Structure-activity relationships in the domain of odorants having marine notes

Article abstract of DOI:10.1002/ejoc.201403365

Continuing our investigations into marine note odorants, we herein describe several new scaffolds. Among them, 2,3-dihydrobenzofuran-2-carbaldehyde is particularly interesting. The results demonstrate that the seven-membered ring with a ketone functional group of the Calone 1951 family can be replaced by a five-membered ring carrying an aldehydefunction. In addition, this work has allowed us to discover the valuable 2-methoxy-4-methylphenyl methyl carbonate (20b), which is very close to vanillin, and 2-methoxy-2,4-dimethyl-1,3-benzodioxole (29d), which belongs to the isoeugenol/dihydroeugenol olfactive family.

Full text of DOI:10.1002/ejoc.201403365

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FULL PAPER
DOI: 10.1002/ejoc.201403365
Structure–Activity Relationships in the Domain of Odorants Having Marine
Notes[‡]
Jean-Marc Gaudin*[a] and Jean-Yves de Saint Laumer[b]
Dedicated with best wishes to Dr. Roger Snowden on the occasion of his 65th birthday
Keywords: Oxygen heterocycles / Structure–activity relationships / Fragrances / Olfactory properties
Continuing our investigations into marine note odorants, we
herein describe several new scaffolds. Among them, 2,3-di-
hydrobenzofuran-2-carbaldehyde is particularly interesting.
The results demonstrate that the seven-membered ring with
a ketone functional group of the Calone 1951® family can
be replaced by a five-membered ring carrying an aldehyde
function. In addition, this work has allowed us to discover the
valuable 2-methoxy-4-methylphenyl methyl carbonate (20b),
which is very close to vanillin, and 2-methoxy-2,4-dimethyl-
1,3-benzodioxole (29d), which belongs to the isoeugenol/di-
hydroeugenol olfactive family.
Introduction
Today marine odorants have an important place in the
palette of modern perfumers. The good olfactory properties
of 2H-1,5-benzodioxepin-3(4H)-ones (1) and 4,5-dihydro-1-
benzoxepin-3(2H)-ones (2), discovered in 1966 by Beere-
boom et al. of Pfizer,[1] are undeniably the starting point of
this story, and for 30 years (1970–2000) Calone 1951® (1a)
was the only compound commercialized in this series (Fig-
ure 1). As mentioned by Hügel and co-workers,[2] Calone
1951® has been used in many perfumes, such as New West
for Her (Aramis, 1990), Escape for Her (C. Klein, 1991),
LЈeau dЈIssey pour homme (I. Miyake, 1994), Polo Sport for
Women (R. Lauren, 1996), and Cool Water for Women (Da-
vidoff, 1997), increasing the popularity of this trend in both
men’s and women’s perfumes.
Figure 1. The Calone 1951® family.
This domain was later revisited,[2–11] and now com-
pounds such as Transluzone (1b), Aldolone® (1c), and
Azurone® (1d) are produced on a ton scale by Firmenich
and Givaudan, and used in fine fragrance as well as in
body- and home-care products (e.g., shower products, air
fresheners, and powder detergents).
Olfactory receptors were discovered by Buck and
Axel,[12–14] but despite this important breakthrough, the
mechanisms of odorant receptor interaction are yet to be
understood. Predicting the odor properties of a new mo-
lecule by rational design remains challenging.[15,16] Never-
theless, the best solution to date for rationalizing the ac-
tivity of odorants is the use of an olfactophore model
(which corresponds to the pharmacophore in drug design).
Having established the chemical space occupied by the
active ligand, the olfactophore, a 3D combination of struc-
tural features, allows the generation of new candidate mo-
lecules without the benefit of the receptor’s structure. For
Calone 1951®, four structural features can be identified
(Figure 2).
[‡] Part 2. Part 1: J. M. Gaudin, O. Nikolaenko, J. Y.
de Saint Laumer, B. Winter, P. A. Blanc, Helv. Chim. Acta 2007,
90, 1245–1265.
[a] Firmenich SA, Corporate R&D Division,
7 Chemin de la Bergère, Meyrin, Switzerland
E-mail: jean-marc.gaudin@firmenich.com
www.firmenich.com
[b] Firmenich SA, Corporate R&D Division,
P. O. Box 239, 1211 Geneva 8, Switzerland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403365.
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J.-M. Gaudin, J.-Y. de Saint Laumer
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and Kozlov et al.[11]). Modifying the spacer between the
aromatic ring and the functional group could also provide
interesting new perspectives. The position and orientation
of the carbonyl group are imposed by the geometry of the
seven-membered ring in the benzodioxepinone series.[6,10]
Attempting to introduce more flexibility by opening the
seven-membered ring, such as in 6 (Figure 4), or by replac-
ing it with a five-membered ring, such as in 7 (Figure 4), to
preserve the marine-ozone character of the compounds is
also extensively described herein.
Figure 2. Structural key elements of the Calone 1951® family.
1. The hydrophobic group: The presence of an alkyl
chain on the benzene ring is essential for the marine activity
of the compound. Previous analyses[6,10] have shown that
positions 7 and 8 (Figure 1) are the most favorable, whereas
the absence of substitution decreases the intensity and leads
to a different odor. The size of the alkyl substituent may
vary from a methyl group to an optimal size of between C3
and C6.
2. The aromatic ring: This ring is present in almost all
compounds having a marine odor. A beneficial interaction
with the receptor is a possibility. The ring could, however,
also be considered a spacer because a molecule such as Ma-
ritima® 4 (Figure 3) has a similar ozone odor but no benz-
ene ring.
Figure 4. Targeted skeletons 5–7.
Results and Discussion
Synthesis
The carbonyl group of Calone 1951® (1a), Transluzone
(1b), and Aldolone® (1c) was easily reduced by using
LiAlH4 to give the corresponding alcohols 8a–c in very
high yields[7] (Scheme 1). The alcohol 8a was etherified or
acetylated to efficiently give 9a–c.[7,18] In contrast, the direct
homologation of Calone 1951® to aldehyde 12 by the
Corey–Chaykovsky reaction was unsuccessful in our hands.
Starting from 10,[19,20] classical epoxidation gave the ex-
pected product 11[21] in modest yield. The isomerization of
11, which is, surprisingly, extremely stable, to aldehyde 12
Figure 3. Typical compounds with marine-watery olfactory notes.
3. The carbonyl group: This functional group is likely using a variety of Brønsted or Lewis acids was unsuccessful.
involved as a hydrogen-bond acceptor in the interaction
with the olfactory receptor.
To synthesize compound 6 (Figure 4), we logically
started from four commercial phenols: guaiacol (13a), 2-
4. The spacer: The spacer lies between the aromatic ring methoxy-4-methylphenol (13b), dihydroeugenol (13c), and
and the hydrogen-bond acceptor function. eugenol (13d; Scheme 2). Classical reactions with chloro-
In this context, we were interested in better understand- acetone, 3-chlorobutan-2-one, and methyl chloroacetate
ing the role of the carbonyl group in the quality and inten- gave the corresponding products 14–16 in very good yields,
sity of the odor. We have good reason to believe that other while allylation using allyl bromide followed by ozonolysis
functional groups, for example, aldehyde, ester, formate, gave the aldehydes 18a–c. The epoxide 19c was obtained
methoxy, or nitrile, could be valid alternatives.
directly by using epibromohydrin, and finally the carb-
Good examples of this assessment are illustrated in Fig- onates 20b–d were synthesized by reaction with methyl
ure 3. Compounds such as Floralozone (3a) and Fleuranil® chloroformate.
(3b) are both known to possess an ozone-watery profile
The next targeted skeleton was 2,3-dihydro-1-benzo-
even though their odors are less characteristic than those furan-2-carbaldehyde 25 (Scheme 3 and Figure 4, 7: X =
of the benzodioxepinone series.[17] This is sometimes also CH2, W = CHO). An efficient approach to its synthesis
the case for para-substituted pyridines, as illustrated by Ma- is already known from readily accessible ortho-substituted
ritima® (4).
phenol 23 by an epoxidation/cyclization reaction. This key
To evaluate the odors of these compounds, we have thus transformation is possible in two successive steps[22] or in
synthesized a series of molecules 5–7 (Figure 4) in which W “one pot” by using either the tert-butyl hydroperoxide
represents various hydrogen-bond acceptors (the main topic (TBHP)/[VO(acac)2] system in dichloromethane in the pres-
of two recent studies published by Hügel and co-workers[7] ence of trifluoroacetic acid,[23] or with the classical m-
2
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Structure-Activity Relationships in Odorants
Scheme 1. Reagents and conditions: a) 0.5 equiv. LiAlH4, Et2O, room temp., 1 h; b) 1.2 equiv. NaH, 1.5 equiv. MeI, DMF (89%);
c) 1.2 equiv. NaH, 1.5 equiv. EtI, DMF (86%); d) 1.2 equiv. Ac2O, pyridine, 100 °C, 2 h (87%); e) 1.3 equiv. m-CPBA, CH2Cl2, 30 °C, 2 d
(29%).
Scheme 2. Reagents and conditions: a) 1.2 equiv. chloroacetone, 1.2 equiv. K2CO3, acetone, reflux; b) 1.2 equiv. 3-chlorobutan-2-one,
1.2 equiv. K2CO3, acetone, reflux; c) 1.2 equiv. methyl chloroacetate, 1.2 equiv. K2CO3, acetone, reflux; d) 1.2 equiv. allyl bromide,
1.2 equiv. K2CO3, acetone, reflux; e) ozone, 0 °C, MeOH/CH2Cl2; f) 1.2 equiv. epibromohydrin, 1.2 equiv. K2CO3, acetone, reflux;
g) 1.27 equiv. methyl chloroformate, 1.5 equiv. pyridine, 0.02 equiv. DMAP, CH2Cl2, room temp., 3 h.
chloroperbenzoic acid.[24] We chose to use the inexpensive
and more industrial peracetic acid to perform this reaction
(60–78% yields). It should also be noted that 24a has been
described by Satyanarayana et al.,[24] but with the incorrect
structure 26. Oxidation of the alcohols 24a–c thus obtained
was more difficult than expected. A number of well-estab-
lished methods, for example, Jones, Swern, and 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) oxidations, gave
poor yields (10–25%) of the desired aldehydes 25a–c. The
2-iodoxybenzoic acid (IBX)/DMSO method used by Ram-
adas and Krupadanam[23] would probably be preferable,
Scheme 3. Reagents and conditions: a) K2CO3, allyl or methallyl
but these conditions were never attempted.
bromide, acetone, reflux (60–78%); b) N,N-dimethylaniline, 200 °C,
48 h (95–94%); c) AcO2H, toluene, 20 °C; d) 1.05 equiv. NaOCl,
(Scheme 4 and Figure 4, 7: X = O, W = OR). Compounds 0.02 equiv. TEMPO, 0.02 equiv. NaBr, NaHCO3, AcOEt, 25 °C.
The last targeted skeleton was 2-alkoxy-1,3-benzodioxole
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Scheme 4. Reagents and conditions: a) 5 equiv. HC(OMe)3, cat. Amberlyst® 15, toluene, reflux; b) 5 equiv. MeC(OMe)3, cat. Amberlyst®
15, toluene, reflux; c) 5 equiv. HC(OEt)3, Amberlyst® 15, toluene, reflux; d) 5 equiv. HC(OPr)3, cat. Amberlyst® 15, toluene, reflux.
28–31 were readily accessible in one step in moderate yields atoms (carbonyl out of the benzenic plane for preferred
(33–77%) from catechol 27 using the corresponding ortho- conformation), is described as a Lilial®-like odor. This
ester.[25–27]
analysis was reported in our previous paper.[6]
The generation of the olfactophore model of Calone
1951® was performed by using the program Phase.[28] The
energy penalty for superimposition on the olfactophore
model is less than 3.5 kcal/mol (OPLS-2005 force field), ex-
cept for Floralozone® (5.5 kcal/mol). The energies were cal-
culated by using Macromodel[30] with constraints on the
atoms involved in the olfactophore model. A large number
of the molecules investigated in this work can be superim-
posed on the main structural features of Calone 1951®. A
few of them are presented in Figure 6. For example, in mol-
Olfactory Evaluations
Based on the structure of Calone 1951®, an olfactophore
model has been designed with the program Phase®.[28] The
olfactophore model comprises the three key elements of Ca-
lone 1951®: A hydrophobic part (green), a benzenic ring
(orange), and a hydrogen-bond acceptor (red). The super-
imposition on the olfactophore model of various molecules
described as being similar to the Calone 1951® odor is pre-
sented in Figure 5.
Figure 5. Olfactophore model proposed for the marine-ozone odor
based on Calone 1951®. Hydrophobic part (green), benzenic ring
(orange) and hydrogen-bond acceptor (red).
This model is closely related to a previous olfactophore
model of the Lilial® analogues published by Winter and co-
workers in 2004.[29] The main difference is the position of
the hydrogen-bond acceptor element. In the present model,
this olfactophore element is placed in the plane defined by
the benzene ring. In the Lilial® model, the hydrogen-bond
acceptor was not in the plane (2.5 Å difference). A close
structural relationship exists between these two odor fami-
lies (Calone® and Lilial®). For example, it is interesting to
observe that Calone 1951® (carbonyl group in the benzenic
plane for the preferred conformation) is described as
strongly marine and ozone, whereas its carba-analogue, in
Figure 6. Superimposition of representative molecules on the olfac-
which the two cyclic oxygen atoms are replaced by carbon tophore model proposed for the marine-ozone odor.
4
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Structure-Activity Relationships in Odorants
ecule 8a, the hydroxy group that replaces the carbonyl sults of the olfactory evaluations are shown in Table 1. As
group of Calone 1951® can play the same role of hydrogen- a first comment, we fully confirm the results obtained by
bond acceptor in the ligand–receptor interaction. The re- Hügel and co-workers[7] for alcohol 8a and the correspond-
Table 1. Olfactory profiles.
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ing acetate 9c. Alcohol 8a fits our model (Figure 5) and has particularly interesting odor that is very close to vanillin.
retained the marine-ozone character, but is much weaker Moreover, this compound is much more stable than vanillin
than Calone 1951®. Moreover, we were pleased to note that and ethyl vanillin, which are well known to sometimes pro-
the descriptors given for 8a by Firmenich’s perfumers (who voke undesired strong brown colorations. We are convinced
were unaware of the literature description) were word-for- that 20b could sometimes be useful as a vanillin replace-
word identical to those used by Hügel et al. Alcohols 8b ment in perfumery.[33]
and 8c are also very weak, probably due to their much
The next question was: Is it possible to replace the seven-
lower volatility compared with the parent ketones (by EPI membered ring of the benzodioxepine and preserve the tar-
calculations,[31] the volatility of Calone 1951® is more than geted marine-ozone-watery character? When the keto
20 times higher than that of the corresponding alcohol). seven-membered ring is replaced by the combination of al-
Acetate 9c has completely lost the marine note. In this case, dehyde five-membered ring, the superimposition on the
the carbonyl oxygen cannot superimpose on our model, and model is preserved, as it is in structure 31a. This is also true
the sp3 oxygen is probably too weak a hydrogen-bond ac- when the five-membered ring incorporates just one oxygen
ceptor.[32] Trying to replace the carbonyl group of the atom, as in structures 25a–c.
benzodioxepinone system with an ether functional group
Compound 25a, having a methyl on the aromatic ring,
also has a negative effect on the quality and intensity of the has a pleasant aldehydic, green, marine odor and is particu-
odor. Compounds 9a and 9b are weak and have totally lost larly substantive and powerful. The introduction of a
the marine-ozone-watery character. These compounds, methyl group at the α position to the aldehyde is clearly
which should in theory fit our model, may lose their activity unfavorable, compound 25b having only a slightly watery
because of the weaker ability of ethers to act as hydrogen- odor. It should be noted that compounds 25a–c, as well as
bond acceptors.[32] The odor of epoxide 11 (which also fits 18b, can be regarded as Humusal 32 analogues, which also
the model) is reminiscent of the fresh marine note with fit our model and possess a fresh, marine, sea breeze char-
shellfish and algae aspects, but is not powerful. These re- acter (Figure 7).
sults round off the series described by Hügel and co-
Increasing the size of the substituent on the aromatic
workers[7] concerning Calone 1951® analogues with a sub- ring leads to a compound that is particularly appreciated
stituent at position 3 of the benzodioxepine ring, and con- by perfumers. 2,3-Dihydro-5-isopropyl-1-benzofuran-2-
firm that the carbonyl group is definitely the best functional carbaldehyde 25c has very nice watermelon, aldehydic,
group for this skeleton.
green, oyster, and ozone notes. Of interest is the fact that
As mentioned in the introduction, allowing a degree of the odors of the corresponding carba-analogues 33a–d (Fig-
freedom by opening the seven-membered ring was our next ure 7), which have a similar conformation, are in general
idea. Doing that could allow the electron-withdrawing more aldehydic, green, muguet and less ozone-marine.[29,34]
group to adopt the best position in space. Floralozone® It seems that here we are at the crossroads between lily-of-
(3a), in which the seven-membered ring is replaced by an the-valley and marine-ozone-watery ingredients, which also
open chain, can be superimposed on the model and still means that the receptor for both should not be very dif-
keep the ozone-watery profile. Unfortunately, the proposed ferent. All of these compounds (25a–c and 33a–d) can
new compounds 14–16, 18, and 19, all of which fit our adopt a conformation (with an energy penalty below 1 kcal)
model, do not possess the ozone-marine odor (Table 1). A in which the carbonyl is slightly out of the plane of the
possible explanation for these observations could be the benzenic ring (1.2 Å) and compatible with both models (our
negative interaction of the free methoxy group (always pres- ozone-watery model and the previous Lilial® model[29]).
ent in this series) with the olfactive receptor. These observa- Consequently, they can potentially interact with both recep-
tions might also indicate that the two oxygen atoms on the tors and have either the ozone-watery or Lilial odor, de-
aromatic ring of the Calone 1951® analogues are more im- pending on the most favorable interaction. Again, concern-
portant for their conformation than for their electronic ef- ing the carba-analogues, the alcohols could themselves have
fect. The carbonates 20b–d clearly cannot be superimposed very good odoriferous properties,[34–36] such as compound
on the model (the carbonyl being too close to the aromatic 34, named Lilyflore® and commercialized by Firmenich
ring) and do not possess the ozone-marine odor. However, (Figure 7). Although Lilyflore® retains and magnifies the
2-methoxy-4-methylphenyl methyl carbonate (20b) has a Lilial®, hydroxycitronellal, muguet notes of the parent alde-
Figure 7. Compounds 32–34.
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(؎)-7-Methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ol (8a): Obtained
in 92% yield from 1a following the procedure described pre-
viously.[18] 1H NMR: δ = 2.24 (s, 3 H), 3.21 (d, J = 9 Hz, 1 H),
4.04 (m, 2 H), 4.23 (m, 2 H), 6.73 (dd, J = 8.0, 1.9 Hz, 1 H), 6.80
(d, J = 1.9 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR: δ
= 20.5 (q), 69.7 (d), 74.7 (t), 74.8 (t), 121.2 (d), 121.9 (d), 124.4 (d),
133.8 (s), 148.8 (s), 150.7 (s) ppm. MS: m/z (%) = 181 (11.2), 180
(100.0) [M]+·, 149 (11.7), 135 (59.8), 123 (33.9), 109 (13.8), 91
(12.9), 78 (18.6), 77 (20.9), 66 (16.7), 51 (13.5).
hyde, unfortunately this is not the case for alcohols 24a,b
with powdery, mimosa, heliotropine notes for 24a and a
curiously coumarin, lactonic odor for 24b.
2-Alkoxy-1,3-benzodioxoles 28–31 cannot be superim-
posed on the model because the distance is too short be-
tween the oxygen atoms and the benzenic ring. Their odors
are quite different from general descriptors, such as burnt,
smoky, phenolic, and leather, and absolutely not ozone-wa-
tery. Increasing the length of the alkoxy chain in 30 and 31
gave compounds that are more terpenic, and even slightly
aldehydic, but weaker. The presence of the methyl group at
position 2 is beneficial, leading to compounds 29a–d having
nice guaiacol, eugenol notes. Compound 29d is particularly
interesting, reminiscent of isoeugenol and dihydroeugenol,
close to cade oil, with top notes more smoky-guaiacol.
(؎)-7-tert-Butyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ol (8b): Ob-
tained in 88% yield from 1b following the procedure described pre-
viously.[18] 1H NMR: δ = 1.26 (s, 9 H), 3.43 (d, J = 9 Hz, 1 H),
4.08 (m, 2 H), 4.21 (m, 2 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.93 (dd, J
= 8.4, 2.4 Hz, 1 H), 7.00 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR: δ =
31.3 (q), 34.2 (s), 69.7 (d), 74.6 (t), 118.4 (d), 120.5 (d), 120.7 (d),
147.2 (s), 148.3 (s), 150.2 (s) ppm. MS: m/z (%) = 223 (3.9), 222
(26.9) [M]+·, 207 (100.0), 151 (9.4), 123 (6.0), 105 (7.9), 91 (6.3), 77
(8.9), 43 (4.7).
(؎)-7-Propyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ol (8c): Obtained
in 87% yield from 1c following the procedure described pre-
viously.[18] 1H NMR: δ = 0.92 (t, J = 7.3 Hz, 3 H), 1.59 (m, 2 H),
2.49 (t, J = 7.8 Hz, 2 H), 2.81 (m, 1 H), 4.05 (m, 2 H), 4.26 (m, 2
H), 6.76 (dd, J = 8.0, 2.2 Hz, 1 H), 6.83 (d, J = 2.2 Hz, 1 H), 6.91
(d, J = 8.0 Hz, 1 H) ppm. 13C NMR: δ = 13.8 (q), 24.4 (t), 37.1
(t), 69.8 (d), 74.7 (t), 74.8 (t), 121.1 (d), 121.3 (d), 123.8 (d), 138.7
(s), 148.9 (s), 150.7 (s) ppm. MS: m/z (%) = 209 (8.1), 208 (60.9)
[M]+·, 179 (100.0), 135 (28.9), 123 (67.2), 105 (9.2), 91 (7.9), 77
(23.5), 57 (10.9), 51 (11.4), 43 (9.1).
Conclusions
This report describes the continuation of our investi-
gations concerning marine note odorants. We have shown
that the seven-membered ring of the Calone family scaffold,
as suggested by our model, can be replaced by a five-mem-
bered ring with retention of both the marine-ozone-watery
olfactory profile and the odor intensity. In addition, the
carbonyl functional group originally present in the seven-
membered ring and presumably responsible for the
hydrogen bond inside the active site of the olfactory recep-
tor can be mimicked by an aldehyde. This is the case for
compounds 2,3-dihydro-5-methyl-1-benzofuran-2-carbal-
dehyde (25a) and 5-isopropyl-2-methyl-2,3-dihydro-1-
benzofuran-2-carbaldehyde (25c). The results confirm the
rules already observed in our preceding work and used to
design the model, but several questions remain unanswered.
In particular, the need for the presence and the role of one
or two oxygen atoms substituted in the aromatic ring is still
confusing, and much work remains to clarify this point.
In addition, this study has allowed the unexpected dis-
covery of two very good compounds: 2-Methoxy-4-meth-
ylphenyl methyl carbonate (20b), which is very close to va-
nillin and ethyl vanillin and is interesting as a stable substi-
tute of these important ingredients, and 2-methoxy-2,4-di-
methyl-1,3-benzodioxole (29d), which belongs to the isoeug-
enol/dihydroeugenol olfactive family.
(؎)-3-Methoxy-7-methyl-3,4-dihydro-2H-1,5-benzodioxepine (9a):
Obtained in 89% yield from 8a following the procedure described
previously.[18] 1H NMR: δ = 2.22 (s, 3 H), 3.43 (s, 3 H), 3.75–3.82
(m, 1 H), 4.17–4.26 (m, 2 H), 4.26–4.34 (m, 2 H), 6.67 (dd, J = 8,
2 Hz, 1 H), 6.74 (d, J = 2 Hz, 1 H), 6.81 (d, J = 8 Hz, 1 H) ppm.
13C NMR: δ = 20.5 (q), 57.1 (q), 71.2 (t), 71.4 (t), 78.5 (d), 120.5
(d), 121.2 (d), 123.6 (d), 132.8 (s), 147.8 (s), 149.6 (s) ppm. MS: m/z
(%) = 194 (100) [M]+·, 161 (6), 149 (21), 135 (67), 123 (7), 121 (10),
105 (6), 94 (10), 91 (10), 77 (18), 71 (48), 66 (15), 51 (10), 45 (10),
41 (15).
(؎)-3-Ethoxy-7methyl-3,4-dihydro-2H-1,5-benzodioxepine (9b): Ob-
tained in 86% yield from 8a following the procedure described pre-
viously,[18] except with the use of iodoethane instead of iodome-
1
thane. H NMR: δ = 1.24 (d, J = 7 Hz, 1 H), 2.23 (s, 3 H), 3.60
(d, J = 7 Hz, 2 H), 3.87–3.94 (m, 1 H), 4.20 (dt, J = 12, 5 Hz, 2
H), 4.32 (dt, J = 12, 5 Hz, 2 H), 6.67 (dd, J = 8, 2 Hz, 1 H), 6.74
(d, J = 2 Hz, 1 H), 6.81 (d, J = 8 Hz, 1 H) ppm. 13C NMR: δ =
15.5 (q), 20.5 (q), 65.1 (t), 71.8 (t), 72.0 (t), 76.9 (d), 120.5 (d), 121.2
(d), 123.5 (d), 132.7 (s), 147.8 (s), 149.6 (s) ppm. MS: m/z (%) =
208 (100) [M]+·, 179 (1), 161 (8), 149 (21), 135 (74), 123 (14), 121
(12), 105 (8), 94 (8), 91 (14), 85 (22), 77 (20), 66 (14), 57 (51), 51
(10), 43 (12), 41 (10).
Experimental Section
General: All reactions were performed under N2. Gas-liquid
chromatography (GLC) and prep GLC: Agilent 6890 instrument
equipped with a flame ionization detector (250 °C) coupled to an
Agilent Chemstation 6.03; Chrompack capillary columns DB-Wax
(15 m, 0.25 mm) and DB-1 (15 m, 0.25 mm). Flash chromatog-
raphy: High-quality silica gel 60 Å particle size, in prepacked car-
tridges from Interchim. Bulb-to-bulb distillation: Büchi GKR-50
oven; b.p. corresponds to the air temperature. NMR: Bruker WH-
(؎)-7-Methylspiro[1,5-benzodioxepine-3,2Ј-oxirane] (11): A mixture
of 10[19,20] (1.0 equiv.) and m-CPBA (1.3 equiv.) in CH2Cl2 (4 mL/
mmol) was stirred at 30 °C for 2 d. The mixture was diluted, ex-
tracted with 10% aq. NaHSO3 soln., washed with satd. aq.
NaHCO3 soln. and brine, dried with MgSO4, and concentrated un-
der vacuum. Flash chromatography on silica gel with a mixture of
ethyl acetate/heptane (3:97) gave the pure epoxide 11 (29% yield).
1H NMR: δ = 2.25 (s, 3 H), 2.84 (s, 2 H), 4.18 (dd, J = 13, 7 Hz,
400, Bruker AMX-360; 1H at 400 MHz and 13C at 90 MHz in 2 H), 4.26 (dd, J = 13, 7 Hz, 2 H), 6.72 (dd, J = 8, 2 Hz, 1 H), 6.78
CDCl3 when not specified; chemical shifts are in ppm relative to
tetramethylsilane. MS: Varian MAT-112 spectrometer (ca. 70 eV);
intensities in % relative to the base peak (100%).
(d, J = 2 Hz, 1 H), 6.85 (d, J = 8 Hz, 1 H) ppm. 13C NMR: δ =
20.5 (q), 50.8 (t), 57.9 (s), 73.6 (t), 73.8 (t), 120.8 (d), 121.4 (d),
124.0 (d), 133.3 (s), 147.4 (s), 149.3 (s) ppm. MS: m/z (%) = 192
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43365
/KAP1
Date: 22-01-15 13:35:20
Pages: 12
J.-M. Gaudin, J.-Y. de Saint Laumer
FULL PAPER
(100) [M]+·, 176 (2), 162 (40), 161 (44), 135 (40), 123 (20), 105 (8), pentane (20:80) gave 3.83 g of (2-methoxyphenoxy)acetaldehyde
1
94 (23), 91 (7), 77 (15), 70 (19), 66 (40), 55 (7), 51 (11).
(18a; yield: 54%). H NMR: δ = 3.89 (s, 3 H), 4.59 (d, J = 1.1 Hz,
2 H), 6.80–7.05 (m, 4 H), 9.90 (t, J = 1.1 Hz, 1 H) ppm. 13C NMR:
δ = 55.8 (q), 74.3 (t), 112.3 (d), 115.0 (d), 120.9 (d), 123.0 (d), 147.3
(s), 149.7 (s), 200.2 (d) ppm. MS: m/z (%) = 167 (8.2), 166 (81.9)
[M]+·, 137 (34.7), 122 (99.3), 109 (12.2), 95 (33.0), 92 (37.2), 77
(100.0), 65 (27.4), 63 (22.4), 52 (31.5).
1-(2-Methoxyphenoxy)-2-propanone (14a). General Procedure
1
(GP 1): Chloroacetone (6.23 g, 1.2 equiv.) was added dropwise to a
mixture of guaiacol (7 g, 56.4 mmol) and potassium carbonate
(9.3 g, 1.2 equiv.) in acetone (80 mL) over a period of 2 h whilst
heating at reflux with stirring. The reaction mixture was heated at
reflux overnight and cooled. Toluene (50 mL) was added and the
mixture was distilled under reduced pressure to remove the acetone.
The organic layer was washed twice with water, then dried with
MgSO4 and the toluene removed under reduced pressure to give
10.1 g of a dark-colored oil. Flash chromatography on silica gel
with a mixture of ethyl acetate/heptane (5:95) gave 8.63 g of 1-(2-
(2-Methoxy-4-methylphenoxy)acetaldehyde (18b): According to
GP 2, obtained in 51% yield from 2-methoxy-4-methylphenol
(13b). 1H NMR: δ = 2.30 (s, 3 H), 3.85 (s, 3 H), 4.55 (d, J = 1.4 Hz,
2 H), 6.60–6.75 (m, 3 H), 9.88 (t, J = 1.4 Hz, 1 H) ppm. 13C NMR:
δ = 21.1 (q), 55.7 (q), 74.6 (t), 113.2 (d), 115.1 (d), 121.0 (d), 132.8
(s), 145.1 (s), 149.4 (s), 200.5 (d) ppm. MS: m/z (%) = 181 (12.0),
180 (100.0) [M]+·, 151 (16.7), 136 (66.0), 122 (13.3), 109 (24.6), 106
1
methoxyphenoxy)acetone (14a; yield: 85%). H NMR: δ = 2.22 (s,
3 H), 3.88 (s, 3 H), 4.59 (s, 2 H), 6.78 (dd, J = 8.2, 1.5 Hz, 1 H), (14.8), 91 (52.8), 77 (25.5), 65 (17.0), 51 (9.4).
6.88 (td, J = 8.1, 1.7 Hz, 1 H), 6.92 (dd, J = 8.0, 1.5 Hz, 1 H), 6.98
(2-Methoxy-4-propylphenoxy)acetaldehyde (18c): According to
(m, 1 H) ppm. 13C NMR: δ = 26.4 (q), 55.9 (q), 74.5 (t), 112.2 (d),
114.3 (d), 120.9 (d), 122.5 (d), 147.4 (s), 149.6 (s), 206.4 (s) ppm.
MS: m/z (%) = 181 (7.9), 180 (68.0) [M]+·, 137 (48.7), 122 (100.0),
109 (11.0), 95 (14.9), 92 (28.8), 77 (67.5), 63 (19.0), 52 (27.2), 43
(45.6).
GP 2, obtained in 53% yield from dihydroeugenol (13c). 1H NMR:
δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.62 (m, 2 H), 2.53 (t, J = 7.3 Hz, 2
H), 3.86 (s, 3 H), 4.54 (d, J = 1.0 Hz, 2 H), 6.68 (dd, J = 8.0,
1.9 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 6.74 (d, J = 1.9 Hz, 1 H),
9.88 (t, J = 1.4 Hz, 1 H) ppm. 13C NMR: δ = 13.8 (q), 24.7 (t),
37.7 (t), 55.7 (q), 74.5 (t), 112.6 (d), 115.0 (d), 120.4 (d), 137.7 (s),
145.3 (s), 149.5 (s), 200.5 (d) ppm. MS: m/z (%) = 209 (13.7), 208
1-(2-Methoxy-4-propylphenoxy)acetone (14c): According to GP 1,
obtained in 95% yield from dihydroeugenol (13c). 1H NMR: δ =
0.93 (t, J = 7.2 Hz, 3 H), 1.61 (m, 2 H), 2.27 (s, 3 H), 2.53 (t, J = (100.0) [M]+·, 179 (58.1), 165 (66.2), 151 (23.7), 137 (30.6), 135
7.2 Hz, 2 H), 3.86 (s, 3 H), 4.55 (s, 2 H), 6.68 (m, 2 H), 6.74 (d, J (22.2), 121 (57.2), 105 (31.5), 95 (27.6), 91 (35.0), 77 (37.5), 65
= 1.5 Hz, 1 H) ppm. 13C NMR: δ = 13.8 (q), 24.7 (t), 26.4 (q), 37.7
(t), 55.8 (q), 74.8 (t), 112.6 (d), 114.3 (d), 120.4 (d), 137.2 (s), 145.4
(s), 149.4 (s), 206.7 (s) ppm. MS: m/z (%) = 223 (15.1), 222 (100.0)
[M]+·, 193 (56.8), 179 (27.3), 165 (54.6), 164 (64.3), 137 (53.2), 135
(21.5), 123 (9.8), 119 (8.9), 105 (22.5), 91 (23.6), 77 (19.8), 43 (20.4).
(18.7), 51 (18.4), 43 (22.5).
(؎)-2-[(2-Methoxy-4-propylphenoxy)methyl]oxirane (19c): Accord-
ing to GP 1, obtained in 43% yield from dihydroeugenol (13c) BY
using 1.2 equiv. of epibromohydrin. 1H NMR: δ = 0.93 (t, J =
7.4 Hz, 3 H), 1.61 (m, 2 H), 2.52 (t, J = 7.4 Hz, 2 H), 2.71 (dd, J
= 5.0, 2.5 Hz, 1 H), 2.86 (dd, J = 5.0, 4.1 Hz, 1 H), 3.37 (m, 1 H),
3.85 (s, 3 H), 4.00 (dd, J = 11.5, 5.5 Hz, 1 H), 4.19 (dd, J = 11.5,
3.7 Hz, 1 H), 6.68 (dd, J = 8.1, 2.0 Hz, 1 H), 6.71 (d, J = 2.0 Hz,
1 H), 6.84 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR: δ = 13.8 (q), 24.7
(؎)-3-(2-Methoxy-4-propylphenoxy)butan-2-one (15c): According
to GP 1, obtained in 74% yield from dihydroeugenol (13c) using
1.2 equiv. of 3-chlorobuten-2-one. 1H NMR: δ = 0.92 (t, J = 7.5 Hz,
3 H), 1.49 (d, J = 6.8 Hz, 3 H), 1.62 (m, 2 H), 2.25 (s, 3 H), 2.52
(t, J = 7.5 Hz, 2 H), 3.84 (s, 3 H), 4.52 (q, J = 6.8 Hz, 1 H), 6.65 (t), 37.7 (t), 45.0 (t), 50.3 (d), 55.9 (q), 70.5 (t), 112.4 (d), 114.4 (d),
(dd, J = 8.1, 1.8 Hz, 1 H), 6.73 (d, J = 8.1 Hz, 1 H), 6.73 (d, J = 120.3 (d), 136.6 (s), 146.0 (s), 149.4 (s) ppm. MS: m/z (%) = 223
1.8 Hz, 1 H) ppm. 13C NMR: δ = 13.8 (q), 17.7 (q), 24.6 (t), 24.8 (9.0), 222 (60.9) [M]+·, 193 (16.8), 165 (38.1), 137 (100.0), 122 (7.7),
(q), 37.7 (t), 55.8 (q), 81.2 (d), 112.8 (d), 116.0 (d), 120.4 (d), 137.4 105 (11.4), 95 (14.6), 91 (11.3), 77 (14.6).
(s), 145.0 (s), 149.8 (s), 210.9 (s) ppm. MS: m/z (%) = 237 (7.7), 236
2-Methoxy-4-methylphenyl Methyl Carbonate (20b). General Pro-
cedure 3 (GP 3): 2-Methoxy-4-methylphenol (13b; 250 mmol) was
dissolved in dry dichloromethane (500 mL) with pyridine
(45.8) [M]+·, 193 (100.0), 178 (8.7), 165 (22.4), 164 (22.5), 137
(29.0), 105 (14.4), 91 (13.8), 77 (10.2), 43 (19.7).
Methyl (2-Methoxy-4-propylphenoxy)acetate (16c): According to
GP 1, obtained in 83% yield from dihydroeugenol (13c) using
1.2 equiv. of methyl chloroacetate. 1H NMR: δ = 0.93 (t, J =
7.5 Hz, 3 H), 1.62 (m, 2 H), 2.53 (t, J = 7.5 Hz, 2 H), 3.78 (s, 3 H),
3.87 (s, 3 H), 4.66 (s, 2 H), 6.67 (dd, J = 8.0, 2.1 Hz, 1 H), 6.72 (d,
(392 mmol) and DMAP (4.26 mmol). Methyl chloroformate
(317 mmol) was added slowly to this solution and the reaction mix-
ture cooled to room temperature for 3 h. The mixture was then
poured into a 2 m HCl solution (120 mL) and the aqueous layer
extracted twice with dichloromethane (3ϫ 50 mL). The combined
J = 2.1 Hz, 1 H), 6.76 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR: δ = organic layers were then washed twice with water (3ϫ 100 mL),
13.8 (q), 24.6 (t), 37.7 (t), 52.1 (q), 55.8 (q), 66.8 (t), 112.6 (d), 114.7 dried with MgSO4, and filtered. The solvent was evaporated and
(d), 120.3 (d), 137.3 (s), 145.3 (s), 149.5 (s), 169.7 (s) ppm. MS: m/z the residue distilled under reduced pressure (120–140 °C, 0.4 mbar)
1
(%) = 239 (9.2), 238 (61.5) [M]+·, 209 (100.0), 165 (37.7), 151 (12.4), to give 38 g (74% yield) of pure carbonate 20b. H NMR: δ = 2.33
135 (9.1), 105 (14.4), 95 (13.9), 91 (14.2), 77 (16.2), 45 (17.0).
(s, 3 H), 3.81 (s, 3 H), 3.87 (s, 3 H), 6.72 (dm, J = 8.0 Hz, 1 H),
6.77 (d, J = 1.9 Hz, 1 H), 6.98 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR:
δ = 21.3 (q), 55.3 (q), 56.0 (q), 114.1 (d), 121.4 (d), 122.6 (d), 137.4
(s), 139.4 (s), 152.1 (s), 154.5 (s) ppm. MS: m/z (%) = 197 (11.3),
196 (100.0), 152 (22.5), 137 (92.7), 109 (44.6), 91 (42.8), 77 (27.2),
67 (2.3), 66 (19.1), 59 (10.3).
(2-Methoxyphenoxy)acetaldehyde (18a). General Procedure
2
(GP 2): According to GP 1, the allyl intermediate 1-(allyloxy)-2-
methoxybenzene (17a) was obtained in 98% yield as a crude oil
from guaiacol (13a) by using 1.2 equiv. of allyl bromide. Crude 17a
(7 g, 42.7 mol) in dichloromethane (200 mL) and methanol (40 mL)
at 0 °C was ozonolyzed (ozone 3.2 g/h). The reaction was purged
for several minutes with pure oxygen, warmed to room tempera-
ture, and then agitated overnight with 2 g of palladium on charcoal
under 1 atm of hydrogen. The reaction mixture was filtered and
concentrated under vacuum to give 5.3 g of the crude product.
Flash chromatography on silica gel with a mixture of diethyl ether/
2-Methoxy-4-propylphenyl Methyl Carbonate (20c): According to
GP 3, obtained in 62% yield from dihydroeugenol (13c). 1H NMR:
δ = 0.95 (t, J = 7.4 Hz, 3 H), 1.64 (m, 2 H), 2.57 (t, J = 7.5 Hz, 2
H), 3.83 (s, 3 H), 3.89 (s, 3 H), 6.74 (dd, J = 8.0, 1.9 Hz, 1 H), 6.78
(d, J = 1.9 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR: δ
= 13.8 (q), 24.5 (t), 38.0 (t), 55.4 (q), 55.9 (q), 112.8 (d), 120.5 (d),
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43365
/KAP1
Date: 22-01-15 13:35:20
Pages: 12
Structure-Activity Relationships in Odorants
121.9 (d), 138.1 (s), 142.0 (s), 150.8 (s), 154.2 (s) ppm. MS: m/z (%) (46) [M]+·, 145 (3), 133 (80), 131 (9), 118 (5), 105 (100), 103 (12),
= 225 (3.6), 224 (26.6), 151 (100.0), 95 (11.4), 91 (8.6), 77 (11.6).
91 (5), 79 (13), 77 (14), 63 (6), 51 (12).
(؎)-2,5-Dimethyl-2,3-dihydro-1-benzofuran-2-carbaldehyde (25b):
Obtained in 25% yield from 24b according to GP 4. H NMR: δ
4-Allyl-2-methoxyphenyl Methyl Carbonate (20d): According to
GP 3, obtained in 40% yield from eugenol (13d). 1H NMR: δ =
3.37 (d, J = 7.0 Hz, 2 H), 3.83 (s, 3 H), 3.89 (s, 3 H), 5.06–5.14 (m,
2 H), 5.95 (m, 1 H), 6.76 (dd, J = 7.9, 2.0 Hz, 1 H), 6.79 (d, J =
2.0 Hz, 1 H), 7.03 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR: δ = 40.1
(t), 55.5 (q), 55.9 (q), 112.8 (d), 116.2 (t), 120.6 (d), 122.1 (d), 137.0
(d), 138.4 (s), 139.3 (s), 150.9 (s), 154.1 (s) ppm. MS: m/z (%) =
223 (10.1), 222 (77.8), 178 (5.7), 163 (51.2), 147 (28.4), 135 (11.5),
115 (12.8), 107 (23.3), 103 (36.1), 91 (35.2), 77 (16.7), 44 (100.0).
1
= 1.54 (s, 3 H), 2.27 (s, 3 H), 2.99 (d, J = 6 Hz, 1 H), 3.44 (d, J =
6 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 6.94 (d, J = 8 Hz, 1 H), 6.95
(s, 1 H), 9.72 (s, 1 H) ppm. 13C NMR: δ = 20.7 (q), 21.2 (q), 37.7
(t), 90.3 (s), 109.4 (d), 125.3 (s), 125.6 (d), 128.8 (d), 130.7 (s), 156.4
(s), 201.4 (d) ppm. MS: m/z (%) = 176 (28) [M]+·, 148 (12), 147
(100), 131 (10), 119 (77), 117 (10), 103 (9), 91 (22), 77 (15), 65 (7),
63 (6), 51 (10), 43 (5), 41 (5).
(؎)-5-Isopropyl-2-methyl-2,3-dihydro-1-benzofuran-2-carbaldehyde
(25c): Obtained in 10% yield from 24c according to GP 4. 1H
NMR: δ = 1.20 (d, J = 7 Hz, 6 H), 1.54 (s, 3 H), 2.15 (d, J = 7 Hz,
1 H), 2.79–2.90 (m, 2 H), 6.77 (d, J = 8 Hz, 1 H), 6.93 (d, J =
8 Hz, 1 H), 7.01 (s, 1 H), 9.73 (s, 1 H) ppm. 13C NMR: δ = 21.3
(q), 24.4 (q), 24.4 (q), 33.6 (d), 37.8 (t), 90.4 (s), 109.4 (d), 122.9
(d), 125.2 (s), 126.4 (d), 142.2 (s), 156.6 (s), 201.5 (d) ppm. MS: m/z
(%) = 204 (19.1) [M]+·, 189 (6.0), 175 (46.1), 133 (100.0), 115 (11.5),
105 (44.8), 91 (12.3), 77 (11.1), 43 (38.4).
(؎)-(5-Methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (24a): Ob-
tained in 65% yield from 4-methyl-2-allylphenol (23a) following the
procedure described previously,[24] except with the use of peracetic
1
acid instead of m-CPBA. H NMR: δ = 2.26 (s, 3 H), 2.34 (br. s,
OH), 2.95 (dd, J = 16, 7 Hz, 1 H), 3.18 (dd, J = 16, 9 Hz, 1 H),
3.66–3.74 (m, 1 H), 3.76–3.84 (m, 1 H), 4.82–4.92 (m, 1 H), 6.65
(d, J = 8 Hz, 1 H), 6.89 (d, J = 8 Hz, 1 H), 6.96 (s, 1 H) ppm. 13C
NMR: δ = 20.7 (q), 31.3 (t), 64.9 (t), 83.1 (d), 109.0 (d), 125.6 (d),
126.6 (s), 128.3 (d), 129.9 (s), 157.0 (s) ppm. MS: m/z (%) = 164
(82) [M]+·, 145 (57), 133 (83), 131 (26), 121 (24), 105 (100), 91 (39),
77 (38), 65 (14), 63 (12), 51 (22).
(؎)-2-Methoxy-5-methyl-1,3-benzodioxole (28a). General Procedure
5 (GP 5): A mixture of 4-methylcatechol (27a; 22.1 g, 178 mmol),
trimethyl orthoformate (5 equiv.), Amberlyst® 15 (4 g), 3 Å molecu-
lar sieves (5 g), and toluene (400 mL) was heated at reflux for 4 h.
The solvent was partially distilled during this time. The reaction
was cooled to room temperature, stirred with magnesium sulfate,
filtered, and concentrated under vacuum. Distillation gave pure
(؎)-(2,5-Dimethyl-2,3-dihydro-1-benzofuran-2-yl)methanol
(24b):
Obtained in 78% yield from 4-methyl-2-methallylphenol (23b) fol-
lowing the procedure described previously,[24] except with the use
1
of peracetic acid instead of m-CPBA. H NMR: δ = NMR: 1.42
(s, 3 H), 2.26 (s, 3 H), 2.85 (d, J = 15.5 Hz, 1 H), 3.20 (d, J =
15.5 Hz, 1 H), 3.60 (d, J = 11.6 Hz, 1 H), 3.65 (d, J = 11.6 Hz, 1
H), 6.63 (d, J = 8.3 Hz, 1 H), 6.90 (d, J = 8.3 Hz, 1 H), 6.96 (s, 1
H) ppm. 13C NMR: δ = 20.7 (q), 23.2 (q), 37.9 (t), 68.2 (t), 88.5
(s), 109.0 (d), 125.8 (d), 126.8 (s), 128.3 (d), 129.7 (s), 156.5 (s) ppm.
MS: m/z (%) = 179 (6.1), 178 (49.7) [M]+·, 159 (10.2), 147 (100.0),
145 (36.2), 121 (37.1), 119 (45.4), 108 (14.3), 103 (6.3), 91 (27.7),
77 (15.3), 65 (7.2), 51 (7.6).
1
compound 28a (54% yield). B.p. (0.23 mbar) 155 °C. H NMR: δ
= 2.27 (s, 3 H), 3.37 (s, 3 H), 6.64 (d, J = 8 Hz, 1 H), 6.70 (s, 1 H),
6.74 (d, J = 8 Hz, 1 H), 6.80 (s, 1 H) ppm. 13C NMR: δ = 21.2 (q),
49.8 (q), 107.6 (d), 109.1 (d), 119.0 (d), 121.6 (d), 131.6 (s), 143.9
(s), 146.0 (s) ppm. MS: m/z (%) = 167 (6.1), 166 (56.2) [M]+·, 135
(100.0), 123 (22.8), 105 (6.2), 95 (9.2), 67 (5.2), 51 (8.8).
(؎)-2-Methoxy-5-propyl-1,3-benzodioxole (28b): Obtained in 35%
1
yield from 4-n-propylcatechol (27b) according to GP 5. H NMR:
(؎)-(5-Isopropyl-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol
(24c): Obtained in 60% yield from 4-isopropyl-2-methallylphenol
(23c) following the procedure described previously,[24] except with
δ = 0.92 (t, J = 7 Hz, 3 H), 1.59 (m, 2 H), 2.51 (t, J = 8 Hz, 2 H),
3.39 (s, 3 H), 6.65 (dd, J = 8, 1 Hz, 1 H), 6.71 (d, J = 1 Hz, 1 H),
6.76 (d, J = 8 Hz, 1 H), 6.80 (s, 1 H) ppm. 13C NMR: δ = 13.7 (q),
24.8 (t), 37.8 (t), 49.9 (q), 107.6 (d), 108.4 (d), 119.1 (d), 121.2 (d),
136.7 (s), 144.0 (s), 146.0 (s) ppm. MS: m/z (%) = 194 (34.8) [M]+·,
166 (11.1), 165 (100.0), 163 (35.6), 137 (13.5), 122 (5.1), 105 (12.5),
77 (15.6), 51 (7.9).
1
the use of peracetic acid instead of m-CPBA. H NMR: δ = 1.21
(t, J = 6.8 Hz, 6 H), 1.42 (s, 3 H), 2.15 (d, J = 6.8 Hz, 1 H), 2.79–
2.90 (m, 2 H), 3.58–3.66 (m, 2 H), 6.65 (d, J = 8 Hz, 1 H), 6.95 (d,
J = 8 Hz, 1 H), 7.01 (s, 1 H) ppm. 13C NMR: δ = 23.2 (q), 24.4
(q), 33.6 (d), 38.0 (t), 68.4 (t), 88.5 (s), 109.0 (d), 123.1 (d), 125.9
(d), 126.7 (s), 141.2 (s), 156.7 (s) ppm. MS: m/z (%) = 207 (8.3),
206 (63.0) [M]+·, 191 (48.7), 175 (62.7), 173 (46.2), 159 (12.1), 145
(17.5), 133 (100.0), 115 (17.0), 105 (34.9), 91 (19.2), 77 (15.8), 43
(21.4).
(؎)-2-Methoxy-4-methyl-1,3-benzodioxole (28d): Obtained in 77%
1
yield from 3-methylcatechol (27d) according to GP 5. H NMR: δ
= 2.26 (s, 3 H), 3.40 (s, 3 H), 6.70 (m, 2 H), 6.75 (dd, J = 7, 7 Hz,
1 H), 6.82 (s, 1 H) ppm. 13C NMR: δ = 14.6 (q), 49.9 (q), 105.8
(d), 118.7 (d), 118.8 (s), 121.4 (d), 123.5 (d), 144.4 (s), 145.4
(s) ppm. MS: m/z (%) = 167 (4.8), 166 (49.6) [M]+·, 136 (8.8), 135
(100.0), 123 (15.4), 106 (6.6), 105 (7.3), 77 (15.6), 51 (7.3).
(؎)-5-Methyl-2,3-dihydro-1-benzofuran-2-carbaldehyde (25a). Gene-
ral Procedure 4 (GP 4): A 13% aq. sol. of sodium hypochlorite
(1.05 equiv.) was added to a mixture of alcohol 24a (1 equiv.), so-
dium hydrogen carbonate, potassium bromide (0.02 equiv.) and
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO; 0.02 equiv.) in ethyl
acetate (3 mL/mmol) at room temperature for 1 h. The organic
layer was then washed twice with brine to neutral pH. Drying over
MgSO4 and concentrating in vacuo gave the crude product. Flash
chromatography (ethyl acetate/cyclohexane, 10:90) afforded the
pure aldehyde 25a as a colorless oil (16% yield). 1H NMR: δ =
2.28 (s, 3 H), 3.29 (dd, J = 16, 6 Hz, 1 H), 3.42 (dd, J = 16, 11 Hz,
1 H), 5.00 (ddd, J = 11, 6, 1 Hz, 1 H), 6.78 (d, J = 8 Hz, 1 H), 6.95
(؎)-2-Methoxy-2,5-dimethyl-1,3-benzodioxole (29a): Obtained in
33% yield from 4-methylcatechol (27a) according to GP 5, except
1
using trimethyl orthoacetate instead of trimethyl orthoformate. H
NMR: δ = 1.76 (s, 3 H), 2.27 (s, 3 H), 3.28 (s, 3 H), 6.61 (d, J =
8 Hz, 1 H), 6.64 (s, 1 H), 6.69 (d, J = 8 Hz, 1 H) ppm. 13C NMR:
δ = 21.2 (q), 24.2 (q), 49.4 (q), 107.2 (d), 108.7 (d), 121.2 (d), 127.8
(s), 131.1 (s), 144.6 (s), 146.6 (s) ppm. MS: m/z (%) = 181 (7.6), 180
(61.7) [M]+·, 150 (12.5), 149 (100.0), 124 (47.7), 120 (21.6), 92 (6.5),
77 (11.1), 57 (7.9), 51 (8.0), 43 (29.5).
(d, J = 8 Hz, 1 H), 6.99 (s, 1 H), 9.82 (d, J = 1 Hz, 1 H) ppm. 13C (؎)-2-Methoxy-2-methyl-5-propyl-1,3-benzodioxole (29b): Obtained
NMR: δ = 20.7 (q), 31.6 (t), 84.8 (d), 109.4 (d), 124.7 (s), 125.5 (d), in 61% yield from 4-n-propylcatechol (27b) according to GP 5, ex-
128.9 (d), 130.9 (s), 156.8 (s), 201.6 (d) ppm. MS: m/z (%) = 162 cept using trimethyl orthoacetate instead of trimethyl orthofor-
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O43365
/KAP1
Date: 22-01-15 13:35:20
Pages: 12
J.-M. Gaudin, J.-Y. de Saint Laumer
FULL PAPER
mate. 1H NMR: δ = 0.93 (t, J = 7 Hz, 3 H), 1.60 (m, 2 H), 1.77 (s,
using tripropyl orthoformate instead of trimethyl orthoformate. 1H
3 H), 2.51 (t, J = 8 Hz, 2 H), 3.29 (s, 3 H), 6.62 (dd, J = 8, 2 Hz,
NMR: δ = 0.92 (t, J = 7.4 Hz, 3 H), 0.93 (t, J = 7.3 Hz, 3 H), 1.54–
1 H), 6.66 (d, J = 2 Hz, 1 H), 6.70 (d, J = 8 Hz, 1 H) ppm. 13C 1.68 (m, 4 H), 2.51 (t, J = 7.7 Hz, 2 H), 3.61 (t, J = 6.6 Hz, 2 H),
NMR: δ = 13.8 (q), 24.2 (q), 24.8 (t), 37.9 (t), 49.4 (q), 107.2 (d),
6.65 (dd, J = 7.7, 2 Hz, 1 H), 6.70 (d, J = 2 Hz, 1 H), 6.75 (d, J =
108.0 (d), 120.8 (d), 127.8 (s), 136.2 (s), 144.7 (s), 146.7 (s) ppm.
7.7 Hz, 1 H), 6.83 (s, 1 H) ppm. 13C NMR: δ = 10.5 (q), 13.7 (q),
MS: m/z (%) = 209 (9.3), 208 (64.3) [M]+·, 193 (7.5), 191 (7.0), 179 22.6 (t), 24.8 (t), 37.8 (t), 65.0 (t), 107.6 (d), 108.5 (d), 118.9 (d),
(74.4), 177 (100.0), 152 (13.8), 148 (13.6), 147 (26.2), 137 (19.3),
123 (55.8), 105 (12.5), 91 (5.6), 77 (18.4), 57 (11.6), 51 (10.6), 43
(23.7).
121.1 (d), 136.5 (s), 144.0 (s), 146.0 (s) ppm. MS: m/z (%) = 223
(3.5), 222 (24.0) [M]+·, 163 (41.2), 152 (26.0), 124 (8.1), 123 (100.0),
77 (6.7).
(؎)-4-Methyl-2-propoxy-1,3-benzodioxole (31d): Obtained in 63%
yield from 4-methylcatechol (27d) according to GP 5, except using
tripropyl orthoformate instead of trimethyl orthoformate. 1H
NMR: δ = 0.94 (t, J = 7 Hz, 3 H), 1.64 (m, 2 H), 2.25 (s, 3 H),
3.61 (t, J = 7 Hz, 2 H), 6.69 (m, 2 H), 6.76 (dd, J = 8, 8 Hz, 1 H),
6.85 (s, 1 H) ppm. 13C NMR: δ = 10.5 (q), 14.6 (q), 22.6 (t), 65.1
(t), 105.8 (d), 118.6 (d), 118.8 (s), 121.2 (d), 123.4 (d), 144.4 (s),
145.4 (s) ppm. MS: m/z (%) = 195 (5.7), 194 (48.1) [M]+·, 136 (7.7),
135 (88.5), 125 (7.9), 124 (100.0), 106 (9.3), 78 (20.0), 77 (15.1).
(؎)-5-tert-Butyl-2-methoxy-2-methyl-1,3-benzodioxole (29c): Ob-
tained in 67% yield from 4-tert-butylcatechol (27c) according to
GP 5, except using trimethyl orthoacetate instead of trimethyl or-
thoformate. 1H NMR: δ = 1.28 (s, 9 H), 1.77 (s, 3 H), 3.30 (s, 3
H), 3.72 (d, J = 8 Hz, 1 H), 6.83 (dd, J = 8, 2 Hz, 1 H), 6.89 (d, J
= 2 Hz, 1 H) ppm. 13C NMR: δ = 24.2 (q), 31.6 (q), 34.6 (s), 49.4
(q), 105.5 (d), 106.8 (d), 117.5 (d), 127.8 (s), 144.3 (s), 145.0 (s),
146.5 (s) ppm. MS: m/z (%) = 223 (4.8), 222 (30.1) [M]+·, 208 (14.8),
207 (100.0), 191 (26.7), 175 (11.8), 151 (31.9), 147 (7.6), 105 (7.1),
77 (8.0), 43 (10.0).
(؎)-2-Methoxy-2,4-dimethyl-1,3-benzodioxole (29d): Obtained in
72% yield from 3-methylcatechol (27d) according to GP 5, except
using trimethyl orthoacetate instead of trimethyl orthoformate. H
Acknowledgments
1
The authors wish to thank Mrs. O. Nikolaenko and P. Millet for
their technical assistance, Mr. R. Brauchli, Firmenich SA, for
NMR analysis, and all of our colleagues for their fruitful dis-
cussions and correction of this manuscript. The authors are espe-
cially grateful to the perfumers at Firmenich SA, with special
thanks to Dr. P. A. Blanc, for their assistance in the olfactory evalu-
ations.
NMR: δ = 1.79 (s, 3 H), 2.25 (s, 3 H), 3.28 (s, 3 H), 6.65 (d, J =
8 Hz, 1 H), 6.65 (d, J = 6 Hz, 1 H), 6.73 (dd, J = 8, 6 Hz, 1 H) ppm.
13C NMR: δ = 14.6 (q), 24.3 (q), 49.4 (q), 105.3 (d), 118.3 (s), 120.9
(d), 123.1 (d), 127.3 (s), 145.0 (s), 146.1 (s) ppm. MS: m/z (%) =
181 (6.6), 180 (56.6) [M]+·, 165 (9.2), 150 (12.6), 149 (100.0), 124
(24.4), 120 (17.7), 105 (6.2), 78 (9.3), 77 (10.4), 57 (7.0), 51 (7.1),
43 (21.3).
(؎)-2-Ethoxy-5-methyl-1,3-benzodioxole (30a): Obtained in 53%
yield from 4-methylcatechol (27a) according to GP 5, except using
triethyl orthoformate instead of trimethyl orthoformate. H NMR:
δ = 1.24 (t, J = 7 Hz, 3 H), 2.28 (s, 3 H), 3.70 (q, J = 7 Hz, 2 H),
6.64 (d, J = 8 Hz, 1 H), 6.69 (s, 1 H), 6.73 (d, J = 8 Hz, 1 H), 6.82
(s, 1 H) ppm. 13C NMR: δ = 14.9 (q), 21.2 (q), 59.1 (t), 107.7 (d),
109.2 (d), 118.8 (d), 121.6 (d), 131.5 (s), 143.8 (s), 146.0 (s) ppm.
MS: m/z (%) = 181 (8.4), 180 (75.0) [M]+·, 136 (8.9), 135 (100.0),
124 (86.3), 123 (33.0), 106 (13.0), 95 (7.6), 78 (32.1), 77 (21.1), 67
(5.7), 55 (5.9), 51 (9.5).
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(؎)-2-Ethoxy-4-methyl-1,3-benzodioxole (30d): Obtained in 41%
yield from 3-methylcatechol (27d) according to GP 5, except using
triethyl orthoformate instead of trimethyl orthoformate. H NMR:
δ = 1.26 (t, J = 7 Hz, 3 H), 2.25 (s, 3 H), 3.72 (q, J = 7 Hz, 2 H),
6.68 (d, J = 7 Hz, 1 H), 6.70 (d, J = 7 Hz, 1 H), 6.76 (dd, J = 7,
7 Hz, 1 H), 6.84 (s, 1 H) ppm. 13C NMR: δ = 14.6 (q), 14.9 (q),
59.3 (t), 105.8 (d), 118.5 (d), 118.8 (s), 121.3 (d), 123.4 (d), 144.3
(s), 145.4 (s) ppm. MS: m/z (%) = 181 (7.7), 180 (69.9) [M]+·, 136
(8.9), 135 (100.0), 124 (77.9), 106 (12.2), 78 (30.2), 77 (19.6), 51
(8.8).
1
(؎)-5-Methyl-2-propoxy-1,3-benzodioxole (31a): Obtained in 53%
yield from 4-methylcatechol (27a) according to GP 5, except using
tripropyl orthoformate instead of trimethyl orthoformate. 1H
NMR: δ = 0.93 (t, J = 7 Hz, 3 H), 1.63 (m, 2 H), 2.28 (s, 3 H),
3.59 (t, J = 7 Hz, 2 H), 6.64 (t, J = 8 Hz, 1 H), 6.69 (s, 1 H), 6.73
(d, J = 8 Hz, 1 H), 6.83 (s, 1 H) ppm. 13C NMR: δ = 10.4 (q), 21.2
(q), 22.6 (t), 64.9 (t), 107.7 (d), 109.1 (d), 118.9 (d), 121.5 (d), 131.4
(s), 143.9 (s), 146.0 (s) ppm. MS: m/z (%) = 195 (5.4), 194 (44.2)
[M]+·, 135 (81.5), 124 (100.0), 106 (9.5), 78 (19.7), 77 (14.5), 51
(5.2).
(؎)-2-Propoxy-5-propyl-1,3-benzodioxole (31b): Obtained in 73%
yield from 4-n-propylcatechol (27b) according to GP 5, except
10
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Job/Unit: O43365
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Date: 22-01-15 13:35:20
Pages: 12
Structure-Activity Relationships in Odorants
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Received: October 17, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O43365
/KAP1
Date: 22-01-15 13:35:20
Pages: 12
J.-M. Gaudin, J.-Y. de Saint Laumer
FULL PAPER
Odorants
J.-M. Gaudin,*
J.-Y. de Saint Laumer ..................... 1–12
Structure–Activity Relationships in the
Domain of Odorants Having Marine Notes
A new class of molecules having marine,
watery olfactory notes has been discovered.
A model built from the Calone 1951® fam-
ily shows that the seven-membered ring
with a ketone group can be replaced by a
five-membered ring bearing an aldehyde.
Interestingly, as a side benefit, a methyl
carbonate compound has been synthesized
that is olfactively very close to vanillin and
has interesting properties.
Keywords: Oxygen heterocycles / Structure–
activity relationships / Fragrances / Olfac-
tory properties
12
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