Odoriferous cyclic ethers via co-halogenation reaction: Facile preparation of nerol oxide, Florol, Florol methyl ether, and Pityol methyl ether

Article abstract of DOI:10.1002/hlca.200790016

A series of odoriferous cyclic ethers, including nerol oxide (1), Floral (2), Floral methyl ether (3), and Pityol methyl ether (4b), were prepared by a versatile synthetic protocol based on co-halogenation with 1,3-dibromo-5,5-dimethylhydantoin (= 1,3-dibromo-5,5-dimethylimidazolidine-2,4- dione; DDH) as the key step. The methodology provides a facile access to important perfumery molecules from abundantly available monoterpene alcohols.

Full text of DOI:10.1002/hlca.200790016

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Odoriferous Cyclic Ethers via Co-Halogenation Reaction: Facile Preparation
of Nerol Oxide, Florolꢀ, Florolꢀ Methyl Ether, and Pityolꢀ Methyl Ether
by PankajGupta a), Vijay K. Sethia), Subhash C. Taneja*a), Bhahwal A. Shaha), Samar S. Andotraa),
Surrinder Koula), Swapandeep S. Chimnib), and Ghulam N. Qazia)
a) Bioorganic Chemistry Division, Regional Research Laboratory, Canal Road, Jammu Tawi-180001,
India (phone: +91-191-2572002; fax +91-191-2548607; e-mail: sc_taneja@yahoo.co.in)
b) Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, India
A series of odoriferous cyclic ethers, including nerol oxide (1), Florolꢀ (2), Florol methyl ether (3),
and Pityolꢀ methyl ether (4b), were prepared by a versatile synthetic protocol based on co-halogenation
with 1,3-dibromo-5,5-dimethylhydantoin (=1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; DDH) as
the key step. The methodology provides a facile access to important perfumery molecules from abun-
dantly available monoterpene alcohols.
Introduction. – Monoterpene cyclic ethers with dihydropyran, tetrahydropyran, and
tetrahydrofuran backbones are well-known for their fresh and stimulating fragrances.
Some important members include rose oxides, nerol oxide, Florolꢀ, Clarycetꢀ, Der-
moxꢀ, Pityolꢀ, and Rhubafuranꢀ 1). Most of these compounds, particularly the tetrahy-
dropyrans, possess a fresh floral fragrance coupled either with a dominant or a subdued
ethereal fresh green note. Nerol oxide and rose oxides, with di- and tetrahydropyran
frameworks, are the natural constituents of many aromatic plants. Rose oxides, for
example, have been isolated from rose oil and also found in the essential oils of Gera-
nium bourbon and Eucalyptus citriodora [1]. Similarly, nerol oxide was first isolated
from Bulgarian rose oil and also detected in several Pelargonium species [2] and differ-
ent grape varieties. Pityol has been identified as a pheromone [3] component of bark
beetle, red pine cone beetle, and white pine cone beetle. Most commercial products
such as Florol, Clarycet, Dermox, and Rhubafuran are non-natural, synthetic prepara-
tions being used in a large number of fragrances and formulations by the industry. So
far, methyl ethers of neither Pityol nor Florol have been synthesized and evaluated.
In the present work, we describe a facile synthetic strategy based on co-halogena-
tion [4] as a key step for the preparation of nerol oxide (1) and Florol (2), as well as
Florol methyl ether (3) and Pityol methyl ether (4b). Earlier, we have developed and
patented an efficient synthesis of racemic and non-racemic rose oxides from citronellol
using the co-halogenation strategy [5]. The successful syntheses of these important per-
fumery compounds prompted us to investigate the general applicability of this strategy
aimed at the preparation of cyclic ethers.
1
)
Most of these compounds are registered trade marks, but will not be marked as such in the following
discussion.
ꢁ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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Results and Discussion. – 1 .Synthesis of Nerol Oxide. There are only a few reported
methods for the preparation of nerol oxide (=3,6-dihydro-4-methyl-2-(2-methylprop-
1-en-1-yl)-2H-pyran; 1). The earliest methods were developed by Ohloff and co-work-
ers [6–8], where natural nerol and (ꢀ)-(R)-linalool were used as starting materials for
the preparation of racemic and optically active 1, respectively. The method of Tyman
and Willis [9] involves acid-catalyzed reaction of 3-methylbut-2-enol with 3-methyl-
but-3-enol. Kitahara et al. [10] reported the conversion of a natural monoterpene b-
ketol to nerol oxide in 25% yield. A US patent [11] also disclosed the formation of 1
via photo-oxidation of nerol proper. In 1999, Wust et al. [12] reported an enantioselec-
tive total synthesis of (S)-nerol oxide ((S)-1) and of rose oxides from isoprene in a
multi-step reaction sequence.
In the present work, nerol oxide was synthesized from nerol (5) by means of co-hal-
ogenation as the key step. The synthetic protocol is outlined in Scheme 1. In the first
step, regioselective bromomethoxylation of 5 with 1,3-dibromo-5,5-dimethylhydantoin
(=1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; DDH) in MeOH was achieved at
low temperature, affording the adduct 6 in 85% yield. Dehydrobromination of 6 was
accomplished by exposure to KOH in MeOH to furnish the dienol 7 in high yield.
Finally, rearrangement to nerol oxide (1) was effected with 10% HCl at 5–108 in
80% yield, the overall yield of 1, thus, being ca. 61 % (Scheme 1).
Scheme 1
i) MeOH, 0–58; 85%. ii) KOH, MeOH, reflux; 89%. iii) 10% aq. HCl; 80%.

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It is interesting to note that when a natural mixture of geraniol/nerol 64 :36 was sub-
jected to the above co-halogenation with DDH at 108, both geometric isomers2) gave
the corresponding mono-adducts. However, only the (2Z)-isomer 7, derived from
nerol, could be cyclized to nerol oxide (22% yield).
2. Synthesis of Florol. Florol (=tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-
4-ol; 2) was developed by Firmenich as an exotic fragrance known for its fresh, soft, and
natural floral note. Today, the compound is widely being used in the making of per-
fumes. Florol is used as a diastereoisomeric pair of racemates, and its exact method
of preparation has not been disclosed by the firm [13]. All the previously reported syn-
theses of 2 [14] are low-yielding and involve complex reaction procedures. In 2004,
Abate et al. [15] reported the first total synthesis of enantiomerically enriched Florol
(2) by a biocatalytic route for the purpose of odor and threshold evaluations. This
method, however, is only of academic interest.
Our co-halogenation strategy for the synthesis of 2 started from an easily available,
natural mixture of geraniol/nerol. As described above for the preparation of 1, reaction
with DDH in MeOH gave the adduct 8, which was immediately (without purification)
subjected to oxymercuration–demercuration with Hg(OAc)2/NaBH4 at moderate tem-
perature (ca. 1 88) to avoid formation of side products. The resulting diol 9 was dehydro-
brominated in the presence of base to afford 10, which was cyclized to 11 obtained as a
syn/anti 72 :28 diastereoisomer mixture. The syn-11 isomer was separated by column
chromatography, the relative configuration being established by NOE experiments
(20% enhancement of the signal for HꢀC(2) upon irradiation of the 4-Me group).
Finally, hydrogenation on Pd/C afforded the racemic syn- and anti-diastereoisomers
of Florol (2). The overall yield of 2 from geraniol/nerol was ca. 45%. The cyclization
step with mineral acid (HCl) somewhat reduced the overall yield due to the formation
of unwanted side products. However, no attempts were made to optimize this step.
3. Synthesis of Florol Methyl Ether. Florol methyl ether (=tetrahydro-4-methoxy-4-
methyl-2-(2-methylpropyl)-2H-pyran; 3) appeared to be an interesting target because
it has not been used so far by the perfumery industry. An alternative route to its syn-
thesis was envisaged in place of direct methylation of Florol (2). As shown in
Scheme 3, we started from 3-methoxycitronellol (12), obtained as a by-product in
25–30% yield along with the major product geraniol/nerol upon reduction of citral/
neral (13) with an excess of NaBH4 in MeOH. Compound 12 was then converted to
syn- and anti-14 (60 :40 diastereoisomer mixture) in almost 70% yield by co-halogen-
ation (! 15), dehydrobromination (! 16), and cyclization (! 14). The cyclic com-
pounds 14 already displayed a mild flowery note resembling that of Florol, but much
weaker in intensity. Finally, hydrogenation of 14 over Pd/C resulted in the formation
of both diastereoisomers of Florol methyl ether (3). The flowery note completely dis-
appeared in the final product, and it became almost odorless. The syn and anti isomers
of 3 were separated by column chromatography, and their structures and relative con-
figurations were established on the basis of 1D- and 2D-NMR experiments.
4. Synthesis of Pityol Methyl Ether. Two enantiomers out of the four possible iso-
mers of Pityol (=tetrahydro-2-(1-methoxy-1-methylethyl)-5-methylfuran; 4a) are nat-
2
)
Geraniol is the (2E)-isomer of nerol (5).

Helvetica Chimica Acta – Vol. 90 (2007)
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Scheme 2
i) DDH, MeOH, 5–108; 85%. ii) 1. Hg(OAc)2 ,THF, H2O; 2. NaBH4, NaOH; 75%. iii) KOH,
MeOH; 88%. iv) 5% aq. HCl; 82%. v) H2, Pd/C; 97%.
Scheme 3
i) NaBH4, MeOH; 25%. ii) DDH, MeOH, 5–108; 92%. iii) KOH, MeOH, reflux; 89%. iv) 10% aq.
HCl; 54% (syn), 38% (anti). v) H2, Pd/C; quant.

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urally occurring pheromones. The (2R,5S)-isomer serves as the male-specific attractant
for the spruce bark beetle Pityophthorus pityographus, and the (2R,5R)-isomer was
identified as the aggregation pheromone of the elm bark beetle Pteleobius vittatus.
Due to its commercial importance, various syntheses of Pityol (4a) have been reported.
Ruthenium(VII) oxide catalyzed cyclization was used to obtain predominantly the anti-
isomer, as reported by Tang and Kennedy [16]. Steinreiber et al. [17] used racemic sul-
catol as a raw material for the enantio- and diastereoconvergent synthesis of Pityol iso-
mers, the key step being lipase-catalyzed ring closure of an oxirane derivative. Ishihara
et al. [18] converted 2-methylhept-2-en-6-one to a mixture of 4a and a tetrahydropyran
isomer via ketal formation, followed by reduction. In a different approach, 3-hydroxy-
butanoate was used as a raw material for the synthesis of the non-racemic diaster-
eoisomers of Pityol [19][20].
Our co-halogenation methodology could be successfully applied to the synthesis of
Pityol methyl ether (4b), as outlined in Scheme 4. Racemic sulcatol (17a) was acety-
lated to 17b, and the latter was subjected to bromomethoxylation to afford the inter-
mediate 18. In the next step, deacetylation and concomitant cyclization was effected
with KOH in MeOH, which gave the target compound 4b in ca. 70% yield. The ratio
of syn- to anti-4b was 15 :85 according to NMR and GC analyses. Both diastereoisom-
ers were separated by column chromatography, and their structures were established by
1D- and 2D-NMR analyses.
Scheme 4
i) Ac2O, CH2Cl2, DMAP cat.; quant. ii) DDH, MeOH, 5–108; 85%. iii) KOH, MeOH, reflux; 82%.
In conclusion, co-halogenation has proved to be a very successful and versatile tool
for the synthesis of odoriferous cyclic ethers such as nerol oxide, Florol, Florol methyl
ether, and Pityol methyl ether. The overall yields of the final products were in all the
syntheses either comparable or better than those reported in the literature.
Experimental Part
1. General. Reagents and solvents were of laboratory-routine (LR) grade. Nerol and citronellol
(>95%) were purchased from Aldrich (Mumbai), and racemic sulcatol (17a) was prepared from natural
citral/neral by retro-aldol reaction in the presence of 5% NaOH, followed by hydro-distillation and puri-
fication (>98%) by column chromatography (CC). Thin-layer chromatography (TLC) was performed on
silica-gel-coated Al plates (Merck). GC Analyses were performed on a GC/MS QP-2000 gas chromato-
graph. IR Spectra were recorded on a FT-IR Bruker 270-30 spectrophotometer; in cmꢀ1. 1H-NMR Spec-

Helvetica Chimica Acta – Vol. 90 (2007)
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tra were recorded on a Bruker 200-MHz spectrometer in CDCl3; chemical shifts d in ppm rel. to Me4Si,
J in Hz. Mass Spectra were recorded on a Jeol MSD-300 or a Bruker Esquire-3000 GC/MS apparatus; in
m/z (rel. %).
2. Synthesis of Racemic Nerol Oxide (1). (2Z)-6-Bromo-3,7-dimethyl-7-methoxyoct-2-en-1-ol (6). In a
flask fitted with a thermometer, a dropping funnel, and a gas inlet, 1,3-dibromo-5,5-dimethylhydantoin
(DDH; 50.0 g, 0.174 mol) was added in small portions with vigorous stirring to a soln. of nerol (50.0 g,
0.324 mol) in anh. MeOH (150 ml) under N2 atmosphere. The temp. during the addition of DDH was
kept between 5 to 108. When the reaction was complete, the mixture was poured in cold H2O and
extracted with AcOEt (3”50 ml). The combined org. layer was washed with 5% aq. Na2CO3 soln.
(3”25 ml), and then washed neutral with H2O (3”30 ml). The org. layer was separated, dried
(Na2SO4), and concentrated under reduced pressure to afford 6 (73.12 g, 85%). Colorless oil. IR
(KBr): 3445, 2977, 1464, 1382, 1367, 1231, 1182, 1130, 1070, 861, 778, 746.
1H-NMR: 1.27, 1.32 (2s, 2
G
Me); 1.74 (s, MeꢀC=); 1.75–1.81 (m, CH2); 2.14 (m, CH2ꢀC=); 3.23 (s, MeO); 3.89 (d, J=11.6,
CHBr); 4.19 (d, J=6.7, CH2OH); 5.51( t, J=6.0, HC=). 13C-NMR: 20.9; 22.7; 23.1; 29.8; 31.1; 49.2;
58.4; 62.8; 76.1; 125.6; 137.3. MS: 265 (2, M+), 185 (5), 170 (15), 153 (35), 139 (12), 135 (12), 123 (10),
109 (17), 85 (15), 73 (100), 79 (16).
(2Z,5E)-3,7-Dimethyl-7-methoxyocta-2,5-dien-1-ol (7). A soln. of crude 6 (70.0 g, 0.265 mol) in
MeOH (200 ml) containing KOH (35.0 g) was heated at reflux for 9 h. Three quarters of the solvent
were removed by distillation at reduced pressure. The remaining contents were poured into cold H2O,
and the mixture was extracted with CHCl3 (4”50 ml). The org. layer was separated, washed neutral
with H2O (3”50 ml), dried (CaCl2), and concentrated under reduced pressure to afford 7 (43.69 g,
89%). Pale-yellow oil. 1H-NMR: 1.25, 1.27 (2s, 2 Me); 1.73 (s, Me); 2.41( d, J=7.2, CH2); 3.14 (s,
MeO); 4.14 (d, J=6.6, CH2OH); 5.47–5.55 (m, 3 CH). 13C-NMR: 23.0; 25.3; 25.4; 34.6; 49.7; 58.3;
74.4; 124.6; 126.8; 136.2; 136.8. MS: 184 (4, M+), 167 (6), 166 (35), 154 (43), 153 (5), 135 (100), 123
(23), 93 (2), 73 (7), 60 (5).
Nerol Oxide (1). To a soln. of crude 7 (40.0 g, 0.217 mol) in hexane (100 ml) was added 5% aq. HCl
(15 ml) at 08, and the mixture was stirred for 2 h. The org. layer was separated, extracted with 5% aq.
NaHCO3 soln. (3”20 ml), washed neutral with H2O (3”30 ml), dried (Na2SO4), concentrated under
reduced pressure, and purified by CC (SiO2) to afford racemic 1 (26.47 g, 80%). Colorless oil. 1H-
NMR: 1.67, 1.70 (2s, 2 Me); 1.74 (s, Me); 2.11 (m, CH2); 4.23 (m, OCH2, OCH); 5.22 (d, J=7, HC=);
5.41( m, HC=). 13C-NMR: 19.6; 23.9; 26.9; 37.2; 66.8; 71.9; 120.9; 126.9; 133.1; 137.3. MS: 152 (3,
M+), 138 (21), 125 (100), 109 (4), 84 (7), 80 (14), 70 (9), 68 (16).
3. Synthesis of Florol. (E/Z)-6-Bromo-3,7-dimethyl-7-methoxyoct-2-en-1-ol (8). Commercial gera-
niol/nerol (50.0 g, 0.324 mol) was converted to the title compound in analogy to the method described
for nerol oxide (1). Yield of 8: 73.12 g (85%). IR (KBr): 3445, 2977, 1464, 1382, 1367, 1231, 1182,
1
1130, 1070, 861, 778, 746. H-NMR: 1.28, 1.33 (2s, 2 Me); 1.79 (s, Me); 1.74–1.81 (m, CH2); 3.22 (s,
MeO); 2.14 (dt, J=10.7, 5.5, CH2C=); 3.42 (t, J=6.1, CHBr); 4.18 (d, J=5.9, CH2OH); 5.48 (t, J=5.9,
HC=). 13C-NMR: 16.3; 19.9; 23.1; 29.8; 31.0; 49.2; 58.4; 62.8; 76.1; 122.6; 137.3. MS: 265 (M+), 185
(5), 170 (15), 153 (35), 139 (12), 135 (12), 123 (10), 109 (17), 85 (15), 73 (100), 79 (16).
6-Bromo-3,7-dimethyl-7-methoxyoctane-1,3-diol (9). A soln. of isomeric 8 (5.3 g, 0.02 mol) in THF
(100 ml) was added to a soln. of Hg(OAc)2 (20 g, 0.062 mol) in THF/H2O 1:1. The mixture was stirred
for 2 h. After completion of the reaction (TLC control), 0.5M NaBH4 (19 g, 0.05 mol) in 3M aq. NaOH
soln. (100 ml) was added, and the mixture was stirred for 2 h. Workup included extraction with
AcOEt (3”30 ml), washing with H2O, and drying. After removal of the solvent, the crude product
was purified by CC (SiO2) to afford 9 (4.24 g, 75%). IR (KBr): 3384, 2974, 1464, 1382, 1368, 1248,
1183, 1130, 1069, 970, 932, 860, 780. 1H-NMR: 1.19 (s, Me); 1.23, 1.26 (2s, 2 Me); 1.41–1.70 (m,
(CH2)2); 1.86–2.04 (m, CH2); 3.16 (s, MeO); 3.77–3.90 (m, CH2OH, CHBr). 13C-NMR: 21.4; 23.5;
26.5; 27.9; 41.2; 41.9; 49.7; 59.5; 64.9; 73.3; 125. MS: 283 (2, M+), 265 (2), 253 (3), 219 (4), 195 (2), 183
(8), 165 (6), 153 (3), 139 (2), 107 (4), 85 (25), 73 (100), 45 (15).
(5E)-3,7-Dimethyl-7-methoxyoct-5-ene-1,3-diol (10). A soln. of crude 9 (2.83 g, 0.01mol) and KOH
(2.0 g) in MeOH (15 ml) was heated at reflux for 9 h. The solvent was removed by distillation at reduced
pressure, bringing the total volume to one fourth. The remaining mixture was extracted with CHCl3
(4”15 ml). The org. layer was washed neutral with H2O (3”15 ml), dried (CaCl2), and concentrated

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Helvetica Chimica Acta – Vol. 90 (2007)
to give a pale-yellow oily substance, which, after CC (SiO2), gave 10 (1.77 g, 88%). Colorless liquid. IR
(KBr): 3447, 2976, 1464, 1382, 1368, 1248, 1183, 1130, 1069, 970, 932, 860, 780. 1H-NMR: 1.22–1.27 (3s, 3
Me); 1.67 (m, CH2); 2.31(d, J=6.2, CH2ꢀC=); 3.16 (s, MeO); 3.91( m, CH2OH); 5.58 (m, 2 HC=). 13C-
NMR: 25.2; 25.3; 26.2; 41.0; 45.2; 49.8; 59.1; 73.0; 74.3; 125.4; 139.3. MS: 202 (3, M+), 185 (4), 144 (13),
103 (6), 85 (21), 73 (100), 69 (14).
(2RS,4RS)- and (2RS,4SR)-3,4,5,6-Tetrahydro-4-methyl-2-(2-methylprop-1-en-1-yl)-2H-pyran-4-ol
(anti- and syn-11, resp.). To a cooled soln. of 10 (2.02 g, 0.01mol) in hexane (100 ml) was added 5%
aq. HCl (15 ml) at 0–58, and the mixture was stirred for 2 h. The org. layer was separated, washed
with 5% aq. NaHCO3 soln. (3”20 ml) and H2O (3”30 ml), dried, and concentrated under reduced pres-
sure to give 11 (1.39 g, 82%; anti/syn 28 :72). The diastereoisomer mixture was separated by CC (SiO2;
hexane/AcOEt 95 :5).
Data of anti-11. IR (KBr): 3425, 2963, 1619, 1451, 1377, 1361, 1758, 1133, 1078, 1051, 1005, 926. 1H-
NMR: 1.42 (s, Me); 1.62 (d, J=7.0, CH2); 1.88–1.90 (2s, Me2C); 1.70–1.86 (m, CH2); 3.50 (m, OCH2);
4.02 (m, OCH); 5.12 (d, J=7.0, HC=).13C-NMR: 18.5; 25.7; 31.8; 38.4; 44.7; 63.4; 67.9; 70.1; 125.7;
135.9. MS: 170 (100, M+), 153 (20), 125 (8), 101 (2), 85 (3).
Data of syn-11. IR (KBr): 3425, 2963, 1619, 1451, 1377, 1361, 1758, 1133, 1078, 1051, 1005, 926. 1H-
NMR: 1.27 (s, Me); 1.62 (d, J=7.0, CH2); 1.76 (2s, Me2C); 1.70–1.88 (m, CH2); 3.84 (dd, J=7.4 , 1.5,
OCH2); 4.38 (dt, J=8.9, 3.4, OCH); 5.14 (d, J=7.0, HC=). 13C-NMR: 18.5; 23.3; 31.8; 38.5; 43.7; 64.4;
66.9; 70.1; 125.7; 135.9. MS: 170 (100, M+), 153 (20), 125 (8), 101 (2), 85 (3).
Florol (=(2SR,4SR)-3,4,5,6-Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol; syn-2). A soln.
of syn-11 (1.70 g, 0.01 mol) in MeOH (30 ml) was hydrogenated at 40 psi over 5% Pd/C (100 mg) to yield
Florol (1.68 g, 97%). Colorless liquid. IR (KBr): 3430, 2963, 1451, 1377, 1361, 1133, 1078, 1051, 1000, 930.
1H-NMR: 3.74–3.87 (m, HeqꢀC(6), HꢀC(2)); 3.68 (dd, J=11.6, 2.1, HaxꢀC(6)); 1.67–2.08 (m, CH2,
CH); 1.41–1.60 (m, CH2); 1.20–1.30 (m, CH2); 1.26 (s, Me); 0.88 (d, J=6.7, Me2C). MS: 172 (5, M+),
54 (25), 139 (20), 115 (58), 71 (100), 43 (75).
4. Synthesis of Florol Methyl Ether (3). 3-Methoxycitronellol (=3,7-Dimethyl-3-methoxyoct-6-en-1-
ol; 12). To a soln. of citral (13; 150 g, 0.986 mol) in MeOH (500 ml) was slowly added NaBH4 (9.65 g,
G
0.255 mol) at r.t. After completion of the reaction, the soln. was poured into cold H2O and extracted
with Et2O (3”100 ml). The org. layer was separated, washed with H2O, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by CC (SiO2; hexane/AcOEt 10 :1) to afford 12 (45.8 g,
1
25%). IR (KBr): 3395, 2969, 2931, 2826, 1671, 1453, 1376, 1343, 1115, 1077, 893, 834. H-NMR: 1.23 (s,
Me); 1.40–2.30 (m, (CH2)3); 1.63, 1.70 (2s, Me2C=); 3.23 (s, MeO); 3.80 (t, J=6.0, CH2OH); 5.16 (t,
J=5.5, HC=). 13C-NMR: 19.1; 23.7; 23.8; 27.1; 39.0; 40.7; 50.3; 60.9; 78.2; 124.5; 132.0. MS: 186 (M+),
171, 154, 122, 120, 108, 102, 85, 69, 56.
6-Bromo-3,7-dimethoxy-3,7-dimethyloctan-1-ol (15). Prepared from 12 (11.1 g, 0.06 mol) in analogy
to 6. Yield: 16.3 g, 92%. IR (KBr): 3390, 2976, 1464, 1382, 1237, 1183, 1072, 966, 860. 1H-NMR: 1.23 (s,
Me); 1.30, 1.33 (2s, Me2C); 3.26 (s, 2 MeO); 1.5–2.4 (m, (CH2)3); 3.53–4.10 (m, CH2OH, CHBr). MS: 297
(M+), 250, 216, 168, 153, 139, 125, 103, 97, 85, 73.
(5E)-3,7-Dimethoxy-3,7-dimethyloct-5-en-1-ol (16). A soln. of 15 (9.8 g, 0.033 mol) in MeOH (50 ml)
containing KOH (5.1g, 0.091mol) was heated at reflux for 9 h. Usual workup and CC gave 16 (6.34 g,
1
89%). Pale-yellow oil. IR (KBr): 3447, 2976, 1650, 1463, 1380, 1074, 907. H-NMR: 1.23 (s, Me); 1.26
(s, Me2C); 1.50–1.70 (m, CH2); 2.31( d, J=6.2, CH2ꢀC=); 3.16, 3.26 (2s, 2 MeO); 3.76 (t, J=6,
CH2OH); 5.46–5.73 (m, 2 HC=). 13C-NMR: 21.9; 24.3; 27.2; 36.7; 41.5; 49.4; 50.6; 61.1; 75.1; 75.7;
125.4; 139.2. MS: 217 ([M+1]+), 185, 167, 144, 103, 97, 85, 73.
(2RS,4SR)- and (2SR,4SR)-3,4,5,6-Tetrahydro-4-methoxy-4-methyl-2-(2-methylprop-1-en-1-yl)-2H-
pyran (syn- and anti-14, resp.). To a soln. of 16 (5.86 g, 0.027 mol) in hexane (50 ml) was added 20%
aq. HCl (3 ml) at 0–58. The mixture was stirred vigorously for 15 min. The org. layer was separated,
washed neutral with H2O, dried (Na2SO4), and concentrated under reduced pressure. The diastereoiso-
meric mixture was separated by CC (SiO2; hexane/AcOEt 20 :1) to afford syn-14 (2.7 g, 54%) and anti-14
(1.9 g, 38%).
1
Data of syn-14. IR (KBr): 2968, 2939, 1677, 1460, 1376, 1256, 1175, 1081, 1001, 912, 821, 728. H-
NMR: 1.14 (s, Me); 1.27 (dd, J=11.4, 2.5, HaxꢀC(3)); 1.47 (dd, J=8.6, 5.5, HeqꢀC(3)); 1.65–1.91 (m,

Helvetica Chimica Acta – Vol. 90 (2007)
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CH2); 1.70 (s, Me2C=); 3.20 (s, MeO); 3.76 (dd, J=7.4, 1.5, OCH2); 4.30 (m, OCH); 5.12 (d, J=8.0, HC=
). 13C-NMR: 18.4; 24.9; 25.7; 35.3; 41.6; 48.7; 63.2; 69.8; 71.4; 125.9; 135.6. MS: 184 (4, M+), 170 (10), 169
(10), 153 (35), 145 (11), 137 (36), 133 (23), 123 (14), 108 (18), 104 (100), 98 (44), 92 (19), 80 (51).
Data of anti-14. IR (KBr): 2971, 2936, 1450, 1401,1376, 1250, 1172, 1092, 1049, 896, 867, 835, 801. 1H-
NMR: 1.32 (s, Me); 1.43–1.81 (m, 2 CH2); 1.68, 1.72 (2s, Me2C=); 3.24 (s, MeO); 3.50 (dd, J=13.0, 3.5,
OCH2); 4.02–4.09 (m, OCH); 5.18 (d, J=7, HC=). 13C-NMR: 18.4; 20.5; 25.7; 36.7; 42.8; 48.1; 65.0; 71.9;
72.1; 125.7; 135.8. MS: 184 (4, M+), 170 (10), 169 (10), 153 (35), 145 (11), 137 (36), 133 (23), 123 (14), 108
(18), 104 (100), 98 (44), 92 (19), 80 (51).
Florol Methyl Ether (=(2SR,4SR)- and (2RS,4SR))-3,4,5,6-Tetrahydro-4-methoxy-4-methyl-2-(2-
methylpropyl)-2H-pyran; syn- and anti-3 resp.). syn-14 or anti-14 (2.0 g, 0.011 mol) were subjected sepa-
rately to hydrogenation at 40 psi in MeOH (30 ml) in the presence of 5% Pd/C (100 mg) to yield 1.98 g
(98%) of the corresponding product 3.
Data of syn-3. IR (KBr): 2954, 2869, 1489, 1464, 1430, 1381, 1369,1306, 1277, 1251, 1176, 1144, 1085,
1039, 912, 865, 835. 1H-NMR: 0.89 (d, J=6.1, Me2C); 1.07–1.22 (m, CH2); 1.51–1.68 (m, CH2); 1.79–1.88
(m, CH2, CH); 3.23 (s, MeO); 3.56–3.77 (m, OCH2, OCH). 13C-NMR: 22.4; 23.4; 24.4; 25.1; 35.4; 42.4;
45.6; 48.7; 63.5; 70.7; 71.5. MS: 186 (2, M+), 171 (5), 155 (2), 139 (17), 112 (31), 109 (1), 101 (10), 98 (1), 83
(4), 81(2), 69 (100), 67 (5).
Data of anti-3. IR (KBr): 2955, 2869, 1467, 1375, 1347, 1250, 1173, 1141, 1089, 1037, 982, 905, 868, 814,
800, 733, 631. 1H-NMR: 0.90 (d, J=6.6, Me2C); 1.07–1.23 (m, CH2); 1.29 (s, Me); 1.33–1.55 (m, CH2);
1.68–1.77 (m, CH2, CH); 3.18 (s, MeO); 3.32–3.49 (m, OCH2); 3.96 (dt, J=11.6, 4.7, OCH). 13C-NMR:
18.4; 20.5; 25.4; 36.7; 42.8; 48.1; 64.4; 72.1; 72.6; 125; 135.8. MS: 186 (2, M+), 171 (5), 155 (2), 139 (17), 112
(31), 109 (1), 101 (10), 98 (1), 83 (4), 81 (2), 69 (100), 67 (5).
5. Synthesis of Pityol Methyl Ether (4). 1,5-Dimethylhex-4-en-1-yl Acetate (17b). To a soln. of racemic
sulcatol (17a; 6.4 g, 0.05 mol) in anh. CH2Cl2 was added Ac2O (6 g, 0.06 mol) and a cat. amount of DMAP
(5 mg). The mixture was kept overnight at r.t., poured in ice-cold H2O, and extracted with CH2Cl2. The
org. layer was washed with H2O, dried, and evaporated to afford 17b (8.45 g, quant.). The anal. data of
17b were identical to those reported in the literature [21].
4-Bromo-5-methoxy-1,5-dimethylhexyl Acetate (18). A soln. of crude 17b (6.8 g, 0.04 mol) in anh.
MeOH (60 ml) was placed in a flask fitted with a thermometer, a dropping funnel, and a gas inlet.
Then, 1,3-dibromo-5,5-dimethylhydantion (DDH; 6.5 g, 0.022 mol) was slowly added under N2 atmos-
phere with vigorous stirring, the temp. being kept between 5 to 108. When the reaction was completed,
the mixture was poured into cold H2O and extracted with AcOEt (3”25 ml). The combined org. layer
was washed with 5% aq. Na2CO3 soln. (3”15 ml) and H2O (3”15 ml), dried (Na2SO4), and concentrated
under reduced pressure to afford 18 (9.55 g, 85%). Colorless oil. IR (KBr): 2979, 1736, 1462, 1370-, 1243,
1182, 1133, 1070, 1022, 958, 852, 778, 748. 1H-NMR: 1.20 (d, J=6.5, Me); 1.27, 1.32 (2s, Me2C); 1.57–1.72
(m, 2 CH2); 2.03 (s, Ac); 3.22 (s, MeO); 3.93 (t, J=7.8, CHBr); 4.88–4.95 (m, OCH). 13C-NMR: 14.2;
19.9; 21.3; 21.4; 23.5; 29.5; 35.2; 49.7; 70.8; 76.8; 77.3; 170.7. MS: 282 (80), 226 (3), 200 (82), 186 (100),
166 (5), 131 (6), 118 (2).
Pityol Methyl Ether (=(2RS,5RS)- and (2SR,5RS)-2,3,4,5-Tetrahydro-2-methyl-5-(1-methoxy-1-
methylethyl)furan; syn- and anti-4 resp.). A soln. of 18 (5.64 g, 0.02 mol) in MeOH (20 ml) containing
KOH (4.0 g, 0.071mol) was heated at reflux for 9 h. The solvent was partly removed by distillation at
reduced pressure to bring the total volume to one fourth. The reaction contents were then poured into
cold H2O and extracted with CHCl3. The org. layer was washed neutral with H2O (3”20 ml), dried
(CaCl2), and concentrated under reduced pressure. The residue was subjected to CC (SiO2; hexane/
1
AcOEt 98 :3) to afford 4 (2.59 g, 82%). A syn/anti ratio of 15 :85 was determined on the basis of H-
and 13C-NMR analyses.
Data of syn-4. IR (KBr): 2973, 1461, 1381, 1367, 1293, 1230, 1181, 1130, 1070, 1021, 997, 867, 836. 1H-
NMR: 1.10 (d, J=5.0, Me); 1.20, 1.30 (2s, Me2C); 1.71–2.20 (m, 2 CH2); 3.15 (s, MeO); 3.81–3.85 (m,
OCH); 3.98 (dd, J=10.9, 1.6, OCH). 13C-NMR: 21.2; 22.8; 25.7; 29.2; 37.8; 49.6; 64.1; 66.8; 67.3; 76.5.
MS: 158 (5, M+), 143 (27), 126 (4), 113 (90), 111 (70), 100 (70), 99 (88), 82 (7), 73 (4), 67 (9), 56 (6),
47 (100).

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Data of anti-4. IR (KBr): 2973, 1461, 1381, 1367, 1293, 1230, 1181, 1130, 1070, 1021, 997, 867, 836. 1H-
NMR: 1.20 (d, J=6.2, Me); 1.29, 1.33 (2s, Me2C); 1.71–2.20 (m, 2 CH2); 3.23 (s, MeO); 3.81–3.85 (m,
OCH); 3.98 (dd, J=10.9, 1.6, OCH). 13C-NMR: 21.4; 23.6; 25.8; 30.1; 38.4; 50.2; 64.7; 67.8; 77.1. MS:
158 (5, M+), 143 (27), 126 (4), 113 (90), 111 (70), 100 (70), 99 (88), 82 (7), 73 (4), 67 (9), 56 (6), 47 (100).
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Received August 31, 2006