s); 131.5, 131.4 (2d); 124.5, 124.2 (2d);
63.3, 63.0 (2d); 52.1 (d); 50.2 (t); 45.9, 45.7 (2t); 41.6 (t); 33.4, 33.1 (2s); 28.6–32.1 (several signals); 22.7 (t);
21.6 (t); 20.7 (q); 19.9 (q); 14.6, 14.5 (2q); 14.1 (q).
(À)-1-[(1S)-(2,6,6-Trimethylcyclohex-2-en-1-yl)-butane-1,3-dione ((À)-(S)-8). An ice-cooled soln. of crude
(S,RS)-4 (1.43 g, max. 6.33 mmol; obtained from (S,RS)-2 (1.90 g, 6.33 mmol)) in acetone (60 ml) was treated
dropwise under vigorous stirring with 0.5M Jones reagent (15 ml) in acetone. After 20 min, the green suspension
was treated with sat. aq. NaCl soln. and pentane, the org. phase washed with H2O+trace of aq. NaHCO3 soln.
(pH ca. 7), H2O, and sat. aq. NaCl soln., dried (Na2SO4), and evaporated, and the residue (1.32 g) subjected to
FC (SiO2 (15 g), cyclohexane/AcOEt 98 :2): 840 mg (64% from (S,RS)-2) of (À)-(S)-8. [a]2D0 =À408 (EtOH,
1
c=0.024). H-NMR ((Z)-enol form): 0.91 (s, 3 H); 0.96 (s, 3 H); 1.18 (m, 1 H); 1.63 (d, J=2, 3 H); 1.68 (m, 1
H); 2.07 (s, 3 H); 2.08 (m, 2 H); 2.34 (br. s, 1 H); 5.53 (s, 1 H); 5.61 (br., 1 H); 10.17 (br., 1 H). 13C-NMR
((Z)-enol form): 194.2 (s); 192.6 (s); 130.6 (s); 123.6 (d); 101.4 (d); 59.5 (d); 32.5 (s); 31.1 (t); 28.0 (q); 27.7
(q); 25.5 (q); 23.2 (q); 22.7 (t). MS: [14].
(+)-1-[(1R)-2,6,6-Trimethylcyclohex-2-en-1-yl)butane-1,3-dione ((+)-(R)-8). As described above, from (R,
RS)-4). [a]2D0 =+404 (EtOH, c=0.035).
3-Hydroxycyclododecanone (19). As described for 2 [13], 17 (10.80 g, 60.0 mmol) was converted into crude
benzyl ether 18 (13.75 g, 80%). A suspension of 18 (13.75 g, max. 47.7 mmol) and 10% Pd/C (1.37 g) in EtOH
(150 ml) was shaken in an H2 atmosphere. After uptake of 1.30 l (13 h), the mixture was filtered over Celite and
1
the filtrate evaporated: 9.61 g (100%) of crude, solid 19. H-NMR: 1.15–1.48 (m, 13 H); 1.50–1.85 (m, 4 H);
2.28 (m, 1 H); 2.61 (m, 1H); 2.65 (m, 1 H); 2.90 (dd, J=16, 4, 1 H); 3.96 (m, 1 H). 13C-NMR: 214.0 (s); 68.9
(d); 44.9 (t); 43.2 (t); 33.4 (t); 25.8 (t); 25.6 (t); 24.2 (t); 23.9 (t); 22.8 (t); 22.3 (t); 21.8 (t). MS: 198 (2), 180
(12), 137 (15), 122 (33), 111 (33), 98 (61), 95 (47), 81 (76), 71 (62), 58 (100), 55 (62), 43 (88).
Cyclododecane-1,3-dione (20). As described for (À)-(S)-8, with 19 (9.61 g, max. 47.7 mmol): 20 (8.90 g).
Bulb-to-bulb distillation afforded 8.19 g (79%) of pure solid 20 (in soln., ca. 36% as (Z)-enol according to
NMR). M.p. 55–578 ([19b]: 57–598).

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Helvetica Chimica Acta – Vol. 88 (2005)
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Received August 12, 2005