Conception, characterization and correlation of new marine odorants

Article abstract of DOI:10.1002/ejoc.200300174

Via a synthetic sequence consisting of PPA-mediated Friedel-Crafts acylation of veratrol (8), Clemmensen reduction, demethylation with TMSI, Williamson ether synthesis employing 3-chloro-2-(chloromethyl)prop-1-ene and in-situ ruthenium tetroxide oxidation, numerous substituted benzo[b][1,4]dioxepinones 15-27 and 2,3-dihydro-1H-5,9-di-oxacyclohepta[f]indenones 7, 13 and 14 were prepared to study their odor-structure correlation. In the course of these studies, we discovered the extremely powerful new marine odorant 7-(3′ -methylbutyl)benzo[b][1,4]dioxepin-3-one (16). On the basis of the measured odor threshold data, an olfactophore model was constructed that rationalizes the observed odor intensities, and indicates an aliphatic hydrophobe at a distance of 6.3 A from the centre of the aromatic-ring binding site. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300174

FULL PAPER
Conception, Characterization and Correlation of New Marine Odorants
Philip Kraft*[a] and Walter Eichenberger[a]
Dedicated wih best wishes to Professor Andrea Vasella on the occasion of his 60th birthday
Keywords: Heterocycles / Fragrances / Olfactation / Odoriferous compounds / Marine perfumery materials /
OdorϪstructure correlation
Via
a
synthetic sequence consisting of PPA-mediated
odorant 7-(3Ј-methylbutyl)benzo[b][1,4]dioxepin-3-one (16).
On the basis of the measured odor threshold data, an olfacto-
phore model was constructed that rationalizes the observed
odor intensities, and indicates an aliphatic hydrophobe at a
distance of 6.3 A from the centre of the aromatic-ring bind-
ing site.
Friedel−Crafts acylation of veratrol (8), Clemmensen reduc-
tion, demethylation with TMSI, Williamson ether synthesis
employing 3-chloro-2-(chloromethyl)prop-1-ene and in-situ
ruthenium tetroxide oxidation, numerous substituted
benzo[b][1,4]dioxepinones 15−27 and 2,3-dihydro-1H-5,9-di-
oxacyclohepta[f]indenones 7, 13 and 14 were prepared to
study their odor−structure correlation. In the course of these
studies, we discovered the extremely powerful new marine
˚
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
a favored 7-exo-trig-ring closure, is easily achieved to afford
3, which is hydrolyzed and decarboxylated to provide the
For many years, Calone 1951 (7-methylbenzo[b]- commercial odorant 4. Besides the commercial product Ca-
[1,4]dioxepin-3-one, 4), which was discovered by Beere- lone 1951 (4), linear and branched C2ϪC4-substituted
boom, Cameron and Stephens at Pfizer in 1966,[1] played a benzo[b][1,4]dioxepin-3-ones were claimed in the original
marginal role in perfumery, for instance as a trace compo- patent,[1] but nothing was known about higher derivatives.
nent in muguet accords. This changed in the early 1990ies,
when the launches of ‘‘New West for her’’ (Aramis, 1990)
and ‘‘Escape’’ (C. Klein, 1991) on the feminine and ‘‘Kenzo
pour homme’’ (Kenzo, 1991) as well as ‘‘LЈeau d’Issey pour
homme’’ (I. Miyake, 1994) on the masculine side initiated
a marine trend.[2] This marine trend reached its peak in
1996/97 with ‘‘Polo Sport Woman’’ (R. Lauren, 1996) cre-
ated by Jim Krivda and ‘‘Cool Water Woman’’ (Davidoff,
1997) by Pierre Bourdon, but still today we see launches of
extreme marine-smelling perfumes like the aquatic chypre
‘‘aquawoman’’ (Rochas, 2002) composed by Michel Almai-
rac with 0.42% of 4, and very likely the marine trend will
Scheme 1. Commercial synthesis of Calone 1951 (4)
come back to life again soon.
Calone 1951 (4) is the basis of all these marine accords,
and though it is often blended with different ozonic, al-
dehydic or watermelon-like odorants, so far there is no
alternative perfumery raw material to convey the typical ol-
factory impression of a seashore. The commercial synthesis
of 4 (Scheme 1) commences with the Williamson reaction
of homopyrocatechol (1) with two equivalents of methyl
bromoacetate affording diester 2. Dieckmann condensation,
We plunged into the chemistry of benzodioxepinones in
an attempt to construct androgynous odorants with musky
and marine characteristics. This note is present in 2,6-di-
bromo-3-methyl-4-nitroanisol (Musk alpha, 5; Figure 1),
which however was removed from the market due to its
phototoxicity. Polycyclic musk odorants, like Galaxolide
(6) as its most popular representative, often possess a meth-
ylated indane skeleton.[3] We thus were curious about con-
structing dioxacyclohepta[f]indenones. But in order not to
go beyond the limit in molecular weight for marine odor-
ants, and since the 7-butylbenzo[b][1,4]dioxepin-3-one was
[a]
Givaudan Schweiz AG, Fragrance Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax: (internat.) ϩ41(0)1-824 29 26
E-mail: philip.kraft@givaudan.com
Eur. J. Org. Chem. 2003, 3735Ϫ3743
DOI: 10.1002/ejoc.200300174
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3735

P. Kraft, W. Eichenberger
FULL PAPER
the highest-substituted marine odorant claimed in the
In the next step, the methyl ether protecting groups of 10
Pfizer patent,[1] we selected 7 with almost the same molecu- had to be cleaved. For this we decided to employ trimethyl-
lar mass as our first target structure.
silyl iodide (TMSI)[7] in acetonitrile.[8] The cleavage of 10
with TMSI was conducted at room temp. to afford after the
usual workup and purification by silica-gel FC in 93% yield
1-methylindan-5,6-diol (11). This diol 11 had already been
reported by Ayer and Singer[9] as the unintended product
of an attempt to correlate 4-(3Ј,4Ј-dihydroxyphenyl)butan-
2-one with zingerone (vanillyl acetone) by demethylation of
the latter with TMSI. Yet, the reported yield was only about
30%, and the synthesis is less practical and less generally
applicable than our approach. The spectroscopic data of 11
prepared on our route matched with those reported by Ayer
and Singer.[9]
Figure 1. A marine-smelling nitro musk 5, a polycyclic nitro musk
6, and our target structure 7
Williamson reaction of 11 with methyl bromoacetate,
Dieckmann condensation and decarboxylation would have
constituted the next transformations according to the prep-
aration of 4 in the Pfizer patent.[1] However, we were look-
ing for a shorter alternative to construct the [1,4]dioxepi-
none ring. Schirmann et al.[10] employed 3-chloro-2-
(chloromethyl)prop-1-ene in a synthesis of 3-methylene-3,4-
dihydro-2H-benzo[b][1,4]dioxepine, which they prepared in
62% yield from pyrocatechol. An alternative reagent for this
transformation of diols to 6-methylene-1,4-dioxepanes is
tris-ω,ω,ω-bromomethylacetophenone as reported by Ner-
del, Mamluk and Weyerstahl.[11] However, the synthesis of
this reagent from the dibromohydrin of pentaerythrol by
monobromination, nitric-acid oxidation, treatment of the
tribromopivalic acid with thionyl chloride, and
FriedelϪCrafts acylation of benzene with the resulting acid
chloride[12,13] is rather complicated, and in preliminary
experiments we obtained better yields employing 3-chloro-
2-(chloromethyl)prop-1-ene, which is commercially avail-
Results and Discussion
1-Methyl-2,3-dihydro-1H-5,9-dioxacyclohepta[f]inden-7-
one (7) can be constructed on paper simply by molding the
butyl side chain into a 3-methyl-[1,2]cyclopentano bridge,
and also our chemical synthesis depicted in Scheme 2 was
straightforward.
able.
Thus,
1-methyl-7-methylene-2,3,7,8-tetrahydro-
1H,6H-dioxacyclohepta[f]indene (12) was prepared from 11
and 3-chloro-2-(chloromethyl)prop-1-ene by slow addition
of a solution of both compounds in dioxane to a refluxing
suspension of potassium carbonate in diethyl ketone.
Though we isolated 12 by silica-gel FC in quite moderate
Scheme 2. Synthesis of the initial target compound 7 from yield of 36%, in general better yields were obtained with
veratrol (8)
the other catechols investigated (see Exp. Sect.).
The last step in our synthetic sequence was the oxidative
cleavage of the methylene double bond of 12. We chose the
Following the protocol of Marquardt[4] with slight aqueous biphase ruthenium-tetroxide oxidation established
modifications, FriedelϪCrafts acylation of veratrol (8) with by Carlsen, Katsuki, Martin and Sharpless.[14] This oxi-
vinylacetic acid in the presence of polyphosphoric acid dation with in-situ generated ruthenium tetroxide furnished
(PPA) furnished 5,6-dimethoxy-3-methylindan-1-one (9) the projected target structure 7 in 50% olfactory pure yield.
after recrystallization in 74% yield. Both Alesso et al.[5] and Disappointingly, 7 did not possess any musk-like odor fa-
Deslongchamps et al.[6] transformed 9 into 5,6-dimethoxy- cets, but instead only a marine note with distinct floral as-
1-methylindane (10) by reaction with a methyl Grignard re- pects. In comparison with Calone 1951 (4), these ad-
agent, acid-catalyzed dehydration of the methyl carbinol in- ditional floral aspects were however interesting to our per-
termediate and subsequent hydrogenation of the formed fumers.
methylindene. We found this rather circuitous, and instead
Following the same sequence, we introduced an ad-
submitted 9 to standard Clemmensen reduction conditions. ditional methyl group in the 1- or 2- position of 7 to study
After purification by flash chromatography (FC) on silica this floral side note. The resulting target structures 13 and
gel, we obtained in 75% yield the methylindane 10, the spec- 14 were synthesized from veratrol and 3,3-dimethylacrylic
troscopic data of which were identical to those reported in acid and tiglic acid, respectively. But in comparison with 7,
the literature.[5,6]
the odor intensity was decreased and the floral character
3736
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3735Ϫ3743

Conception, Characterization and Correlation of New Marine Odorants
FULL PAPER
diminished. 1,2-Dimethyl-2,3-dihydro-1H-5,9-dioxacyclo- bulky substituents, the C5H11 group of 16 on the contrary
hepta[f]inden-7-one (14) possessed even a blend odor of increased the intensity dramatically. So was there a hydro-
walnut and fenugreek oil with sea water and lichens (Fig- phobic binding pocket that so far had been missed? This
exciting question motivated us to synthesize the n-pentyl
analogue 17 as well as the isomeric C6-substituted deriva-
tives 18Ϫ22, all of which with the exception of the last one
22 possessed intense and interesting marine notes (Fig-
ure 2). In comparison with 18Ϫ21, the 2-ethylbutyl-substi-
tuted 22 was quite weak, but still in the marine direction
with a pleasant fruity twist. The n-heptyl analogue 23 was
more powerful than 22 but its marine note was also rela-
tively weak. With the slightly marine but mainly hesperidic,
mandarin-like n-octyl analogue 24 we then reached the limit
of the molecular dimensions of the putative marine recep-
tor.
Often the isobutenyl moiety of terpenes can be replaced
by a phenyl group without changing the overall odor
characteristics.[2,18,19] So would a benzyl substituent be able
to mimic the isopentyl group of 16? The answer is no, be-
cause 25, which was also synthesized via the general pro-
cedure developed, was found to be very weak, and mainly
leathery in character, though a slight marine tonality was
detectable by the evaluating perfumers. We completed our
series of new marine odorants with 26 and 27. 7-(2Ј-Methyl-
propyl)benzo[b][1,4]dioxepin-3-one (26) is interesting since
it is weaker than both the known propyl and butyl analogs,
so its ramification seems not to reach the postulated ad-
ditional hydrophobic binding site. The allyl analogue 27 is
however again very potent and possesses a pleasant marine
note with some reminiscence to water melons and ozone. It
Figure 2. Overview of the marine odorants synthesized
was synthesized from eugenol by cleavage of the phenolic
methyl ether group employing lithium chloride in refluxing
DMF according to a method of Piras and co-workers.[20]
ure 2). In order to increase the floral character, we planned 4-Allylpyrocatechol was obtained in 50% yield after 44 h
to switch back from 5,9-dioxacyclohepta[f]indenones to reaction time, usual workup and purification by silica-gel
benzo[b][1,4]dioxepinones; and thus, we cut the bond be- FC. This was then transformed into 27 according to the
tween C-1 and C-10a in 14. The resulting seco-target mol- Pfizer route[1] outlined in Scheme 1. Williamson reaction
ecule 15 was synthesized from veratrol (8) and 2-methylbu- with methyl bromoacetate in the presence of sodium me-
tyric acid according to our general procedure. Indeed the thoxide afforded methyl 4-allyl-2-(ethoxycarbonylmeth-
floral character again increased, and the compound was oxy)phenoxyacetate in 65% yield, which was subjected to
also more intense than 13 and 14 with an odor threshold Dieckmann cyclization and decarboxylation to provide 27
of 0.08 ng/L air (Figure 2). The best compound of the in 42% yield (see Exp. Sect.). In this case, we could not
whole series was however the isomeric 3Ј-methylbutyl-sub- employ our sequence because the in-situ generated ru-
stituted benzo[b][1,4]dioxepinone 16, the 1(10a)-seco deriva- thenium tetroxide would have cleaved not only the methyl-
tive of 13, for which an odor threshold of 0.014 ng/L air ene but also the allylic double bond. In general however, the
was determined. It emanates a very intense and diffusive, sequence presented in Scheme 2 provides a shorter, easier to
linear, marine odor, with some reminiscence to 2,6,10-tri- perform and more flexible access to benzo[b][1,4]dioxepi-
methylundec-9-en-1-al (Adoxal), the Darzen’s glycidic es- none systems.
ter condensate of hydrogenated pseudo-ionone with alkyl
chloroacetate. Adoxal possesses a floral-aldehydic odor,
and this together with the intense marine aspects of Calone
1951 (4) makes 16 highly attractive for perfumery.[17] Be-
sides, 16 is more intense and less salty than Calone 1951
(4), so fresher and more crisp in tonality, more closer to the
Olfactophore Model
With this series of marine odorants, complemented by
actual olfactory impression of a sea breeze rather than that some compounds resynthesized from the patent litera-
of sea water.
ture,[1,21] we had an exhaustive data set for the
Interesting was also of course, that while the intensity of structureϪodor correlation of the small class of marine
the known derivatives of 4 decreased with more heavier and odorants. We used this data set that is summarized in
Eur. J. Org. Chem. 2003, 3735Ϫ3743
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P. Kraft, W. Eichenberger
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Table 1. Experimental and calculated odor threshold values of the
compounds 7 and 13Ϫ24 as well as those of related benchmarks
Figure 3. The olfactophore model generated with the Catalyst
software
Table 1 to generate a computational olfactophore model
with the Catalyst software.[22] An olfactophore model, a
special case of a pharmacophore model, is a representation
of generalized molecular features that are key for a certain
odor.[2] It consists of hydrogen-bond acceptors (depicted in
green) that orient the molecule on the receptor site, aro-
matic (depicted in yellow) as well as aliphatic (depicted in
blue) binding sites, and excluded volumes (depicted in black)
that are inaccessible for the molecule. Within a certain en-
ergy range, in this case 3 kcal·molϪ1, the conformer that
fits the olfactophore model best is selected by the software.
Its activity is then estimated on the basis of the degree of
mapping of the molecular features with those of the com-
puter receptor model. That way, odor thresholds can be cal-
culated and compared with the experimental data.
Figure 3 shows our marine olfactophore model with 16
bound to the features of this hypothesis. The diagram below
indicates the mutual distances of these features, and the cal-
culated odor threshold values are given in Table 1, set
against the experimental data. Considering the fact that
most of the thresholds are very low, and distributed in a
relatively narrow range, the correlation of 0.59 is quite
receptor. It is in a way less diluted by inactive conformers,
and this may account for the observed discrepancy.
In summary, more powerful and also more characteristic
marine odorants were synthesized by increasing the chain
length of the 7-alkyl substituent of benzo[b][1,4]dioxepi-
nones beyond the bounds of the known derivatives of Ca-
lone 1951 (4).[1] This indicates the presence of a hydro-
˚
phobe at a distance of 6.3 A from the centre of the aromatic
ring binding site of the receptor. The synthetic sequence
presented in addition opens up a short, easy to perform and
flexible access to benzo[b][1,4]dioxepinones.
Experimental Section
IR: Bruker VECTOR 22/Harrick SplitPea micro ATR (attenuated-
total-reflection), Si. NMR: Bruker AVANCE DPX-400, TMS int.
(δ ϭ 0 ppm). MS: Finnigan MAT 95 or HP Chemstation 6890 GC/
5973 Mass Sensitive Detector. FC: Merck Kieselgel 60 (particle size
40Ϫ63 µm). TLC: Merck Kieselgel 60 F254 (particle size 5Ϫ20 µm,
layer thickness 250 µm on glass, 5 cm ϫ 10 cm); visualization re-
good. In any case, we clearly see the importance of the ali- agent: PMA spray soln. for TLC, Merck 1.00480.0100. Melting
˚
points: Büchi Melting Point B545 (uncorr.). Elemental analyses:
Eidgenössische Materialprüfungs- und Forschungsanstalt (EMPA),
Überlandstrasse 129, Dübendorf. All reactions were performed un-
der nitrogen using reagents and solvents (puriss. or purum grade)
from Fluka without further purification. The odor thresholds were
determined by GC-olfactometry:[23,24] Different dilutions of the
sample substance were injected into a gas chromatograph in de-
scending order of concentration until the panelist failed to detect
the respective substance at the sniffing port. The panelist smelled
in blind and pressed a button on perceiveing an odor. If the re-
phatic hydrophobe 6.3 A away from the aromatic binding
site. However, if this hydrophobe is not occupied, still a ‘‘re-
sidual activity’ of 0.6 ng/L air is calculated, even for less
active compounds like 22, 24 and 25. So the model could
still be improved by adding more excluded volumes that
would hinder these molecules from binding to the hydro-
gen-bond acceptors. Another major outlier is Calone 1951
(4) with a measured threshold of 0.031 ng/L air vs. 0.53 ng/
L air calculated. Since 4 just bears one methyl group, it
has less conformations that may hinder the docking to the corded time matched the retention time, the sample was further
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Eur. J. Org. Chem. 2003, 3735Ϫ3743

Conception, Characterization and Correlation of New Marine Odorants
FULL PAPER
diluted. The last concentration detected at the correct retention
time is the individual odor threshold. The reported threshold values
are the geometrical means of the individual odor thresholds of the
different panelists.
1 H, 10-H) ppm. 13C NMR (CDCl3): δ ϭ 19.8 (q, 1-Me), 30.7 (t,
C-2), 35.2 (t, C-3), 38.9 (d, C-1), 73.8/73.9 (2t, C-6,-8), 112.0 (t, ϭ
CH2), 115.3/116.3 (2d, C-4,-10), 138.4 (s, C-7), 143.6 (s, C-10a),
144.3 (s, C-3a), 148.2/148.3 (2s, C-4a,-9a) ppm. MS (EI):
m/z (%) ϭ 91 (65) [C7H7ϩ], 105 (25) [C8H9ϩ], 117 (19)/131 (26)/145
1-Methyl-2,3-dihydro-1H-5,9-dioxacyclohepta[f]inden-7-one
(7).
(33) [CnH2nϪ9ϩ], 173 (24) [Mϩ Ϫ CH3 Ϫ CO], 201 (81) [Mϩ
Ϫ
General Procedure: A mixture of veratrol (8, 19.1 mL, 150 mmol)
and vinylacetic acid (19.2 mL, 225 mmol) in 83% PPA (230 g) was
stirred for 15 h at 60 °C prior to pouring into ice/water (1:1,
500 mL). After stirring for 30 min at room temp., the product was
extracted with Et2O (3 ϫ 200 mL). The combined organic extracts
were washed with 2  aq. NaOH (2 ϫ 100 mL), water (100 mL)
and brine (50 mL), dried (Na2SO4) and concentrated in a rotary
evaporator. Crystallization (EtOAc/pentane) of the resulting resi-
due furnished 5,6-dimethoxy-3-methylindan-1-one (9, 22.8 g, 74%),
the physical data of which were identical with those reported in
ref.[4]
CH3], 216 (100) [Mϩ].
At room temp., NaIO4 (6.50 g, 30.5 mmol) was added with vigor-
ous stirring to a mixture of 12 (6.60 g, 30.5 mmol) in MeCN
(140 mL), water (140 mL) and CCl4 (90 mL). After stirring for
30 min, RuCl3 (0.30 g, 1.50 mmol, 5 mol %) was added, and stirring
was continued for 48 h with another portion of RuCl3 (0.30 g,
1.50 mmol, 5 mol %) being added after 6 h. The reaction mixture
was poured into water (500 mL), and the product extracted with
CH2Cl2 (3 ϫ 200 mL). The combined organic extracts were washed
with 20% aq. NaHSO3 (200 mL) and water (200 mL), and then
dried (Na2SO4). After evaporation of the solvent in a rotary evap-
orator silica-gel FC (pentane/Et2O, 4:1, Rf ϭ 0.32) furnished 1-
methyl-2,3-dihydro-1H-5,9-dioxacyclohepta[f]inden-7-one (7, 3.3 g,
50%) as colorless crystals, mp. 79Ϫ80 °C. IR (ATR): ν˜ ϭ 1323/
1280/1256/1351 cmϪ1 (ν ring), 1735 cmϪ1 (ν CϭO), 1041 cmϪ1 (ν
CϪOϪC sym.), 1482/1439/1577 cmϪ1 (ν CϭC, Ar), 1155 cmϪ1 (ν
CϪOϪC asym.). 1H NMR (CDCl3): δ ϭ 1.24 (d, J ϭ 7.0 Hz, 3 H,
1-Me), 1.60 (qd, J ϭ 12.4, 8.7 Hz, 1 H, 2-Hb), 2.30 (tdd, J ϭ 12.4,
7.7, 3.9 Hz, 1 H, 2-Ha), 2.74 (ddd, J ϭ 15.7, 8.7, 7.7 Hz, 1 H, 3-
Hb), 2.82 (ddd, J ϭ 15.7, 8.7, 3.9 Hz, 1 H, 3-Ha), 3.10 (br. sext,
J ϭ 7.0 Hz, 1 H, 1-H), 4.65/4.66 (2s, 4 H, 6-,8-H2), 6.80 (s, 1 H, 4-
H), 6.83 (s, 1 H, 10-H) ppm. 13C NMR (CDCl3): δ ϭ 19.8 (q, 1-
Me), 30.7 (t, C-2), 35.1 (t, C-3), 38.9 (d, C-1), 75.4/75.5 (2t, C-6,-
8), 115.2/116.2 (2d, C-4,-10), 139.2 (s, C-10a), 144.4 (s, C-3a), 146.8/
147.0 (2s, C-4a,-9a), 205.0 (s, C-7) ppm. MS (EI): m/z (%) ϭ 91
(97) [C7H7ϩ], 103 (20) [C8H7ϩ], 115 (13) [C8H19ϩ], 175 (14) [Mϩ Ϫ
CH3 Ϫ CO], 203 (100) [Mϩ Ϫ CH3], 218 (57) [Mϩ]. C13H14O3
(218.3): calcd. C 71.54, H 6.47; found C 71.51, H 6.38. Odor: Lin-
ear, very intense, marine with distinct floral aspects. Odor thresh-
old: 0.26 ng/L air.
Concd. aq. HCl (4 mL) was added to a suspension of Zn dust
(53.3 g, 815 mmol) in water (74 mL). After stirring at room temp.
for 30 min, the supernatant was decanted and water (42 mL) fol-
lowed by concd. aq. HCl (55 mL) was added dropwise to the resi-
due with cooling in an ice bath. A solution of 9 (28.0 g, 136 mmol)
in toluene (53 mL) was added, and the reaction mixture was re-
fluxed for 3d, with an additional quantity of concd. aq. HCl
(55 mL) being added after 48 h. The reaction mixture was cooled
down to room temp., and poured into water (200 mL), the product
was extracted with Et2O (300 mL). The combined organic extracts
were washed with water (100 mL) and brine (25 mL), dried
(Na2SO4), and concentrated in a rotary evaporator. Silica-gel FC
(pentane/Et2O, 9:1, Rf ϭ 0.23) of the resulting residue provided
5,6-dimethoxy-1-methylindane (10, 19.6 g, 75%), the spectroscopic
data of which were identical to those reported in the ref.[5,6]
At room temp. under N2, Me3SiI (TMSI, 27.5 mL, 202 mmol) was
added dropwise with stirring in the course of 90 min into a solution
of 10 (19.4 g, 101 mmol) in MeCN (150 mL). Stirring was con-
tinued at room temp. for 2.5 days, with an additional quantity of
Me3SiI (TMSI, 10.0 mL, 73.5 mmol) being added after 48 h. The
reaction mixture was poured into water (500 mL), and extracted
with Et2O (2 ϫ 200 mL). The combined extracts were washed with
40% aq. NaHSO3 (100 mL), water (100 mL) and brine (50 mL),
dried (Na2SO4) and concentrated in a rotary evaporator. Silica-gel
FC (pentane/Et2O, 2:1, Rf ϭ 0.28) furnished 1-methylindan-5,6-
diol (11, 15.5 g, 93%), the spectroscopic data of which matched
with those reported in the ref.[9]
1,1-Dimethyl-2,3-dihydro-1H-5,9-dioxacyclohepta[f]inden-7-one
(13): Following the general procedure, FriedelϪCrafts acylation
(88% yield) of veratrol (8, 20.7 g, 150 mmol) with 3,3-dimethylac-
rylic acid (22.5 g, 225 mmol), followed by Clemmensen reduction
(69% yield), demethylation (9% yield), Williamson ether synthesis
(39% yield) and in-situ RuO4 oxidation (50% yield) furnished after
final silica-gel FC (pentane/Et2O, 4:1, Rf ϭ 0.34) the odoriferous
title compound 13 (300 mg). IR (ATR): ν˜ ϭ 1322/1253/1281/1350
cmϪ1 (ν ring), 1040/1067 cmϪ1 (ν CϪOϪC), 1484/1438 cmϪ1 (ν
With vigorous stirring, a mixture of 11 (15.3 g, 93.2 mmol) and 3-
chloro-2-(chloromethyl)prop-1-ene (11.6 g, 92.8 mmol) in dioxane
(50 mL) was added dropwise during a period of 5 h to a refluxing
suspension of K2CO3 (25.7 g, 186 mmol) in Et2CO (200 mL). After
completion, stirring was continued at reflux for 1 h prior to vacuum
filtration of the formed inorganic precipitate after cooling. The pre-
cipitate was washed with acetone, and the combined organic solu-
tions were concentrated under reduced pressure. By FC (pentane/
1
CϭC, Ar), 1736 cmϪ1 (ν CϭO). H NMR (CDCl3): δ ϭ 1.22 (s, 6
H, 1-Me2), 1.92 (t, J ϭ 7.2 Hz, 2 H, 2-H2), 2.79 (t, J ϭ 7.2 Hz, 2
H, 3-H2), 4.66/4.67 (2s, 4 H, 6-,8-H2), 6.75 (s, 1 H, 4-H), 6.81 (s, 1
H, 10-H) ppm. 13C NMR (CDCl3): δ ϭ 28.4 (2q, 1-Me2), 29.3 (t,
C-3), 41.7 (t, C-2), 43.6 (s, C-1), 75.4/75.5 (2t, C-6,-8), 114.0 (d, C-
10), 116.3 (d, C-4), 139.0 (s, C-3a), 146.8/147.2 (2s, C-4a,-9a), 148.3
(s, C-10a), 205.1 (s, C-7) ppm. MS (EI): m/z (%) ϭ 133 (33)
[C9H9Oϩ], 145 (6) [C11H13ϩ], 161 (7) [Mϩ Ϫ CH3 Ϫ 2CO], 189 (2)
[Mϩ Ϫ CH3 Ϫ CO], 217 (100) [Mϩ Ϫ CH3], 232 (30) [Mϩ]. Odor:
Marine-aldehydic, floral-rosy with some reminiscence of citronel-
loxy acetaldehyde [(3,7-dimethyl-6-octenyloxy)acetaldehyde]. Odor
threshold: 0.55 ng/L air.
Et2O, 19:1, Rf
ϭ 0.66) on silica gel 1-methyl-7-methylene-
2,3,7,8-tetrahydro-1H,6H-5,9-dioxacyclohepta[f]indene (12, 7.30 g,
36%) was isolated. IR (ATR): ν˜ ϭ 1322/1276 cmϪ1 (ν ring), 1485/
1451/1419/1577 cmϪ1 (ν CϭC, Ar), 1031 cmϪ1 (ν CϪOϪC sym.),
1155 cmϪ1 (ν CϪOϪC asym.). 1H NMR (CDCl3): δ ϭ 1.22 (d,
J ϭ 7.2 Hz, 3 H, 1-Me), 1.60 (dddd, J ϭ 16.1, 8.6, 7.8, 7.3 Hz, 1
H, 2-Hb), 2.27 (dddd, J ϭ 16.1, 7.8, 7.3, 3.8 Hz, 1 H, 2-Ha), 2.74
(E/Z)-1,2-Dimethyl-2,3-dihydro-1H-5,9-dioxacyclohepta[f]inden-7-
one (14): Following the general procedure, FriedelϪCrafts acyl-
(dt, J ϭ 15.4, 7.8 Hz, 1 H, 3-Hb), 2.79 (ddd, J ϭ 15.4, 8.6, 3.8 Hz, ation of veratrol (8, 20.7 g, 150 mmol) with tiglic acid (22.5 g,
1 H, 3-Ha), 3.07 (br. sext, J ϭ 7.3 Hz, 1 H, 1-H), 4.70 (s, 4 H, 6-, 225 mmol) with subsequent Clemmensen reduction (80% yield),
8-H2), 5.05 (t, J ϭ 1.0 Hz, 2 H, ϭCH2), 6.75 (s, 1 H, 4-H), 6.77 (s,
followed by demethylation (84% yield), Williamson ether synthesis
Eur. J. Org. Chem. 2003, 3735Ϫ3743
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3739

P. Kraft, W. Eichenberger
FULL PAPER
(53% yield) and in situ RuO4 oxidation (38% yield) furnished after
[Mϩ Ϫ C4H9], 191 (7) [Mϩ Ϫ C3H7], 234 (52) [Mϩ]. C14H18O3
final silica-gel FC (pentane/Et2O, 4:1, Rf ϭ 0.34) the odoriferous
(234.3): calcd. C 71.77, H 7.74; found C 71.78, H 7.82. Odor: Very
title compound 14 (4.60 g). IR (ATR): ν˜ ϭ 1736 cmϪ1 (ν CϭO), intense and diffusive, linear, marine, with some reminiscence of Ad-
1324/1263/1289/1352 cmϪ1 (ν ring), 1484/1439 cmϪ1 (ν CϭC, Ar), oxal (2,6,10-trimethylundec-9-en-1-al). Odor threshold: 0.014 ng/
1042 cmϪ1 (ν CϪOϪC sym), 1159 cmϪ1 (ν CϪOϪC asym). 1H L air.
NMR (CDCl3): δ ϭ 0.95/1.08/1.17/1.24 (4d, J ϭ 7.0 Hz, 6 H, 1-,2-
7-Pentylbenzo[b][1,4]dioxepin-3-one (17): Following the general pro-
Me), 1.91Ϫ2.02 (m, 1 H, 2-H), 2.41 (dd, J ϭ 15.0, 9.6 Hz)/2.49 (dd,
cedure, FriedelϪCrafts acylation of veratrol (8, 41.5 g, 300 mmol)
J ϭ 15.0, 6.4 Hz)/2.55 (dd, J ϭ 14.0, 6.8 Hz)/2.59 (dd, J ϭ 14.0,
with valeric acid (46.0 g, 450 mmol) with subsequent Clemmensen
reduction (21% yield), followed by demethylation (39% yield), Wil-
liamson ether synthesis (58% yield) and in-situ RuO4 oxidation
(17% yield) furnished after final silica-gel FC (pentane/Et2O, 4:1,
7.2 Hz) [2 H, 3-H2], 2.89 (td, J ϭ 15.7, 7.2 Hz)/3.06 (quint, J ϭ
7.2 Hz) [1 H, 1-H], 4.65/4.66 (2s, 4 H, 4-,8-H2), 6.76Ϫ6.80 (m, 2
H, 4-,10-H) ppm. 13C NMR (CDCl3): δ ϭ 14.5/15.0/17.5/18.3 (4q,
1-,2-Me), 38.6/39.4 (2t, C-3), 38.2/41.8/44.4/46.2 (4d, C-1,-2), 75.4/
75.5/75.5/75.6 (4d, C-6,-8), 115.1/115.6/116.1/116.4 (4d, C-4,-10),
138.3/138.4 (2s, C-3a), 144.2/144.4 (2s, C-10a), 146.7/146.8/146.9/
Rf ϭ 0.25) the odoriferous title compound 17 (500 mg). IR (ATR):
ν˜ ϭ 1502/1435/1580 cmϪ1 (ν CϭC, Ar), 1265/1304/1201 cmϪ1 (ν
ring), 1050 cmϪ1 (ν CϪOϪC), 1740 cmϪ1 (ν CϭO). 1H NMR
147.0 (4s, C-4a,-9a), 205.0/205.1 (2s, C-7) ppm. MS (EI): m/z (%) ϭ
(CDCl3): δ ϭ 0.89 (t, J ϭ 7.0 Hz, 3 H, 5Ј-H2), 1.28Ϫ1.35 (m, 4 H,
77 (13)/91 (19)/105 (20)/133 (20)/161 (7)/175 (4) [CnH2nϪ7ϩ], 189
3Ј-,4Ј-H2), 1.59 (br. quint, J ϭ 7.6 Hz, 2 H, 2Ј-H2), 2.51 (t, J ϭ
(18) [Mϩ Ϫ CH3 Ϫ CO], 203 (1) [Mϩ Ϫ C2H5], 217 (100) [Mϩ
Ϫ
7.8 Hz, 2 H, 1Ј-H2), 4.68/4.70 (2s, 4 H, 2-,4-H2), 6.77 (dd, J ϭ 8.0,
2.0 Hz, 1 H, 8-H), 6.81 (d, J ϭ 2.0 Hz, 1 H, 6-H), 6.90 (d, J ϭ
8.0 Hz, 1 H, 9-H) ppm. 13C NMR (CDCl3): δ ϭ 13.9 (q, C-5Ј),
22.4 (t, C-4Ј), 30.9/31.3 (2t, C-2Ј,-3Ј), 34.8 (t, C-1Ј), 75.4/75.6 (2t,
C-2,-4), 120.3/120.5 (2d, C-6,-9), 123.5 (d, C-8), 138.9 (s, C-7),
146.0/147.8 (2s, C-5a,-9a), 204.7 (s, C-3) ppm. MS (EI): m/z (%) ϭ
77 (18) [C6H5ϩ], 91 (10) [C7H7ϩ], 135 (9) [Mϩ Ϫ C4H9Ϫ C2H2O],
149 (22) [Mϩ Ϫ C4H9 Ϫ CO], 177 (100) [Mϩ Ϫ C4H9], 191 (8) [Mϩ
Ϫ C3H7], 205 (1) [Mϩ Ϫ C2H5], 234 (42) [Mϩ]. Odor: Intense, mar-
ine, floral with aldehydic nuances. Odor threshold: 0.013 ng/L air.
CH3], 232 (70) [Mϩ]. Odor: Blend of walnut, fenugreek oil
(Trigonella foenum-graecum), sea water and lichens. Odor thresh-
old: 1.16 ng/L air.
7-(2Ј-Methylbutyl)benzo[b][1,4]dioxepin-3-one (15): Following the
general procedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g,
150 mmol) with 2-methylbutyric acid (24.6 mL, 225 mmol) with
subsequent Clemmensen reduction (16% yield), followed by de-
methylation (74% yield), Williamson ether synthesis (52% yield)
and in-situ RuO4 oxidation (17% yield) furnished after final silica-
gel FC (pentane/Et2O, 4:1, Rf ϭ 0.31) the odoriferous title com-
pound 15 (300 mg). IR (ATR): ν˜ ϭ 1501/1434/1460/1580 cmϪ1 (ν
CϭC, Ar), 1265/1302/1201 cm-1 (ν ring), 1050 cmϪ1 (ν CϪOϪC),
7-(4Ј-Methylpentyl)benzo[b][1,4]dioxepin-3-one (18): Following the
general procedure, FriedelϪCrafts acylation (98% yield) of veratrol
(8, 20.7 g, 150 mmol) with iso-caprylic acid (26.1 g, 225 mmol) with
subsequent Clemmensen reduction (11% yield), followed by de-
methylation (45% yield), and Williamson ether synthesis with sub-
sequent in-situ RuO4 oxidation (30% yield) furnished after final
silica-gel FC (pentane/Et2O, 4:1, Rf ϭ 0.24) the odoriferous title
compound 18 (500 mg). IR (ATR): ν˜ ϭ 1502/1418/1466/1580 cmϪ1
(ν CϭC, Ar), 1265/1304/1201 cmϪ1 (ν ring), 1050 cmϪ1 (ν
1
1740 cmϪ1 (ν CϭO). H NMR (CDCl3): δ ϭ 0.84 (d, J ϭ 6.4 Hz,
3 H, 2Ј-Me), 0.90 (t, J ϭ 7.5 Hz, 3 H, 4Ј-H2), 1.16 (mc, 1 H, 3Ј-
Hb), 1.39 (mc, 1 H, 3Ј-Ha), 1.60 (mc, 1 H, 2Ј-H), 2.28 (dd, J ϭ 11.6,
8.0 Hz, 1 H, 1Ј-Hb), 2.53 (dd, J ϭ 11.6, 6.0 Hz, 1 H, 1Ј-Ha), 4.68/
4.70 (2s, 4 H, 2-,4-H2), 6.74 (dd, J ϭ 8.0, 2.0 Hz, 1 H, 8-H), 6.78
(d, J ϭ 2.0 Hz, 1 H, 6-H), 6.90 (d, J ϭ 8.0 Hz, 1 H, 9-H) ppm. 13
C
NMR (CDCl3): δ ϭ 11.3 (q, C-4Ј), 18.8 (q, 2Ј-Me), 29.0 (t, C-3Ј),
36.4 (d, C-2Ј), 42.2 (t, C-1Ј), 75.4/75.6 (2t, C-2,-4), 120.3/121.0 (2d,
C-6,-9), 124.3 (d, C-8), 137.6 (s, C-7), 146.1/147.7 (2s, C-5a,-9a),
204.7 (s, C-3) ppm. MS (EI): m/z (%) ϭ 77 (11) [C6H5ϩ], 91 (7)
[C7H7ϩ], 135 (5) [Mϩ Ϫ C4H9Ϫ C2H2O], 149 (4) [Mϩ Ϫ C4H9 Ϫ
CO], 177 (100) [Mϩ Ϫ C4H9], 191 (2) [Mϩ Ϫ C3H7], 205 (1) [Mϩ
Ϫ C2H5], 219 (1) [Mϩ Ϫ CH3], 234 (26) [Mϩ]. Odor: Intense, mar-
ine-floral. Odor threshold: 0.08 ng/L air.
1
CϪOϪC), 1741 cmϪ1 (ν CϭO). H NMR (CDCl3): δ ϭ 0.88 (2d,
J ϭ 6.4 Hz, 6 H, 4Ј-Me2), 1.18Ϫ1.24 (m, 2 H, 3Ј-H2), 1.53Ϫ1.61
(m, 4 H, 2Ј-H2, 4Ј-H), 2.50 (t, J ϭ 7.8 Hz, 2 H, 1Ј-H2), 4.68/4.70
(2s, 4 H, 2-,4-H2), 6.78 (dd, J ϭ 8.0, 4.0 Hz, 1 H, 8-H), 6.82 (d,
J ϭ 4.0 Hz, 1 H, 6-H), 6.90 (d, J ϭ 8.0 Hz, 1 H, 9-H) ppm. 13C
NMR (CDCl3): δ ϭ 22.4 (2q, 4Ј-Me2), 27.7 (d, C-4Ј), 29.1 (t, C-
2Ј), 35.1 (t, C-1Ј), 38.4 (t, C-3Ј), 75.4/75.6 (2t, C-2,-4), 120.3/120.5
(2d, C-6,-9), 123.5 (d, C-8), 138.9 (s, C-7), 146.0/147.8 (2s, C-5a,-
9a), 204.8 (s, C-3) ppm. MS (EI): m/z (%) ϭ 77 (13) [C6H5ϩ], 91
7-(3Ј-Methylbutyl)benzo[b][1,4]dioxepin-3-one (16): Following the
general procedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g,
150 mmol) with iso-valeric acid (24.8 mL, 225 mmol) with sub-
sequent Clemmensen reduction (41% yield), followed by demethyl-
ation (92% yield), Williamson ether synthesis (57% yield) and in-
situ RuO4 oxidation (32% yield) furnished after final silica-gel FC
(8) [C7H7ϩ], 135 (7) [Mϩ Ϫ C5H11Ϫ C2H2O], 149 (16) [Mϩ
Ϫ
C5H11Ϫ CO], 177 (100) [Mϩ Ϫ C5H11], 191 (1) [Mϩ Ϫ C4H9], 205
(3) [Mϩ Ϫ C3H7], 248 (38) [Mϩ]. Odor: Marine, floral-aldehydic.
Odor threshold: 0.038 ng/L air.
7-(3Ј-Methylpentyl)benzo[b][1,4]dioxepin-3-one (19): Following the
(pentane/Et2O, 4:1, Rf ϭ 0.38) the odoriferous title compound 16 general procedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g,
(2.30 g). IR (ATR): ν˜ ϭ 1502/1435/1581/1467 cmϪ1 (ν CϭC, Ar),
150 mmol) with 3-methylvalerianic acid (28.2 mL, 225 mmol) with
subsequent Clemmensen reduction (10% yield), followed by de-
1265/1304/1201 cmϪ1 (ν ring), 1050 cmϪ1 (ν CϪOϪC sym), 1740
1
cmϪ1 (ν CϭO). H NMR (CDCl3): δ ϭ 0.92 (d, J ϭ 6.4 Hz, 6 H, methylation (67% yield), Williamson ether synthesis (42% yield)
3Ј-Me2), 1.46/1.47 (2td, J ϭ 8.0, 6.8 Hz, 2 H, 2Ј-H2), 1.57 (nonett,
and in-situ RuO4 oxidation (16% yield) furnished after final silica-
J ϭ 6.8 Hz, 1 H, 3Ј-H), 2.52 (t, J ϭ 8.0 Hz, 2 H, 1Ј-H2), 4.67/4.69 gel FC (pentane/Et2O, 4:1, Rf ϭ 0.32) the odoriferous title com-
(2s, 4 H, 2-,4-H2), 6.77 (dd, J ϭ 8.2, 2.4 Hz, 1 H, 8-H), 6.82 (d, pound 19 (140 mg). IR (ATR): ν˜ ϭ 1502/1435/1460/1580 cmϪ1 (ν
J ϭ 2.4 Hz, 1 H, 6-H), 6.90 (d, J ϭ 8.4 Hz, 1 H, 9-H) ppm. 13C CϭC, Ar), 1265/1304/1202 cmϪ1 (ν ring), 1051 cmϪ1 (ν CϪOϪC),
1
NMR (CDCl3): δ ϭ 22.36 (2q, 3Ј-Me2), 27.43 (d, C-3Ј), 32.69 (t,
1741 cmϪ1 (ν CϭO). H NMR (CDCl3): δ ϭ 0.87 (t, J ϭ 7.2 Hz,
C-1Ј), 40.53 (t, C-2Ј), 75.35/75.63 (2t, C-2,-4), 120.27/120.50 (d, C- 3 H, 5Ј-H3), 0.91 (d, J ϭ 6.4 Hz, 3 H, 3Ј-Me), 1.18 (mc, 1 H, 2Ј-
6,-9), 123.45 (d, C-8), 138.99 (s, C-7), 146.00/147.86 (2s, C-5a,-9a), Hb), 1.34Ϫ1.43 (m, 3 H, 2Ј-Ha, 4Ј-H2), 1.56Ϫ1.62 (m, 1 H, 3Ј-H),
204.71 (s, C-3) ppm. MS (EI): m/z (%) ϭ 77 (26) [C6H5ϩ], 135 (12)
2.48 (ddd, J ϭ 14.0, 10.0, 6.4 Hz, 1 H, 1Ј-Ha), 2.56 (ddd, J ϭ 14.0,
[Mϩ Ϫ C4H9 Ϫ C2H2O], 149 (21) [Mϩ Ϫ C4H9 Ϫ CO], 177 (100) 10.4, 5.2 Hz, 1 H, 1Ј-Hb), 4.66/4.67 (2s, 4 H, 2-,4-H2), 6.78 (dd, J ϭ
3740
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3735Ϫ3743

Conception, Characterization and Correlation of New Marine Odorants
FULL PAPER
8.2, 2.4 Hz, 1 H, 8-H), 6.82 (d, J ϭ 2.0 Hz, 1 H, 6-H), 6.90 (d, J ϭ
8.4 Hz, 1 H, 9-H). 13C NMR (CDCl3): δ ϭ 11.1 (q, C-5Ј), 18.9 (q,
3Ј-Me), 29.2 (t, C-4Ј), 32.4 (t, C-1Ј), 33.8 (d, C-3Ј), 38.2 (t, C-2Ј),
CϭC, Ar), 1265/1301/1202 cmϪ1 (ν Ring), 1050 cmϪ1 (ν CϪOϪC),
1
1740 cmϪ1 (ν CϭO). H NMR (CDCl3): δ ϭ 0.87 (t, J ϭ 7.4 Hz,
6 H, 4Ј-,2ЈЈ-H3), 1.28 (br. quint, J ϭ 7.4 Hz, 4 H, 3Ј-,1ЈЈ-H2), 1.46
75.4/75.6 (2t, C-2,-4), 120.3/120.5 (2d, C-6,-9), 123.5 (d, C-8), 139.1 (br. sept, J ϭ 7.4 Hz, 1 H, 2Ј-H), 2.44 (d, J ϭ 7.2 Hz, 2 H, 1Ј-H2),
(s, C-7), 146.0/147.9 (2s, C-5a,-9a), 204.7 (s, C-3) ppm. MS (EI): 4.68/4.70 (2s, 4 H, 2-,4-H2), 6.74 (dd, J ϭ 8.0, 2.0 Hz, 1 H, 8-H),
m/z (%) ϭ 77 (21) [C6H5ϩ], 92 (14) [C7H8ϩ], 135 (11) [Mϩ
C5H11Ϫ C2H2O], 149 (16) [Mϩ Ϫ C5H11Ϫ CO], 177 (100) [Mϩ
Ϫ
6.79 (d, J ϭ 2.0 Hz, 1 H, 6-H), 6.89 (d, J ϭ 8.0 Hz, 1 H, 9-H) ppm.
Ϫ
13C NMR (CDCl3): δ ϭ 10.7 (2q, C-4Ј,-2ЈЈ), 24.8 (2t, C-3Ј,-1ЈЈ),
C5H11], 191 (4) [Mϩ Ϫ C4H9], 205 (7) [Mϩ Ϫ C3H7], 248 (45) [Mϩ]. 38.6 (t, C-1Ј), 42.4 (d, C-2Ј), 75.4/75.6 (2t, C-2,-4), 120.3/121.0 (2d,
Odor: Marine, animalic, civet-like, floral-aldehydic, slightly remi-
niscent of citronelloxy acetaldehyde ([3,7-dimethyl-6-octenyl]oxya-
cetaldehyde). Odor threshold: 0.043 ng/L air.
C-6,-9), 124.3 (d, C-8), 137.8 (s, C-7), 146.0/147.7 (2s, C-5a,-9a),
204.7 (s, C-3) ppm. MS (EI): m/z (%) ϭ 77 (10) [C6H5ϩ], 91 (6)
[C7H7ϩ], 135 (6) [Mϩ Ϫ C5H11 Ϫ C2H2O], 149 (2) [Mϩ Ϫ C5H11
Ϫ CO], 177 (100) [Mϩ Ϫ C5H11], 191 (1) [Mϩ Ϫ C4H9], 205 (2)
[Mϩ Ϫ C3H7], 248 (23) [Mϩ]. Odor: Very weak, marine, fruity.
Odor threshold: 4.70 ng/L air.
7-(2Ј-Methylpentyl)benzo[b][1,4]dioxepin-3-one (20): Following the
general procedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g,
150 mmol) with 3-methylvalerianic acid (28.3 mL, 225 mmol) with
subsequent Clemmensen reduction (23% yield), followed by de-
methylation (63% yield), Williamson ether synthesis (88% yield)
and in-situ RuO4 oxidation (22% yield) furnished after final silica-
gel FC (pentane/Et2O, 9:1, Rf ϭ 0.26) the odoriferous title com-
pound 20 (1.10 g). IR (ATR): ν˜ ϭ 1501/1434/1460/1580 cm-1 (ν Cϭ
7-Heptylbenzo[b][1,4]dioxepin-3-one (23): Following the general
procedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g,
150 mmol) with œnanthylic acid (31.9 mL, 225 mmol) with sub-
sequent Clemmensen reduction (10% yield), followed by demeth-
ylation (75% yield), Williamson ether synthesis (53% yield) and in-
C, Ar), 1265/1303/1201 cmϪ1 (ν ring), 1049 cmϪ1 (ν CϪOϪC), situ RuO4 oxidation (8% yield) furnished after final silica-gel FC
1740 cmϪ1 (ν CϭO). 1H NMR (CDCl3): δ ϭ 0.83 (d, 3 H, 2Ј-Me), (pentane/Et2O, 9:1, Rf ϭ 0.33) the odoriferous title compound 23
0.88 (t, J ϭ 7.0 Hz, 3 H, 5Ј-H3), 1.11Ϫ1.40 (m, 4 H, 3Ј-,4Ј-H2), (100 mg). IR (ATR): ν˜ ϭ 1502/1435/1580 cmϪ1 (ν CϭC, Ar), 1265/
1.68 (mc, 1 H, 2Ј-H), 2.26 (dd, J ϭ 13.6, 8.4 Hz, 1 H, 1Ј-Hb), 2.54 1304/1201 cmϪ1 (ν Ring), 1051 cmϪ1 (ν CϪOϪC), 1741 cmϪ1 (ν
(dd, J ϭ 13.6, 6.0 Hz, 1 H, 1Ј-Ha), 4.68/4.70 (2s, 4 H, 2-,4-H2), 6.73
(dd, J ϭ 8.0, 2.0 Hz, 1 H, 8-H), 6.78 (d, J ϭ 2.0 Hz, 1 H, 6-H),
CϭO). 1H NMR (CDCl3): δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H, 7Ј-H3),
1.27Ϫ1.33 (m, 8 H, 3Ј-H2Ϫ6Ј-H2), 1.57 (br. quint, J ϭ 7.8 Hz, 2
6.89 (d, J ϭ 8.0 Hz, 1 H, 9-H) ppm. 13C NMR (CDCl3): δ ϭ 14.2 H, 2Ј-H2), 2.51 (t, J ϭ 7.8 Hz, 2 H, 1Ј-H2), 4.68/4.70 (2s, 4 H, 2-,
(q, C-5Ј), 19.2 (q, 2Ј-Me), 20.0 (t, C-4Ј), 34.5 (d, C-2Ј), 38.8 (t, C-
4-H2), 6.77 (dd, J ϭ 8.4, 2.0 Hz, 1 H, 8-H), 6.81 (d, J ϭ 2.0 Hz, 1
3Ј), 42.6 (t, C-1Ј), 75.4/75.6 (2t, C-2,-4), 120.3/121.0 (2d, C-6,-9), H, 6-H), 6.90 (d, J ϭ 8.4 Hz, 1 H, 9-H) ppm. 13C NMR (CDCl3):
124.3 (d, C-8), 137.6 (s, C-7), 146.1/147.7 (2s, C-5a,-9a), 204.8 (s, δ ϭ 14.0 (q, C-7Ј), 22.5 (t, C-6Ј), 29.0/29.1 (2t, C-3Ј,-5Ј), 31.2/31.7
C-3) ppm. MS (EI): m/z (%) ϭ 77 (9) [C6H5ϩ], 91 (6) [C7H7ϩ], 135 (2t, C-2Ј,-4Ј), 34.9 (t, C-1Ј), 75.4/75.6 (2t, C-2,-4), 120.3/120.5 (2d,
(5) [Mϩ Ϫ C5H11Ϫ C2H2O], 149 (3) [Mϩ Ϫ C5H11Ϫ CO], 177 (100) C-6,-9), 123.5 (d, C-8), 138.9 (s, C-7), 146.0/147.8 (2s, C-5a,-9a),
[Mϩ Ϫ C5H11], 205 (2) [Mϩ Ϫ C3H7], 248 (21) [Mϩ]. Odor: Marine, 204.7 (s, C-3) ppm. MS (EI): m/z (%) ϭ 77 (13) [C6H5ϩ], 91 (9)
floral-aldehydic. Odor threshold: 0.38 ng/L air.
[C7H7ϩ], 135 (8) [Mϩ Ϫ C6H13 Ϫ C2H2O], 149 (18) [Mϩ Ϫ C6H13
Ϫ CO], 177 (100) [Mϩ Ϫ C6H13], 191 (2) [Mϩ Ϫ C5H11], 219 (4)
[Mϩ Ϫ C3H7], 262 (39) [Mϩ]. Odor: Weak, mandarine, a bit ink-
like. Odor threshold: 1.65 ng/L air.
7-Hexylbenzo[b][1,4]dioxepin-3-one (21): Following the general pro-
cedure, FriedelϪCrafts acylation of veratrol (8, 41.5 g, 300 mmol)
with caproic acid (52.3 g, 450 mmol) with subsequent Clemmensen
reduction (18% yield), followed by demethylation (86% yield), Wil-
7-Octylbenzo[b][1,4]dioxepin-3-one (24): Following the general pro-
liamson ether synthesis (55% yield) and in-situ RuO4 oxidation cedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g, 150 mmol)
(52% yield) furnished after final silica-gel FC (pentane/Et2O, 4:1, with caprylic acid (35.7 mL, 225 mmol) with subsequent Clem-
Rf ϭ 0.32) the odoriferous title compound 21 (2.60 g). IR (ATR): mensen reduction (10% yield), followed by demethylation (68%
ν˜ ϭ 1502/1435/1580 cmϪ1 (ν CϭC, Ar), 1265/1304/1201 cmϪ1 (ν
Ring), 1051 cmϪ1 (ν CϪOϪC), 1741 cmϪ1 (ν CϭO). 1H NMR
yield), Williamson ether synthesis (48% yield) and in-situ RuO4 oxi-
dation (36% yield) furnished after final silica-gel FC (pentane/
(CDCl3): δ ϭ 0.88 (t, J ϭ 6.8 Hz, 3 H, 6Ј-H3), 1.27Ϫ1.35 (m, 6 H, Et2O, 9:1, Rf ϭ 0.32) the odoriferous title compound 24 (1.10 g).
3Ј-H2Ϫ5Ј-H2), 1.57 (br. quint, J ϭ 8.0 Hz, 2 H, 2Ј-H2), 2.51 (t, J ϭ IR (ATR): ν˜ ϭ 1502/1435/1580 cmϪ1 (ν CϭC, Ar), 1265/1304/1201
1
7.8 Hz, 2 H, 1Ј-H2), 4.67/4.69 (2s, 4 H, 2-,4-H2), 6.77 (dd, J ϭ 8.0,
4.0 Hz, 1 H, 8-H), 6.81 (d, J ϭ 4.0 Hz, 1 H, 6-H), 6.90 (d, J ϭ
cmϪ1 (ν Ring), 1052 cmϪ1 (ν CϪOϪC), 1741 cmϪ1 (ν CϭO). H
NMR (CDCl3): δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H, 7Ј-H3), 1.27Ϫ1.30
8.0 Hz, 1 H, 9-H) ppm. 13C NMR (CDCl3): δ ϭ 14.0 (q, C-6Ј), (m, 10 H, 3Ј-H2Ϫ7Ј-H2), 1.57 (br. quint, J ϭ 7.8 Hz, 2 H, 2Ј-H2),
22.5 (t, C-5Ј), 28.8 (t, C-3Ј), 31.2/31.6 (2t, C-2Ј,-4Ј), 34.9 (t, C-1Ј),
75.4/75.6 (2t, C-2,-4), 120.3/120.5 (2d, C-6,-9), 123.5 (d, C-8), 138.9
2.51 (t, J ϭ 7.8 Hz, 2 H, 1Ј-H2), 4.67/4.69 (2s, 4 H, 2-,4-H2), 6.76
(dd, J ϭ 8.4, 2.0 Hz, 1 H, 8-H), 6.81 (d, J ϭ 2.0 Hz, 1 H, 6-H),
(s, C-7), 146.0/147.8 (2s, C-5a,-9a), 204.7 (s, C-3) ppm. MS (EI): 6.89 (d, J ϭ 8.4 Hz, 1 H, 9-H) ppm. 13C NMR (CDCl3): δ ϭ 14.0
m/z (%) ϭ 77 (16) [C6H5ϩ], 91 (9) [C7H7ϩ], 135 (9) [Mϩ Ϫ C5H11 (q, C-8Ј), 22.5 (t, C-7Ј), 29.1/29.3/29.3 (3t, C-3Ј,-5Ј,-6Ј), 31.2/31.8
Ϫ C2H2O], 149 (21) [Mϩ Ϫ C5H11 Ϫ CO], 177 (100) [Mϩ Ϫ C5H11], (2t, C-2Ј,-4Ј), 34.9 (t, C-1Ј), 75.3/75.6 (2t, C-2,-4), 120.3/120.5 (2d,
191 (2) [Mϩ Ϫ C4H9], 205 (3) [Mϩ Ϫ C3H7], 248 (43) [Mϩ]. Odor: C-6,-9), 123.5 (d, C-8), 138.8 (s, C-7), 146.0/147.8 (2s, C-5a,-9a),
Marine, aquatic. Odor threshold: 0.019 ng/L air.
204.7 (s, C-3) ppm. MS (EI): m/z (%) ϭ 77 (12) [C6H5ϩ], 91 (8)
[C7H7ϩ], 135 (9) [Mϩ Ϫ C7H15 Ϫ C2H2O], 149 (18) [Mϩ Ϫ C7H15
Ϫ CO], 177 (100) [Mϩ Ϫ C7H15], 191 (2) [Mϩ Ϫ C6H13], 233 (4)
[Mϩ Ϫ C3H7], 276 (47) [Mϩ]. Odor: Very weak, a bit of manda-
rines. Odor threshold: 4.05 ng/L air.
7-(2Ј-Ethylbutyl)benzo[b][1,4]dioxepin-3-one (22): Following the
general procedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g,
150 mmol) with 2-ethylbutyric acid (28.3 mL, 225 mmol) with sub-
sequent Clemmensen reduction (30% yield), followed by demeth-
ylation (72% yield), and Williamson ether synthesis with sub-
sequent in-situ RuO4 oxidation (7% yield) furnished after final sil-
7-Benzylbenzo[b][1,4]dioxepin-3-one (25): Following the general
procedure, FriedelϪCrafts acylation of veratrol (8, 20.7 g,
ica-gel FC (pentane/Et2O, 9:1, Rf ϭ 0.31) the odoriferous title com- 150 mmol) with benzoic acid (27.5 g, 225 mmol) with subsequent
pound 22 (500 mg). IR (ATR): ν˜ ϭ 1501/1434/1459/1580 cmϪ1 (ν
Clemmensen reduction (15% yield), followed by demethylation
Eur. J. Org. Chem. 2003, 3735Ϫ3743
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3741

P. Kraft, W. Eichenberger
FULL PAPER
(70% yield), Williamson ether synthesis (48% yield) and in-situ
RuO4 oxidation (62% yield) furnished after final silica-gel FC (pen-
tane/Et2O, 4:1, Rf ϭ 0.27) the odoriferous title compound 25
(500 mg). IR (ATR): ν˜ ϭ 1501/1435/1579/1453 cmϪ1 (ν CϭC, Ar),
1265/1301/1201 cmϪ1 (ν Ring), 1049 cmϪ1 (ν CϪOϪC), 1739 cmϪ1
(ν CϭO). 1H NMR (CDCl3): δ ϭ 3.88 (s, 2 H, 1Ј-H2), 4.65/4.66
(2s, 4 H, 2-,4-H2), 6.78 (dd, J ϭ 8.0, 2.0 Hz, 1 H, 8-H), 6.81 (d,
J ϭ 2.0 Hz, 1 H, 6-H), 6.91 (d, J ϭ 8.0 Hz, 1 H, 9-H), 7.16Ϫ7.30
(m, 5 H, 2ЈЈ-H Ϫ6ЈЈ-H) ppm. 13C NMR (CDCl3): δ ϭ 40.9 (t, C-
1Ј), 75.4/75.6 (2t, C-2,-4), 120.7/121.0 (2d, C-6,-9), 124.0 (d, C-8),
126.1 (d, C-4ЈЈ), 128.4/128.7 (4d, C-2ЈЈ,-3ЈЈ,-5ЈЈ,-6ЈЈ), 137.1 (s, C-
1ЈЈ), 140.6 (s, C-7), 146.5/148.0 (2s, C-5a,-9a), 204.5 (s, C-3) ppm.
MS (EI): m/z (%) ϭ 77 (12) [C6H5ϩ], 91 (22) [C7H7ϩ], 115 (24)
[C9H7], 128 (9) [C10H8], 141 (46) [C11H9], 152 (20) [C12H8], 169 (23)
[C13H13], 181 (8) [Mϩ Ϫ C3H5O2], 195 (6) [Mϩ Ϫ C2H3O2], 211 (9)
[Mϩ Ϫ C2H3O], 225 (12) [Mϩ Ϫ CHO], 254 (100) [Mϩ]. Odor:
Very weak, leathery, slightly marine. Odor threshold: 6.80 ng/L air.
pentane, 1:1, Rf ϭ 0.35) on silica gel to afford methyl 4-allyl-2-
(ethoxycarbonylmethoxy)phenoxyacetate (21.4 g, 65%).
A solution of methyl 4-allyl-2-(ethoxycarbonylmethoxy)phenoxy-
acetate (69.0 g, 234 mmol) in THF (500 mL) was added dropwise
with stirring to a suspension of NaH (12.0 g, 500 mmol) in THF
(500 mL), and the resulting mixture was refluxed for 20 h. After
cooling down, the reaction mixture was poured into ice/water (1:1,
1.5 L) and by addition of 2  aq. HCl pH 2 was adjusted. The
product was extracted with Et2O (3 ϫ 2 L), and the combined or-
ganic solutions were dried (Na2SO4). After evaporation of the sol-
vent in a rotary evaporator, the resulting residue was dissolved in
EtOH (400 mL). Then 2  aq. HCl (400 mL) was added, and the
reaction mixture was heated to reflux for 20 h, prior to pouring
into ice/water (1:1, 1.5 L) and extraction of the product with Et2O
(4 ϫ 1.5 L). The combined organic extracts were washed with water
(1 L) and brine (100 mL), dried (Na2SO4) and concentrated in a
rotary evaporator. Silica-gel FC (pentane/Et2O, 4:1, Rf ϭ 0.37) of
the resulting residue provided 7-allylbenzo[b][1,4]dioxepin-3-one
(27, 20.0 g, 42%) as colorless odoriferous liquid. IR (ATR): ν˜ ϭ
1502/1581/1436/1639 cmϪ1 (ν CϭC, Ar), 1742 cmϪ1 (ν CϭO),
1267/1305 cmϪ1 (ν ring), 1051 cmϪ1 (ν CϪOϪC). 1H NMR
(CDCl3): δ ϭ 3.30 (d, J ϭ 6.8 Hz, 2 H, 1Ј-H2), 4.67/4.69 (2s, 2-,4-
7-(2Ј-Methylpropyl)benzo[b][1,4]dioxepin-3-one (26): Following the
general procedure, FriedelϪCrafts acylation (68% yield) of veratrol
(8, 20.7 g, 150 mmol) with benzoic acid (27.5 g, 225 mmol) fol-
lowed by Clemmensen reduction (75% yield), demethylation (68%
yield), Williamson ether synthesis (63% yield) and in situ RuO4
oxidation (53% yield) furnished after final silica-gel FC (pentane/ H2), 5.05Ϫ5.10 (m, 2 H, 3Ј-H2), 5.92 (mc, 1 H, 2Ј-H), 6.77Ϫ6.93
Et2O, 4:1, Rf ϭ 0.31) the odoriferous title compound 26 (2.10 g).
(m, 3 H, 6-,8-,9-H) ppm. 13C NMR (CDCl3): δ ϭ 39.2 (t, C-1Ј),
75.4/75.6 (2t, C-2,-4), 116.0 (t, C-3Ј), 120.6/120.7 (2d, C-6,-9), 123.7
IR (ATR): ν˜ ϭ 1501/1434/1580/1466 cmϪ1 (ν CϭC, Ar), 1265/1303/
1202 cmϪ1 (ν Ring), 1049 cmϪ1 (ν CϪOϪC), 1739 cmϪ1 (ν CϭO). (d, C-8), 135.9 (s, C-7), 136.9 (d, C-2Ј), 146.5 (s, C-9a), 148.0 (s, C-
1H NMR (CDCl3): δ ϭ 0.90 (d, J ϭ 7.0 Hz, 6 H, 2Ј-Me2), 1.82 5a), 204.6 (s, C-3) ppm. MS (EI): m/z (%) ϭ 91 (97) [C7H7ϩ], 120
(nonett, J ϭ 7.0 Hz, 1 H, 2Ј-H), 2.39 (d, J ϭ 7.0 Hz, 2 H, 1Ј-H2), (25) [C7H4O2ϩ], 161 (13) [Mϩ Ϫ C2H3O], 175 (6) [Mϩ Ϫ CHO],
4.68/4.70 (2s, 4 H, 2-,4-H2), 6.74 (dd, J ϭ 8.0, 2.0 Hz, 1 H, 8-H),
6.78 (d, J ϭ 2.0 Hz, 1 H, 6-H), 6.90 (d, J ϭ 8.0 Hz, 1 H, 9-H) ppm.
13C NMR (CDCl3): δ ϭ 22.2 (2q, 2Ј-Me2), 30.0 (d, C-2Ј), 44.3 (t,
204 (100) [Mϩ]. C12H12O3 (204.2): calcd. C 70.57, H 5.92; found
C 70.59, H 5.81. Odor: Linear, very intense, marine-floral note,
reminiscent of O3, water-melons and fatty aldehydes. Odor thresh-
C-1Ј), 75.4/75.6 (2t, C-2,-4), 120.3/121.0 (2d, C-6,-9), 124.2 (d, C- old: 0.051 ng/L air.
8), 137.6 (s, C-7), 146.1/147.7 (2s, C-5a,-9a), 204.7 (s, C-3) ppm.
MS (EI): m/z (%) ϭ 71 (11) [C6H5ϩ], 91 (6) [C7H7ϩ], 135 (5)
[C8H7O2ϩ], 149 (5) [C9H9O2ϩ], 177 (100) [Mϩ Ϫ C3H7], 220 (27)
Acknowledgments
We are grateful to G. Brunner, J. Märki and J. Schmid for spectro-
[Mϩ]. Odor: Marine, ozone, aldehydic. Odor threshold: 1.65 ng/
L air.
scopic data, to C. Denis for olfactory evaluation, as well as to M.
Rothaupt, K. Grman and their panelists A. Bopp, G. Brunner, R.
Cannas, A. Flückiger, B. Fontana, O. Gey, J. Hotz, H. Koch, A.
Kreis, T. Reinmann, J. J. Rouge, B. Schilling, E. Senn, M. Stang, W.
Stauch and A. Valero for the determination of the odor thresholds.
Thanks are also due to M. Gautschi for careful proof-reading of
the manuscript.
7-Allylbenzo[b][1,4]dioxepin-3-one (27): LiCl (292 g, 6.89 mol) was
added to a solution of eugenol (354 mL, 2.30 mmol) in DMF
(3.7 L), and the mixture was refluxed for 44 h, with additional por-
tions of LiCl (292 g, 6.89 mol) being added after 4 h, 22 h and 29 h.
The reaction mixture was allowed to cool down to room temp.,
and diluted with toluene (2 L). The formed precipitate was filtered
off and washed with toluene, the washings were combined with the
organic solution and concentrated in a rotary evaporator. Silica-
gel FC (Et2O/pentane, 1:1, Rf ϭ 0.37) provided 4-allylpyrocatechol
(173 g, 50%).
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3742
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3735Ϫ3743

Conception, Characterization and Correlation of New Marine Odorants
FULL PAPER
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Received March 27, 2003
Eur. J. Org. Chem. 2003, 3735Ϫ3743
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3743