Synthesis of benzodioxepinone analogues via a novel synthetic route with qualitative olfactory evaluation

Article abstract of DOI:10.1002/hlca.200790085

Marine odorants represent a minor yet diverse class of substances within the fragrance industry, of which 7-methyl-2H-1,5-benzodioxepin-3(4H)-one (1) is commercially known as Calone 1951, a synthetic first in the area of marine-fragrance chemistry. To determine the extent to which the characteristic marine odor of Calone 1951 corresponds to the substitution at the benzo portion of the molecule, a variety of aromatic substituents were incorporated into the benzodioxepinone structure (Scheme 1, Table 3). In light of the difficulty experienced in applying patented literature to deriving the analogues 12-18, particularly those with electron-withdrawing substituents, an alternative synthetic scheme was implemented for the construction of all analogues in favorable yields (Scheme 4, Table 3). Formation of the hydroxy-protected dihalo alkylating agent 24 via epoxide cleavage of epichlorohydrin (Scheme 3) allowed etherification favoring dihalo displacement and subsequent intramolecular ring closure (-→26a-g). THP Deprotection followed by oxidation of the alcohols 27a-g to the ketones 12-18 provided a general pathway to the benzodioxepinone products. The influence of the substituent nature on odor activity revealed a diverse scope of olfactory character (Table 4).

Full text of DOI:10.1002/hlca.200790085

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Helvetica Chimica Acta – Vol. 90 (2007)
Synthesis of Benzodioxepinone Analogues via a Novel Synthetic Route with
Qualitative Olfactory Evaluation
by Britta Drevermann, Anthony R.Lingham , Helmut M.Hügel *, and Philip J.Marriott
School of Applied Sciences (Chemistry), RMIT University, GPO Box 2476V, Melbourne,
Victoria, 3001, Australia
(phone: þ (61 3) 9925 2626; fax: þ (61 3) 9925 3747; e-mail: helmut.hugel@rmit.edu.au)
Marine odorants represent a minor yet diverse class of substances within the fragrance industry, of
which 7-methyl-2H-1,5-benzodioxepin-3(4H)-one (1) is commercially known as Calone 1951ꢀ, a
synthetic first in the area of marine-fragrance chemistry. To determine the extent to which the
characteristic marine odor of Calone 1951ꢀ corresponds to the substitution at the benzo portion of the
molecule, a variety of aromatic substituents were incorporated into the benzodioxepinone structure
(Scheme 1, Table 3). In light of the difficulty experienced in applying patented literature to deriving the
analogues 12 – 18, particularly those with electron-withdrawing substituents, an alternative synthetic
scheme was implemented for the construction of all analogues in favorable yields (Scheme 4, Table 3).
Formation of the hydroxy-protected dihalo alkylating agent 24 via epoxide cleavage of epichlorohydrin
(Scheme 3) allowed etherification favoring dihalo displacement and subsequent intramolecular ring
closure (!26a – g). THPDeprotection followed by oxidation of the alcohols 27a – g to the ketones 12 –
18 provided a general pathway to the benzodioxepinone products. The influence of the substituent nature
on odor activity revealed a diverse scope of olfactory character (Table 4).
Introduction. – The distinct marine-odor character and substantivity of Calone
1951ꢀ (¼ 7-methyl-2H-1,5-benzodioxepin-3(4H)-one; 1), first synthesized by Beer-
eboom, Cameron, and Stephens (Pfizer) [1] has contributed to its incorporation in the
fragrance industry. Calone 1951ꢀ is used for seabreeze accords in fragrances such as
ꢀEscapeꢁ (C. Klein, 1991), ꢀPolo Sport Womanꢁ (R. Lauren, 1996), and ꢀCool Water
Womanꢁ (Davidoff, 1997) [2]. Amongst traditional fragrance groups such as woody and
floral, Calone 1951ꢀ has become an prominent compound in an atypical, formerly
unestablished marine-fragrance category.
The novel properties of Calone 1951ꢀ render it suitable as a template for
structureꢀodor-relationship (SOR) applications. The significant olfactory influence of
the heterocycle O-atoms is evident in the contrast of odor character between the
benzoxepinone 2 and the annulenone structures 3 – 5 or benzodioxepines 1 and 6. Some
olfactory data for analogues of 1 are presented in Table 1.
Olfactory analysis of the benzoxepinone 2, also prepared by Beereboom et al. [1],
was restricted to the term ꢀwatermelon ketoneꢁ, and a-keto-substituted derivatives of
both 1 and 2 were assigned the same odor description. The annulenone analogue 3 was
prepared by Kubota and Isemura in 1931 and described as exhibiting a bitter almond/
peppermint odor [3]. More recently, benzocycloheptanones 4 and 5 were synthesized
by Yoshii and co-workers [4] who defined them as possessing a lily-of-the-valley
fragrance, with the presence of a marine accord in 5, the carbocyclic equivalent of 1.
ꢂ 2007 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
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Table 1. Molecular Features of some Benzodioxepinone Odorants
X
Y
R
R2, R3
Odor character
1
2
3
4
5
6
7
O
O
CH2
CH2
CH2
O
O
7-Me
H
H
7-tBu
7-Me
7-n-Pr
7-straight-chain and
branched alkyl
marine, floral nuance
watermelon, green
bitter almond, peppermint
lily-of-the-valley
lily-of-the-valley, marine
aldehydic
marine, floral, aldehydic, fruity, with ozone,
animalic, and ink-like appearances
marine, aldehydic, floral, with citrus, nutty,
and lichen facets
CH2
CH2
CH2
CH2
O
O
O
8
O
O
H, Me
The 7-propyl-2H-1,5-benzodioxepin-3(4H)-one (6) was prepared by Gaudin and Blanc
[5], and a range of other 7-substituted varieties 7 have been designed by Kraft [6] for
which olfactory accords are dominated by marine, floral, aldehydic, and fruity notes.
Tricyclic indenodioxepinone structures 8, also synthesized by Kraft, provided novel and
reasonably intense marine analogues with the occasional citrus inflection, and singular
nutty, moss, and animalic/civet appearances.
In our current studies pertaining to the odor properties of benzodioxepinone
systems, we considered the modification of substitution and functionality at the
aromatic ring and supported by qualitative olfactory analysis for consideration in
ongoing SOR (structure – odor-relationship) studies by our group [7]. Preparation of
benzodioxepinones substituted at the benzo moiety required introduction of an
alternate broadly applicable synthetic pathway due to the diverse nature of the
substituents. Limitations of the current approach (see below, Scheme 1) are examined,
and the application of a simple but novel methodology towards benzodioxepinone
syntheses (see below, Scheme 4) will be discussed.
Results and Discussion. – The current synthetic methodology for the preparation of
benzodioxepinone structures is presented in Scheme 1 (Procedure A) [1]. Our previous
studies suggested that the Williamson ether synthesis conducted under microwave
irradiation can lead to improvements in yield and purity of dietherified intermediates
[8]. This is advantageous in the preparation of fragrance chemicals, as structurally
related impurities are often difficult to remove and can persist in the benzodioxepinone
products, causing erroneous olfactory evaluation. A range of benzodioxepinone
analogues, i.e., 12 – 18 were prepared under Williamson reaction conditions from the
corresponding ortho-dihydroxy-substituted aromatics 9a – g (Table 2) and a 2 mol-
equiv. excess of methyl bromoacetate (Scheme 1). Differences in reactivity were
observed in the formation of diester derivatives 10a – g, depending on the method of

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 1. Procedure A
a) K2CO3, BrCH2COOCH3, DMF. b) KOtBu, THF. c) 2m HCl, aq. EtOH.
a) For R1, see Tables 2 (9a – g and 10a – g) and 3 (12 – 18)
heating used, i.e., microwave or conventional heating (Table 2). Yields for 10d and 10e
[9] obtained from the catechols (¼ benzene-1,2-diols) 9d and 9e containing electron-
withdrawing substituents were improved with microwave heating. The degree of
influence of substitution at the benzo moiety on the remainder of the molecule was
evident in the NMR data of intermediates 10a – g, 11a – g (see below), and
benzodioxepinones 12 – 18 (see below)1).
Table 2. Microwave vs. Conventional Methods for the Williamson Etherification. Highest yields are
given.
R1
9
Yield [%] of 10
Purity [%] of 10a)
3-Me
3-MeO
H
4-NO2
4-CHO
4-tBu
a
b
c
d
e
f
92b)
66b)
88b)
74c)
79c)
75b)
96b)
95
98
98
100
91
98
(C(4))ꢀCH¼CHꢀCH¼CHꢀ(C(5))
g
97
a) Purity determined by GC/MS prior to column chromatography. b) Yield of isolated product obtained
by the conventional method (90 – 1008, 2 h). c) Yield of isolated product obtained by the microwave
method (200 W, 4 min).
Heteronuclear HMBC data verified the connectivity of the CH2 and benzene moieties of all
analogues of 10. The 1H- and 13C-NMR chemical shifts of the CH2 groups of 11 and target analogues 12 –
1
)
Arbitrary atom numbering; for systematic names, see Exper. Part.

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18 (see below) were established by HMQC and HMBC analysis. The nonequivalence of the two CH2 and
the two MeO groups in the 1H- and 13C-NMR spectra of 10 established that the inductive electronic effect
of the R1 substituent influences the entire molecular structure. As expected, this is evident in ortho-
substituted derivatives 10a (d(H) 4.69 (CH2(1’’)) and 4.60 (CH2(2))) and 10b (d(H) 4.65 (CH2(1’’)) and
4.64 (CH2(2))1)). The inductive effect on the terminal MeO groups from 4’-substitution is prominent in
the NMR data of 10d (d(H) 3.82 (Me(3)O) and 3.81 (Me(3’’)O); d(H) 4.83 (CH2(2)) and 4.80
(CH2(1’’))), whereby the lone pair of the NO2 group enhanced electron-donating resonance effects. The
inductive strength of the aldehyde moiety in 10e (d(H) 4.81 (CH2(1’’)) and 4.78 (CH2(2))) did not match
the effect of the nitro group and seemed restricted to the CH2 groups, as did the influence of the t-butyl
group in 10f (d(H) 4.72 (CH2(1’’)) and 4.68 (CH2(2))).
The subsequent Dieckmann condensation reaction of the symmetrical hetero-ester
chains of 10 resulted in regioisomer mixtures 11. Preliminary experiments have been
published previously [8]. Our trials to form the b-keto esters returned varying yields of
cyclized products 11 with KOtBu in THF. Cyclization attempts to produce 11 mediated
by the presence of a Lewis acid (TiCl4) [10] gave no product after 48 h at 808. The
symmetrical side chains prevented ring closure despite the use of 0.5 mol-equiv. of
TiCl4 to encourage formation of the mono- rather than di-titanium enolate. Rosnati and
De Marchi likewise reported unsuccessful efforts to prepare the oxobenzodioxepine-
carboxylate structure by Dieckmann cyclization [11]. We noticed that the formation of
isomers 11 with KOtBu/THF required 10 to be ꢁ 98% pure; the presence of minor
impurities led to decomposition and poor product yields (30 – 50%). The separation of
the regioisomers was unnecessary since subsequent decarbomethoxylation of both
isomers led to the desired benzodioxepinone products. The Dieckmann condensation
for the cyclization of substituted diesterified catechols was not as general as we had
anticipated. Diesters 10a – c,f provided good yields of cyclized material 11a – c,f (82 –
87%); however, the yields of diesters 11d,e,g were irreproducible and complex product
mixtures were formed.
The formation of bicyclic benzodioxane impurities 6- and 7-R1-benzo[1,4]dioxin-
2-one 20 [8] (Scheme 2), first noticed during the synthesis of the Calone 1951ꢀ
precursors (R1 ¼ Me) were the major recurring by-products appearing in highly
variable yields in the product mixtures of the Dieckmann condensation. Product
mixtures containing both 11 and the major impurities 20 (R1 ¼ Me) are a viscous resin
and difficult to separate, which Carter et al. [12] also discovered in their quest to
synthesize acetic acid derivatives of catechol, resorcinol, and quinol. Rudimentary
Scheme 2. Major Impurities of the Dieckmann condensation of 10: 6- and 7-R1-benzo[1,4]dioxin-2-one
a) For R1, see Table 2

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isolation of 20a (R1 ¼ Me) revealed it as a red resin, devoid of olfactory character, that
forms a brittle solid on prolonged exposure to the atmosphere. Corresponding
analogues 20a – g (for a – g, see Table 2) exhibited similar physical properties of which
20b [13], 20c [14], 20d [14], 20f [13], and 20g [15] have previously been prepared.
Initially it was suspected that the main impurity appearing in the synthesis of all
analogues 11 were substituted derivatives 20. Complex cyclization mixtures obtained
for 11d,e required separation by HPLC, and inconsistencies arose when NMR data of
the isolated by-products were compared with GC/MS results. HPLC Separation was
also employed to purify the target products 15, 16, and 18, establishing by subsequent
NMR analysis that these impurities were the ether-cleavage products 21 (Fig. 1) [16].
Conclusions that KOtBu-mediated Dieckmann condensation caused the formation of a
mono-alkylated catechol that thermally cyclized in the GC injector port to the sterically
favored 6-membered heterocyclic ring were concordant with both NMR and GC/MS
data. On-column transesterification of 21 to the ethyl ester derivative provided a
compound which was resistant to cyclization under GC conditions, thus confirming the
formation of a mono-alkylated species from 10d,e under Dieckmann cyclization
conditions.
Fig. 1. Monoalkylated impurities present in the product mixtures containing 11d and 11e
We established by means of rudimentary ChemDraw models (MM2 and PM3
optimized), that aromatic substitution of the benzodioxepinone system has a significant
influence on the geometric conformation adopted by the heterocyclic ring. The
dependence of perceptible 1D-NMR shift differences on the kind and position of the
functional groups in intermediates 10a – g and 11a – g and in benzodioxepinones 12 – 18
supported this. Archer and Claret [17] published results on the twist angle (q) along the
bond between the aromatic ring and the O-atoms of the heteroalicyclic ring obtained
from the extinction coefficients in the UV spectra indicative of p ! p* transitions.
Their modelling investigations led to the conclusion that the heteroalicyclic ring adopts
either a more stable, rigid chair form or a flexible skewed pseudo twist-boat
conformation, and that the boat conformation is only adopted by a negligible
percentage of the compound due to steric constraints.
Semi-empirical calculations (MOPAC; AM1 followed by PM3) and ab initio
models with HOMO/LUMO predictions were used to interpret differences in
reactivity. Presenting compound 10d as a representative in Fig. 2, the difficulty for
compounds 10d and 10e, and to an extent for 10c [18] and 10g, to cyclize became
evident. LUMO Hybridization is towed away from the alicyclic portion and
concentrated around the aromatic ring, unlike those with electron-donating alkyl
substituents as demonstrated by the 4-methyl isomer 10 (R1 ¼ 4-Me; Fig. 3). Based on

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Fig. 2. LUMO (left) and HOMO (right) representations of the 4-nitro compound 10d (R1 ¼ 4-NO2)
Fig. 3. LUMO (left) and HOMO (right) representations of compound the 4-methyl isomer 10 (R1 ¼ 4-
Me)
these models, intramolecular cyclization is substantially hindered for 10d due to a lack
of available orbitals for acceptance of electrons required in the formation of a new
s bond. For the decarbomethoxylation (Scheme 1) in the absence of LUMO around the
reaction site, the energy required for bond breaking and forming for the saponified side
chain is much greater than that offered by external HOMO. Other factors such as
polarization and potential tautomerism may also contribute. Electron-donating
aromatic substituents present in compounds 10a,b,f assist in localizing the charge of
the O-atoms and destabilization of the aromatic ring. Conversely the electron-
withdrawing substituents of 10d,e and the conjugated naphthodioxepine system of 10g
contribute to resonance stabilization of the aromatic ring, resulting in hindered
cyclization. Of compounds 11a – g, the MeO derivative 11b is the only product obtained
as a solid and the only intermediate for which the NMR data shows no distinguishable
regioisomers, although GC/MS data reveals an 81:19 isomer ratio. The isomeric ratios
for 11a, 11d, 11e, and 11f are 30 :70, 57:43, 100 and 51:49, respectively. Signals due to
1
the enol form of compounds 11a – g were not observed in the H-NMR or FT-IR
spectra, and CH and CH2 signals were confirmed by DEPT-135, COSY, and HMQC
analysis.
For the liberation of the target benzodioxepinones 12 – 18 (Table 3) a single-step
acidic decarbomethoxylation of 11 (Scheme 1) afforded more desirable results than

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Table 3. Yields of Target Analogues 12 – 18
R1
Procedure A
Procedure B
Yield [%]a) Purity [%]b) Yield [%]a) Purity [%]b)
12 6-Me
13 6-MeO
14
95
10
2
11
84
7
97
99
87
53
69
95
81
56
87
60
84
52
73
61
78
86
98
99
93
94
58
14
H
15 7-NO2
16 7-CHO
17 7-tBu
18 (C(7))ꢀCH¼CHꢀCH¼CHꢀ(C(8))
a) Yield following purification with respect to 11 (Procedure A) or 27 (Procedure B). b) Purity by GC/
MS prior to purification by column chromatography or HPLC.
initial saponification under basic conditions followed by acidic decarboxylation. In
agreement with our electronic considerations, those variants 10 with an electron-
withdrawing substituent at the aromatic moiety were more susceptible to nucleophilic
alkoxy attack during the formation of 11d and 11e, and as a result, the latter were also
less vulnerable to decarbomethoxylation. Purification of the decarbomethoxylated
analogues 12 – 18 was dependent on the type of aromatic substituent present.
Analogues with electron-donating aromatic substituents such as 12, 13, and 17 could
be effectively purified by vacuum distillation, whereas those with an electron-
withdrawing substituent or no electron-donating contributor, i.e., 14 [19], 15, 16, and
1
18, demanded separation by HPLC. Analysis of the H-NMR data of the benzodiox-
epinone target analogues revealed a characteristic CH2 s for the unsubstituted aromatic
products 14 and 18, and two separate CH2 signals for compounds containing aromatic
substitution (see Exper. Part).
The low yields of 15 and 16 (Table 3) and the inherent instability of compounds 11d
and 11e required a more viable approach to the ketone ring to access the broader scope
of analogues containing reactive or strongly electron-withdrawing aromatic substitu-
ents. Single-step trials to form the benzodioxepinone adduct by Rosnati et al. [11] have
included the reaction between catechol and 1,3-dichloroacetone in the presence of N,N-
dimethylpyridin-4-amine (DMAP) with no success. A study by these authors on the
alkaline condensation of catechol with 1,3-dichloropropan-2-ol briefly described the
formation of the 1,5-benzodioxepin ring as a minor impurity. Modification of this
generally unutilized approach was applied to our current studies with the incorporation
of a protected 1,3-dihalo alcohol. Our group has successfully applied this novel
synthetic route (Procedure B) to generate analogues 12 – 18 (Table 3). Thus, 1-bromo-
3-chloropropan-2-ol was prepared by acid-catalyzed epoxide opening of epichlorohy-
drin (22; Scheme 3) with HBr to give the secondary alcohol 23 exclusively. anti-
Markovnikov-type regioselectivity is commonly encountered for these ambident
substrates (Shargi and co-workers) [20]. The trimethylsilyl group was initially

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Scheme 3
a) HBr (48%), r.t. b) DHP, P O5, r.t.
2
implemented as a protecting group for 23; however, it proved too labile for
etherification reactions even at milder temperatures. Thus, the robust (under basic
conditions) protecting group tetrahydropyran (THP) was introduced by reaction of 23
with 3,4-dihydro-2H-pyran (DHP) and P2O5 as catalyst under solvent-free conditions
[21], to produce 24 as a distillable colorless oil in 91% yield.
The experimental approach employed in Procedure B (Scheme 4) involved initial
reaction of the benzene-1,2-diols 9a – g with an equimolar amount of alkylating agent
24 to expediently form the stable monoalkylated intermediate 25 by chemoselective
displacement of the Br-atom as shown by GC/MS. Intramolecular etherification of the
second OH group with the chloroalkane moiety gave the cyclized 7-membered ring
upon prolonged heating in DMF. Although the Cl-displacement required 24 h, no
dimeric structures or polymeric material were formed. Initial trials involved the use of
Scheme 4. Procedure B
a) K2CO3, DMF, reflux. b) V2O5, H2O2, 708. c) KMnO4, 4% KOH soln., r.t. (for R1 ¼ NO2 or CHO,
oxalyl chloride, DMSO, Et3N, ꢀ 788).
a) For R1, see Tables 2 (9a – g) and 3 (12 – 18)

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NaH but produced inferior results to K2CO3 in DMF, which was sufficient to deliver
clean mixtures of the cyclized products 26 in excellent yields. Deprotection of 26 with
silica chloride [22] according to a protocol by Firouzabadi et al. was successful in the
removal of THP, but was accompanied by significant decomposition. A trial of a dual
oxidative deprotection with b-cyclodextrin (deprotection) and N-bromosuccinimide
(NBS; oxidation) in H2O/acetone [23] resulted in a small yield of the a-bromo carbonyl
compound after 15 min, and with incorporation of a Br-scavenger returned only the
starting alcohol. A KMnO4/CuSO4 hydrate with an alcohol catalyst [24] was attempted,
also to no avail. A NaBrO3/NH4Cl reagent [25] in aqueous MeCN, recommended for
oxidative deprotection of silyl ethers resulted in attack at the fusion atoms forming
over-oxidized catechol derivatives. Deprotection of the THPgroup ( Scheme 4) with
V2O5 catalyst under conditions developed by Patel and co-workers [26] produced the
alcohol in quantitative yield under mild conditions. The aldehyde derivative 26e was
also successfully deprotected with V2O5 avoiding over-oxidation and polymerization.
Esterification of the aldehyde was avoided by the use of MeCN rather than MeOH as
solvent as suggested by Patel and co-workers. The 1H-NMR signal for the proton at the
stereogenic center C(3) of 26a – g characteristically overlapped with the diastereotopic
1
CH2(2) and CH2(4) protons. The ambiguous H-NMR resonance was clarified by
COSY and HMQC experiments in each case.
Oxidation of the secondary alcohols 27 (Scheme 4) with KMnO4 in benzene and
under PTC-assisted biphasic conditions (PTC ¼ phase-transfer catalyst) failed to
provide the oxidized product in greater than 5% yield. Aqueous basic conditions
suggested by Rosnati et al. were found to be optimal for the oxidative activity of
KMnO4 and provided the ketone products 12 – 14 and 17 – 18 at room temperature in
good yields (Table 3). Surprisingly, the aqueous acidic workup resulted in chlorinated
by-products when CH2Cl2 was used as extraction solvent, so Et2O was used instead.
Permanganate was not a suitable oxidizing agent for the formation of benzodiox-
epinone analogues with electron-withdrawing aromatic substituents. Application of
Swern-oxidation conditions by using oxalyl chloride and DMSO gave reproducible
formation of the nitro and aldehyde derivatives 15 and 16 in 84% and 52%, respectively
and in favorable purity (99% and 93%, resp., Table 3). HMQC and HMBC couplings
established CH2/fusion atom correlations for all target analogues (including 19, see
below) and the intermediates 26 and 27 [27].
Halogenated compounds rarely appear in the fragrance-chemistry arena, in part
due to their inherent toxicity. In determining the importance of the aromatic moiety to
the Calone 1951ꢀ headspace, the accessible aromatic halo-substitution product 19
provided an informative addition to the analogue group. Bromination of Calone 1951ꢀ
(1) gave 19, the single molecule in this series not derived from a catechol. This
bromination was based on a system developed by Kikuchi, Sakaguchi, and Ishii [28]
(Scheme 5), i.e., a two-phase system for the in situ generation of hypobromous acid
(HOBr) from NaBrO3/NaHSO3 in the aqueous phase, which is suspected to form a
cationic bromine species. Bromination of the aromatic ring occurred selectively at the
ortho position to the Me group as predicted by the activating Me group.
Olfactory Evaluation. – The diverse range of synthesized analogues incorporated
many which maintained the original marine-odor attribute of 1, namely 12, 13, 17, and

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19 and to a lesser extent 15 and 16 (Tables 4 and 5). In all cases, the odor threshold was
largely increased compared to 1, as indicated by a low perceived intensity for the range
of analogues. Aromaticity, particularly as benzylic functionality is prevalent in
compounds used for their fragrant properties. The patent released by Pfizer allocated
a general olfactory assessment of ꢀwatermelon greenꢁ to a range of benzodioxepinone
Table 4. Olfactory Data for Analogues 12 – 19
Qualitative olfactory dataa)
12
13
Fresh, floral-aldehydic odor of green and woody-marine tonality
Sweet-spicy, green-marine, floral, slightly earthy, walnut-like
nuances, relatively weak
14
15
16
17
18
Green-floral, balsamic odor in the direction of Peru and Tolu
balsam resinoid, a slight marine salty aspect
Fruity-spicy, balsamic odor with a slight woody inflection and a
distant powdery-vanillic sweetness, weak
Sweet, powdery scent reminiscent of vanilla with a spicy-balsamic
undertone
Fresh, marine, ozony odor, a green and walnut-like nuance,
slightly floral
Oily, floral-green, and a slightly metallic odor, a very weak
watery-floral, Calone-like inflection, weak
19
Marine-ozony, ethereal, walnut-like odor, with salty aspects
and a floral-fruity, geranium-like inflection, slightly earthy;
same intensity and tenacity as 17
a) Data provided by Philip Kraft and Alain E. Alchenberger, Givaudan Switzerland AG, Fragrance
Research.

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Helvetica Chimica Acta – Vol. 90 (2007)
Table 5. Graphic Representation of Olfactory Characteristics of Compounds 12 – 19. Black: present;
grey: present but weak; white: absent.
12
Me
13
MeO
14
H
15
NO2
16
CHO
17
18
Benzo
19
R1
tBu
7-Me, 8-Br
marine
green
floral
aldehyde
woody/earthy
nutty
fruity
vanillic
balsamic
metallic
salty
oily
spicy
Scheme 5
a) NaBrO3, NaHSO3, H2O/cyclohexane, 85%.
compounds including 14 and 17 of our work. Compound 14 and 18 exhibit similar odor
profiles concordant with their comparable molecular attributes: a benzo and a naphtho
fusion component, respectively. The green note is preserved, however, the marine
aspect is weakened for both structures, indicating the importance of aromatic
substitution to the typical Calone 1951ꢀ olfactory character. Interestingly, complete
absence of substitution converts the fragrance emanated to a sweet array, particularly
by the reference to balsam of Peru and Tolu that typically exhibit deep, rich sweetness.
Both the nitro and aldehyde derivatives 15 and 16, respectively, displayed individual
olfactory characteristics. The marine character is completely removed in both cases,
with introduction of fruity, sweet, balsamic tonalities, with a hint of spiciness for 15. The
t
steric bulk introduced by the Bu and Br groups in 17 and 19, respectively, may
contribute to the walnut inflection perceived for both. Compound 18 serves as an
interesting comparison, maintaining the marine aspect understandably as the entire
Calone 1951ꢀ molecular skeleton is preserved for this analogue. The marine odor is
steered in a more salty direction, accompanied by floral notes, as also often detected in
the headspace from 1. To preserve the characteristic Calone 1951ꢀ odor, substitution is
not restricted to the 7-position as demonstrated when comparing compounds 12, 13, 16,
and 18. The type of functionality present at the aromatic ring, rather than its position, is
more active in deconstructing the marine-odor character, as exhibited by the
qualitative assessment of 14 – 16.

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Conclusion. – The presence of the aromatic Me substituent in Calone 1951ꢀ
complements but is not critical for the essential marine odor characteristic. In
conjunction with the presence of the C¼O group in the aliphatic ring which was
previously studied [7], it is evident from our observations that aromatic-ring
substitution modifies the odor perception of the marine character of Calone 1951ꢀ.
Financial support from the School of Applied Science, RMIT University, is acknowledged. Utmost
thanks to Daniel Dias for technical assistance with HPLC, and Nicole Benedek for ab initio molecular
modelling. We are indebted to Philip Kraft and Alain E. Alchenberger (Givaudan, Switzerland) for
olfactory evaluation. We also thank Julie Niere for assistance with NMR, in conjunction with Paul
Morrison and Frank Antolasic for support with GC and GC/MS instrumentation. Appreciation for
technical assistance and advice related to gas chromatography/olfactometry (GCO) to Jean-Pierre
Dufour and Graham Eyres, University of Otago, New Zealand. We are grateful to Michael Malcmann
(Warlock Engineering) and Raymond Lingham for provision of microwave apparatus.
Experimental Part
1. General. Potassium tert-butoxide and methyl bromoacetate were supplied by Merck. Otherwise, all
reagents were obtained from Aldrich Chemical Co. and used without further purification. THF was dried
over CaH2, followed by distillation from sodium/benzophenone. DMF was dried over CaH2, followed by
distillation over molecular sieves (4 Š). Synthesis of Calone 1951ꢀ (1) by means of the microwave heating
procedures has been discussed previously [8], and intermediates 10d and 10e were more efficiently
prepared by the microwave methodology. Microwave experiments were performed in a prototype
microwave applicator ꢀMDV2.4ꢁ and with a 0-700 W variable power microwave source (2m172)2). FC:
Merck silica gel 60 (0.040 – 0.063 mm). CC ¼ Column chromatography. TLC: Merck silica gel 60 F254
(particle size 5 – 40 mm, layer thickness 0.2 mm on aluminium, 20 ꢂ 20 cm); visualization by UV light
(254 nm). Semiprep. HPLC: Varian Prostar (model 210); Phenomenex column (250 ꢂ 10 mm, 5m ODS
(3)); MeCN/H2O 33 :67; 3.5 ml/min flow rate; UV/VIS detection. IR: Perkin-Elmer Spectrum-2000
Fourier-transform IR spectrophotometer. NMR: Bruker Avance-300 (300 MHz) spectrometer, Varian
Gemini-200 (200 MHz) spectrometer, referenced to SiMe4 with the solvent resonance as the internal
standard (CHCl3: d(H) 7.26) unless otherwise stated. MS/GC: Hewlett-Packard 6890 GC with BPX-5
column/5973 mass-selective detector.
2. Calculations. Molecular-model calculations were performed by using density functional theory
(DFT), as implemented in the Dmol3 program package. The PBE functional was used in combination
with the DNPbasis set (double numerical plus polarization). All calculations were all-electron and spin-
restricted. Each model was charge-neutral. The geometry of each model was optimized, without
constraints. Electron-density maps, HOMOs and LUMOs were calculated for the relaxed structures.
3. Calone 1951ꢃ (1) and Analogues 12 – 18: General Procedure A. 2,2’-[(4-Methyl-1,2-phenyl-
ene)bis(oxy)]bis[acetic Acid] Dimethyl Ester (10; R1 ¼ 4-Me). Conventional Method: Ground, oven-
dried K2CO3 (9.00 g, 65.12 mmol) and methyl bromoacetate (6.00 ml, 63.38 mmol) were added
sequentially to a soln. of 9 (R1 ¼ 4-Me; 2.00 g, 16.11 mmol) in anh. DMF (100 ml). The soln. was
heated to 1208 for 2 h, then the hot mixture was poured into ice/H2O (200 ml) and extracted with CH2Cl2
(3 ꢂ 100 ml). The combined org. phase was washed with 5% aq. NaOH soln. (2 ꢂ 50 ml) followed by H2O
(2 ꢂ 50 ml), dried (MgSO4), and concentrated. The obtained yellow oil was purified by vacuum CC
(silica gel (short column), pentane, then AcOEt/pentane 1:9 ! 3 :7) followed by bulb-to-bulb
distillation: 10 (R1 ¼ 4-Me; 3.37 g, 78%). White solid. M.p. (pentane) 43 – 448.
Microwave Procedure: The reagents were combined as described for the conventional procedure,
and the soln. was irradiated for 4 min at 200 W under N2. Workup of the mixture was performed
according to the conventional procedure: 10 (R1 ¼ 4-Me; 3.60 g, 83%).
2
)
Provided on trial by Warlock Engineering: www.warlock.com.au/chemreactor.htm.

1018
Helvetica Chimica Acta – Vol. 90 (2007)
Methyl 3,4-Dihydro-7-methyl-3-oxo-2H-1,5-benzodioxepine-2-carboxylate (11; R1 ¼ 7-Me). Under
an inert atmosphere, a soln. of 10 (3.72 g, 13.88 mmol) in anh. THF (35 ml) was added within 5 min to a
stirred mixture of KOtBu (3.11 g, 27.71 mmol) in anh. THF (35 ml) with cooling in an ice/H2O bath. The
soln. was then transferred to an oil bath at 708 and heated for 30 min before quenching in a stirred
mixture of 0.2m HCl (200 ml) in ice (200 g). The acidic soln. was extracted with CH2Cl2 (3 ꢂ 100 ml) and
the combined org. phase washed with H2O (2 ꢂ 150 ml) and concentrated: 11 (R1 ¼ 7-Me; 3.00 g, 92%).
Viscous yellow-brown oil consisting of a mixture of regioisomers and requiring storage at ꢀ 208. After
prolonged storage, purification by CC (silica gel, hexane/AcOEt 1:1) was necessary prior to use.
7-Methyl-2H-1,5-benzodioxepin-3(4H)-one (1). To a soln. of 11 (R1 ¼ 7-Me; 1.00 g, 4.24 mmol) in
EtOH (10 ml) was added 2m HCl (50 ml), and the soln. was heated at 908 while stirring in an oil bath.
After 2 h, the mixture was poured into ice/H2O (100 ml) and extracted with CH2Cl2 (3 ꢂ 100 ml). The
combined org. extract was washed with H2O (1 ꢂ 200 ml), dried (MgSO4), and concentrated and the
obtained brown semi-solid subjected to bulb-to-bulb distillation (708/0.5 Torr): 1 (0.59 g, 78%). White
crystalline solid. M.p. (pentane) 38 – 398 (lit.3) 38 – 408).
4. Calone 1951ꢀ (1) and Analogues 12 – 18. General Procedure B. 1-Bromo-3-chloropropan-2-ol (23).
A 48% HBr soln. (28.3 g) was added dropwise to neat epichlorohydrin (¼2-(chloromethyl)oxirane; 22;
15.0 g, 162 mmol) within 2 h under vigorous stirring. The soln. was stirred for an additional 45 min, then
mixed with Et2O (150 ml) and washed with sat. NaHCO3 soln. (3 ꢂ 50 ml). The org. phase was dried
(MgSO4) and concentrated and the residue distilled under vacuum (54 – 568/5 Torr): 23 (20.0 g, 71%).
Clear oil. IR (neat): 3380s (br.), 2961m, 2894w, 1625w, 1426s, 1382m, 1344m, 1295m, 1261s, 1225m,
1135m, 1088s, 1067s, 1039s. 1H-NMR (300 MHz, CDCl3): 4.03 (quint., J ¼ 5.3, HꢀC(2)); 3.70 (d, J ¼ 5.7,
CH2(3)); 3.56 (d, J ¼ 5.3, CH2(1)); 2.64 (s, OH). 13C-NMR (75 MHz, CDCl3): 70.3 (C(2)); 46.4 (C(3));
34.7 (C(1)). 1H,1H-COSY (CDCl3): 3.98 (HꢀC(2))/3.63 (HꢀC(3)); 3.98 (HꢀC(2))/3.51 (HꢀC(1)); 3.65
(HꢀC(1), HꢀC(3))/2.58 (OH). 1H,13C-HMQC (CDCl3): HꢀC(2)/C(2) (70.5); CH2(3)/C(3) (46.7);
CH2(1)/C(1) (34.9). EI-MS: 125 (96), 123 (100), 95 (6), 93 (6), 81 (18), 79 (50).
2-[2-Bromo-1-(chloromethyl)ethoxy]tetrahydro-2H-pyran (24). To 3,4-dihydro-2H-pyran (5.30 g,
63.00 mmol), 23 (10.0 g, 57.66 mmol) was added neat, followed by a cat. amount of P2O5 (0.10 g,
0.35 mmol). The soln. was warmed to 608 in a water bath for 1 h and then allowed to reach r.t. and stirred
for an additional hour. The resulting mixture was dissolved in Et2O (150 ml) and washed with sat.
NaHCO3 soln. (3 ꢂ 50 ml), the org. phase dried (MgSO4) and concentrated, and the residue distilled
under vacuum (101 – 1028/50 Torr): 24 (13.5 g, 91%). Clear oil. IR (neat): 2940m, 2868w, 2853w, 1437w,
1395w, 1382w, 1344w, 1323w, 1284w, 1261w, 1199m, 1178w, 1148w, 1122m, 1075m, 1054s, 1029s. 1H-NMR
(300 MHz, CDCl3): 4.78 – 4.77 (m, HꢀC(2)); 4.06 – 3.98 (m, ClCH2CH); 3.92 – 3.48 (m, CH2(6)); 3.83 –
3.48 (m, ClCH2, BrCH2); 1.82 – 1.50 (m, CH2(3), CH2(4), CH2(5)). 13C-NMR (75 MHz, CDCl3): 98.8
(C(2)); 75.5 (CH); 62.7 (C(6)); 44.2 (ClCH2); 31.9 (BrCH2); 30.5 (C(3)); 25.2 (C(5)); 19.2 (C(4)).
1H,13C-HMQC (CDCl3): CH2(2)/C(2) (99.1); HꢀC(1)/C(1) (75.6); CH2(6)/C(6) (62.7); HaꢀC(1)/ClCH2
(44.7); HbꢀC(1)/ClCH2 (44.6); CH2(2)/C(2) (32.4); CH2(3)/C(3) (30.3); CH2(5)/C(5) (25.3); CH2(4)/
C(4) (19.2). EI-MS: 257 (10, Mþ), 255 (8), 209 (2), 207 (2), 203 (2), 202 (2), 201 (2), 200 (3), 157 (16),
155 (12), 137 (4), 135 (4), 121 (5), 101 (4), 95 (3), 93 (2), 85 (100), 77 (6), 75 (18), 67 (7), 56 (20).
3,4-Dihydro-7-methyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-1,5-benzodioxepine (26; R1 ¼ 7-Me).
Ground oven-dried K2CO3 (2.22 g, 16.06 mmol) was added in one portion to a soln. of 9 (0.50 g,
4.03 mmol) in DMF, and the soln. was heated to 1008. Then a soln. of 24 (0.70 g, 2.72 mmol) in DMF was
added dropwise over 30 min and the soln. stirred at 1208 for 24 h. The hot soln. was poured into a stirred
ice/H2O (200 ml) mixture and saturated with NaCl before extraction with CH2Cl2 (3 ꢂ 75 ml). The
combined org. phase was washed with H2O (2 ꢂ 100 ml), dried (MgSO4), and concentrated: 26 (0.98 g,
92%). Deep brown viscous oil. IR (neat): 3436 (br.), 3031w, 2942s, 2871s, 2738w, 2660w, 2578w, 2251w,
2227w, 2052w, 2017w, 1871w, 1724w, 1614w, 1579m, 1505s, 1455m, 1442m, 1415w, 1381w, 1355m, 1305s,
1
1262s, 1201s, 1185m, 1150m, 1128s, 1075s, 1034s. H-NMR (300 MHz, CDCl3): 6.91 – 6.66 (m, HꢀC(6),
HꢀC(8), HꢀC(9)); 4.74 (t, J ¼ 3.5, HꢀC(2’)); 4.42 – 4.00 (m, CH2(2), HꢀC(3), CH2(4)); 3.93 – 3.86 (m,
HaꢀC(6’)); 3.57 – 3.50 (m, HbꢀC(6’)); 2.23 (s, Me); 1.89 – 1.50 (m, CH2(3’), CH2(4’), CH2(5’)). 13C-NMR
Material safety data sheet of 7-methyl-3,4-dihydro-2H-1,6-benzodioxepine-3-one (Calone 1951ꢃ);
Ganone Agan Aroma and Fine Chemicals Ltd.
3
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Helvetica Chimica Acta – Vol. 90 (2007)
1019
(75 MHz, CDCl3): 149.6 (C(9a)); 147.8 (C(5a)); 132.7 (C(7)); 124.4 (C(8)); 123.4 (C(9)); 121.2 (C(6));
98.4 (C(2’)); 74.4 (C(3)); 73.0 (C(4)); 72.1 (C(2)); 62.7 (C(6’)); 30.7 (C(3’)); 25.3 (C(5’)); 20.5 (Me);
19.41 (C(4’)). 1H,1H-COSY (CDCl3): 4.66 (HꢀC(2’))/1.61 (CH2(3’)); 3.81 (HbꢀC(6’))/3.45 (HaꢀC(6’));
3.81 (HꢀC(6’))/1.49 (CH2(5’)). 1H,13C-HMQC (CDCl3): HꢀC(3)/C(3) (74.5); CH2(4)/C(4) (73.4);
CH2(2)/C(2) (72.1); CH2(6’)/C(6’) (62.7). EI-MS: 264 (77, Mþ), 236 (3), 208 (4), 206 (2), 180 (20), 162
(22), 149 (7), 135 (35), 11 (133), 124 (8), 123 (9), 105 (7), 99 (6), 91 (7), 85 (100), 77 (10), 67.1 (19), 57
(23), 55 (10).
3,4-Dihydro-7-methyl-2H-1,5-benzodioxepin-3-ol (27). Vanadium pentoxide (14 mg, 0.11 mmol) was
added to a 30% H2O2 soln. (0.90 ml), and the mixture was stirred at 08 for 10 min. The catalyst mixture
was then added to a soln. of 26 (0.50 g, 1.89 mmol) in MeCN (20 ml) and heated at 708 for 15 – 20 min, or
until the soln. ceased effervescing and became dark green. The MeCN was evaporated and the crude
material solubilized in 2m NaHCO3 (50 ml). Extraction of the product was achieved with CH2Cl2 (3 ꢂ
40 ml), and the org. phase washed with sat. NaHCO3 soln. (1 ꢂ 60 ml) and concentrated: opaque resin
which solidified upon cooling to give 27 (0.26 g, 76%). White solid. M.p. (heptane) 56 – 588. IR (KBr):
3210 (br.), 3083m, 2988m, 2961m, 2922m, 2866m, 2714w, 1611w, 1578m, 1509s, 1443m, 1414w, 1383w,
1360w, 1344s, 1300s, 1290s, 1275s, 1261s, 1202m, 1151m, 1137s, 1116m, 1103w, 1042s. 1H-NMR (300 MHz,
CDCl3): 6.89 (d, J ¼ 8.1, HꢀC(9)); 6.80 (s, HꢀC(6)); 6.78 (d, J ¼ 8.1, HꢀC(8)); 4.35 – 4.25 (m, HaꢀC(2),
HaꢀC(4)); 4.08 – 3.99 (m, HbꢀC(4), HꢀC(3), HbꢀC(2)); 2.78 (s, OH); 2.24 (s, Me). 13C-NMR
(75 MHz, CDCl3): 150.2 (C(9a)); 148.3 (C(5a)); 133.0 (C(7)); 123.7 (C(8)); 121.5 (C(9)); 120.7 (C(6));
74.6 (C(2)); 74.4 (C(4)); 69.1 (C(3)); 20.3 (Me). 1H,1H-COSY (CDCl3): 4.30 (HaꢀC(2))/4.03
(HbꢀC(2)); 4.30 (HaꢀC(4))/4.03 (HbꢀC(4)). 1H,13C-HMQC (CDCl3): CH2(2)/C(2) (74.5); CH2(4)/
C(4) (74.4); HꢀC(3)/C(3) (69.2). EI-MS: 180 (100, Mþ), 161 (2), 149 (11), 135 (51), 123 (28), 109 (11),
107 (5), 106 (5), 95 (8), 94 (9), 91 (10), 78 (13), 77 (14), 66 (10), 65 (6) 57 (2), 51 (6).
7-Methyl-2H-1,5-benzodioxepin-3(4H)-one (1). To a 4% aq. KOH soln. (20 ml) and KMnO4 (1.75 g,
11.07 mmol) at 0 – 58 was added 27 (0.40 g, 2.22 mmol) in one portion. The soln. was stirred for 2.5 h, then
the MnO2 was removed by vacuum filtration and the filter cake washed with Et2O (2 ꢂ 20 ml). The
filtrate was acidified by the dropwise addition of conc. HCl soln. to pH 2, and then extracted with Et2O
(3 ꢂ 30 ml). The combined org. phase was washed with sat. NaHCO3 soln. (1 ꢂ 50 ml), dried (MgSO4),
and concentrated and the obtained yellow resin purified by bulb-to-bulb distillation (708/0.5 Torr): 1
(0.35 g, 87%). Crystalline white solid. M.p. (pentane) 38 – 398. IR (KBr): 3448w, 3057w, 2991w, 2920w,
2859w, 1742s, 1614w, 1582w, 1506s, 1466w, 1435m, 1414w, 1303s, 1265s, 1207m, 1150m, 1119m, 1053s.
1H-NMR (300 MHz, CDCl3): 6.90 – 6.75 (m, HꢀC(6), HꢀC(8), HꢀC(9)); 4.70 (s, CH2(4)); 4.67 (s,
CH2(2)); 2.27 (s, Me). 13C-NMR (75 MHz, CDCl3): 204.8 (C(3)); 147.9 (C(9a)); 146.1 (C(5a)); 133.8
(C(7)); 124.3 (C(8)); 121.2 (C(9)); 120.6 (C(6)); 75.8 (C(2)); 75.5 (C(4)); 20.5 (Me). EI-MS: 178 (100,
Mþ), 150 (2), 149 (3), 135 (24), 122 (6), 108 (8), 94 (89), 91 (17), 89 (12), 77 (17), 66 (74), 63 (14), 51
(18), 39 (21).
5. Benzodioxepinone 12 by Procedure A. 2,2’-[(3-Methyl-1,2-phenylene)bis(oxy)]bis[acetic Acid]
Dimethyl Ester (10a). As described in Exper. 3 (conventional method), with 9a (1.00 g, 8.05 mmol).
Purification involved bulb-to-bulb distillation (1608/0.4 Torr) performed twice: 10a (1.99 g, 92%). Clear
pale yellow oil. The microwave procedure provided 10a in 36% yield. IR (neat): 3002m, 2955s, 2853m,
2112w, 1774s, 1749s, 1646w, 1604m, 1587m, 1488s, 1440s, 1380m, 1304m, 1262m, 1183m, 1114m, 1070m,
1027m. 1H-NMR (300 MHz, CDCl3)1): 6.89 – 6.60 (m, HꢀC(4’), HꢀC(5’), HꢀC(6’)); 4.69 (s, CH2(1’’));
4.60 (s, CH2(2)); 3.74 (s, Me(3’’)O); 3.72 (s, Me(3)O); 2.28 (s, arom. Me). 13C-NMR (75 MHz, CDCl3)1):
169.9 (C(2’’)O); 168.9 (C(1)O); 149.8 (C(1’)); 145.9 (C(2’)); 132.3 (C(3’)); 124.1 (C(4’)); 123.7 (C(5’));
111.5 (C(6’)); 69.0 CH2(1’’)); 65.6 (CH2(2)); 51.6 (Me(3)O, Me(3’’)O); 15.8 (arom. Me). EI-MS: 268 (16,
Mþ), 209 (5), 207 (3), 195 (11), 176 (11), 163 (12), 149 (15), 135 (75), 121 (3), 109 (17), 91 (19), 77 (21),
65 (17), 63 (5), 59 (9), 51 (10), 45 (100).
Methyl 3,4-Dihydro-6-methyl-3-oxo- and 3,4-Dihydro-9-methyl-3-oxo-2H-1,5-benzodioxepine-2-carb-
oxylate (11a). As described in Exper. 3, with 10a (1.00 g, 3.73 mmol): 11a (0.72 g, 82%). Caramel-colored
oil. IR (neat): 3474m, 2956s, 2572w, 1742s, 1677m, 1632w, 1594m, 1477s, 1440s, 1337m, 1274s, 1250m,
1217s, 1202s, 1100s, 1071m, 1045m. 1H-NMR (300 MHz, CDCl3): Regioisomer 1: 6.93 – 6.83 (m, HꢀC(7),
HꢀC(8), HꢀC(9)); 5.36 (s, HꢀC(2)); 4.81 (d, J ¼ 16.7, HaꢀC(4)); 4.62 (d, J ¼ 16.7, HbꢀC(4)); 3.86 (s,
MeO); 2.22 (s, arom. Me); Regioisomer 2: 6.93 – 6.83 (m, HꢀC(7), HꢀC(8), HꢀC(9)); 5.37 (s,

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Helvetica Chimica Acta – Vol. 90 (2007)
HꢀC(4)); 4.87 (d, J ¼ 16.7, HaꢀC(2)); 4.56 (d, J ¼ 16.7, HbꢀC(2)); 3.85 (s, MeO); 2.28 (s, arom. Me).
13C-NMR (75 MHz, CDCl3): Regioisomer 1: 199.7 (C(3)); 165.4 (CO2); 147.1 (C(9a)); 145.9 (C(5a));
130.7 (C(6)); 125.2 (C(7)); 124.0 (C(8)); 118.1 (C(9)); 81.8 (C(2)); 76.4 (C(4)); 52.9 (MeO); 15.9 (arom.
Me); Regioisomer 2: 199.6 (C(3)); 165.4 (CO2); 147.3 (C(9a)); 145.4 (C(5a)); 130.0 (C(6)); 126.4 (C(7));
122.8 (C(8)); 118.8 (C(9)); 81.8 (C(4)); 76.4 (C(2)); 58.4 (MeO); 18.2 (arom. Me). EI-MS: 236 (100,
Mþ), 204 (4), 177 (22), 149 (66), 135 (48), 121 (22), 105 (5), 94 (47), 77 (28), 66 (34), 51 (13), 39 (18).
6-Methyl-2H-1,5-benzodioxepin-3(4H)-one (12). As described in Exper. 3, with 11a (1.02 g,
4.32 mmol). The obtained brown oily 12 (0.56 g, 72%) which was bulb-to-bulb distilled at 50 – 608/
0.2 Torr: 12 (0.11 g, 14%). Clear oil. IR (KBr): 3024w, 2964w, 2939w, 2906w, 2839w, 1790m, 1738s, 1613w,
1592m, 1492m, 1475s, 1440m, 1419w, 1380w, 1324m, 1296m, 1274s, 1258s, 1205m, 1191m, 1101s, 1080m.
1H-NMR (300 MHz, CDCl3): 6.86 (br. s, HꢀC(7), HꢀC(8), HꢀC(9)); 4.74 (s, CH2(4)); 4.70 (s, CH2(2));
2.23 (s, Me). 13C-NMR (75 MHz, CDCl3): 205.1 (C(3)); 148.4 (C(9a)); 146.9 (C(5a)); 130.4 (C(6)); 125.4
(C(7)); 123.0 (C(8)); 118.6 (C(9)); 75.6 (C(4)); 75.5 (C(2)); 16.1 (Me). EI-MS: 178 (100, Mþ), 150 (5),
135 (32), 122 (2), 108 (5), 94 (82), 77 (17), 66 (77), 51 (17), 39 (19).
6. Benzodioxepinone 12 by Procedure B. 3,4-Dihydro-6-methyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]-
2H-1,5-benzodioxepine (26a). As described in Exper. 4, with 9a (0.50 g, 4.03 mmol): 26a (0.95 g, 90%).
Brown viscous oil. IR (neat): 3452 (br.), 3075w, 3017w, 2943s, 2870s, 2739w, 1906w, 1835w, 1724w, 1649w,
1624w, 1593m, 1477s, 1455m, 1440m, 1402w, 1379w, 1355m, 1302s, 1272s, 1248m, 1194s, 1159m, 1128s,
1
1084s, 1034s. H-NMR (300 MHz, CDCl3): 6.77 (s, HꢀC(7), HꢀC(8), HꢀC(9)); 4.75 (ꢀtꢁ, HꢀC(2’));
4.45 – 4.23 (m, CH2(2), HꢀC(3), CH2(4)); 3.95 – 3.87 (m, HaꢀC(6’)); 3.57 – 3.50 (m, HbꢀC(6’)); 2.21 (s,
Me); 1.90 – 1.51 (m, CH2(3’), CH2(4’), CH2(5’)). 13C-NMR (75 MHz, CDCl3): 150.0 (C(9a)); 148.5
(C(5a)); 130.0 (C(6)); 124.4 (C(7)); 122.0 (C(8)); 118.4 (C(9)); 98.4 (C(2’)); 74.4 (C(3)); 72.9 (C(2));
71.9 (C(4)); 62.7 (C(6’)); 30.7 (C(3’)); 25.3 (C(5’)); 19.5 (C(4’)); 16.2 (Me). EI-MS: 264 (58, Mþ), 236 (6),
208 (3), 206 (1), 180 (14), 162 (21), 149 (8), 135 (38), 124 (5), 123 (6), 105 (5), 99 (5), 94 (5), 91 (7), 85
(100), 77 (10), 67 (18), 57 (22), 55 (8).
3,4-Dihydro-6-methyl-2H-1,5-benzodioxepin-3-ol (27a). As described in Exper. 4, with 26a (0.70 g,
2.65 mmol): 27a (0.41 g, 85%). Clear oil which solidified to a white solid upon cooling. M.p. (heptane)
34 – 388. IR (KBr): 3265 (br.), 2964m, 2920m, 2860w, 1589w, 1528w, 1477s, 1438m, 1377w, 1343w, 1292s,
1278s, 1247m, 1196s, 1161w, 1138s, 1087s, 1045s, 1011m. 1H-NMR (300 MHz, CDCl3): 6.86 (s, HꢀC(7),
HꢀC(8), HꢀC(9)); 4.35 – 4.25 (m, HꢀC(3)); 4.08 – 3.99 (m, CH2(2), CH2(4)); 2.60 (br. s, OH); 2.24 (s,
Me). 13C-NMR (75 MHz, CDCl3): 151.4 (C(9a)); 149.7 (C(5a)); 131.0 (C(6)); 125.5 (C(7)); 123.2 (C(8));
119.2 (C(9)); 74.8 (C(2)); 74.4 (C(4)); 69.7 (C(3)); 16.1 (Me). EI-MS: 180 (100, Mþ), 161 (3), 149 (16),
136 (22), 135 (62), 124 (21), 123 (24), 109 (12), 107 (4), 105 (5), 95 (5), 94 (9), 91 (12), 89 (2), 78 (11), 77
(16), 66 (11), 57 (3), 52 (5), 51 (7).
6-Methyl-2H-1,5-benzodioxepin-3(4H)-one (12). As described in Exper. 4, with 27a (0.40 g,
2.22 mmol). The obtained yellow resin was purified by bulb-to-bulb distillation at 50 – 608/0.2 Torr: 12
(0.22 g, 56%). Clear oil.
7. Benzodioxepinone 13 by Procedure A. 2,2’-[(3-Methoxy-1,2-phenylene)bis(oxy)]bis[acetic Acid]
Dimethyl Ester (10b). As described in Exper. 3 (conventional method), with 9b (2.51 g, 17.9 mmol).
Purification involved bulb-to-bulb distillation (1908/0.5 Torr) performed twice: 10b (3.35 g, 66%). Clear
oil. The microwave procedure provided 10b in 45% yield. IR (KBr): 2954w, 2918w, 2843w, 1757s, 1602m,
1499m, 1479s, 1445m, 1397w, 1387w, 1306m, 1259m, 1217s, 1182m, 1125s, 1093m, 1069m. 1H-NMR
(300 MHz, CDCl3)1): 6.94 – 6.45 (m, HꢀC(4’), HꢀC(5’), HꢀC(6’)); 4.65 (s, CH2(1’’)); 4.64 (s, CH2(2));
3.79 (s, arom. MeO); 3.75 (s, Me(3’’)O); 3.72 (s, Me(3)O). 13C-NMR (75 MHz, CDCl3)1): 169.4 (C(1)O);
169.1 (C(2’’)O); 153.3 (C(1’)); 151.2 (C(3’)); 137.3 (C(2’)); 123.8 (C(5’)); 107.8 (C(4’)); 106.7 (C(6’)); 69.5
(CH2(2)); 66.6 (CH2(1’’)); 56.1 (arom. MeO); 51.6 (Me(3)O, Me(3’’)O). EI-MS: 284 (85, Mþ), 252 (2),
211 (64), 192 (12), 165 (20), 153 (87), 137 (9), 125 (40), 107 (29), 95 (32), 77 (15), 65 (12), 51 (16), 45
(100).
Methyl 3,4-Dihydro-6-methoxy-3-oxo- and 3,4-Dihydro-9-methoxy-3-oxo-2H-1,5-benzodioxepine-2-
carboxylate (11b). As described in Exper. 3, with 10b (3.32 g, 11.69 mmol). Trituration with EtOH
provided 11b (2.50 g, 85%). White crystalline solid. M.p. (EtOH) 117 – 1198. IR (KBr): 2962m, 2897w,
2847w, 1767s, 1741s, 1596m, 1486s, 1473s, 1441m, 1435m, 1416w, 1345m, 1319m, 1277s, 1259m, 1246m,
1
1214s, 1204s, 1176s, 1105s, 1080s, 1068m, 1034m. H-NMR (300 MHz, CDCl3): 6.92 – 6.60 (m, HꢀC(7),

Helvetica Chimica Acta – Vol. 90 (2007)
1021
HꢀC(8), HꢀC(9)); 5.36 (s, HꢀC(2)); 4.75 (d, J ¼ 16.6, HaꢀC(4)); 4.54 (d, J ¼ 16.6, HbꢀC(4)); 3.88 (s,
arom. MeO); 3.84 (s, COOMe). 13C-NMR (75 MHz, CDCl3): 198.9 (C(3)); 164.9 (CO2); 150.9 (C(9a));
148.3 (C(6)); 137.0 (C(5a)); 122.6 (C(8)); 113.4 (C(7)); 108.0 (C(9)); 82.4 (C(2)); 76.9 (C(4)); 56.4 (arom.
MeO); 52.9 (COOMe). EI-MS: 252 (97, Mþ), 209 (16), 193 (15), 165 (28), 151 (30), 137 (9), 110 (46), 95
(100), 79 (19), 65 (16), 51 (31), 39 (53).
6-Methoxy-2H-1,5-benzodioxepin-3(4H)-one (13). As described in Exper. 3, with 11b (1.10 g,
4.36 mmol) in a minimum amount of EtOH/CH2Cl2 2 :1 for 2.5 h. Aq. workup involved neutralization
with NaHCO3 prior to extraction: 13 (0.81 g, 95%). White crystals. M.p. (pentane) 130 – 1328. IR (KBr):
3030w, 2962m, 2897w, 2847w, 1767s, 1740s, 1596m, 1486s, 1474s, 1441m, 1435m, 1415w, 1345w, 1319m,
1277m, 1259m, 1247m, 1214s, 1204s, 1176m, 1105s, 1080m, 1068m, 1034w. 1H-NMR (300 MHz, CDCl3):
6.94 – 6.62 (m, HꢀC(7), HꢀC(8), HꢀC(9)); 4.87 (s, CH2(4)); 4.73 (s, CH2(2)); 3.87 (s, MeO). 13C-NMR
(75 MHz, CDCl3): 204.2 (C(3)); 151.5 (C(6)); 149.4 (C(9a)); 138.4 (C(5a)); 122.9 (C(8)); 113.1 (C(7));
106.7 (C(9)); 76.2 (C(2)); 75.6 (C(4)); 56.3 (MeO). EI-MS: 194 (100, Mþ), 166 (2), 151 (63), 137 (3), 123
(5), 110 (32), 107 (18), 95 (75), 79 (10), 77 (5), 65 (10), 51 (15), 39 (21). HR-ESI-MS: 195.0650
(C10H10Oþ4 , [M þ 1]þ; calc. 195.0657).
8. Benzodioxepinone 13 by Procedure B. 3,4-Dihydro-6-methoxy-3-[(tetrahydro-2H-pyran-2-
yl)oxy]-2H-1,5-benzodioxepine (26b). As described in Exper. 4, with 9b (0.50 g, 3.57 mmol): 26b
(0.91 g, 91%). Brown viscous oil. IR (neat): 3436 (br.), 2944s, 2873m, 2853m, 2744w, 2251w, 1673m,
1652m, 1598m, 1588m, 1489s, 1476s, 1456m, 1441m, 1387w, 1356w, 1311m, 1273m, 1248m, 1202s, 1183w,
1
1162w, 1119s, 1103s, 1077s, 1093s, 1024s. H-NMR (300 MHz, CDCl3): 6.87 – 6.78 (m, HꢀC(8)); 6.62 –
6.51 (m, HꢀC(7), HꢀC(9)); 4.96 – 4.43 (m, HaꢀC(2), HaꢀC(4)); 4.56 – 4.04 (m, HbꢀC(2), HꢀC(3),
HbꢀC(4)); 5.10 (t, J ¼ 3.5, HꢀC(2’)); 3.84 (s, MeO); 3.56 – 3.49 (m, CH2(6’)); 1.87 – 1.53 (m, CH2(3’),
CH2(4’), CH2(5’)). 13C-NMR (75 MHz, CDCl3): 151.2 (C(6)); 143.9 (C(9a)); 139.8 (C(5a)); 120.6 (C(8));
113.2 (C(9)); 110.4 (C(7)); 98.0 (C(2’)); 74.1 (C(3)); 72.3 (C(2)); 70.2 (C(4)); 62.9 (C(6’)); 56.1 (MeO);
30.7 (C(3’)); 25.3 (C(5’)); 23.2 (C(4’)). EI-MS: 280 (50, Mþ), 252 (13), 224 (4), 196 (29), 178 (18), 165
(7), 151 (36), 149 (11), 140 (12), 125 (5), 107 (14), 95 (18), 85 (100), 77 (5), 67 (20), 57 (29), 55 (15), 51
(6).
3,4-Dihydro-6-methoxy-2H-1,5-benzodioxepin-3-ol (27b). As described in Exper. 4, with 26b (0.77 g,
2.75 mmol): 27b (0.41 g, 76%). Yellow resin. IR (neat): 3459 (br.), 3099w, 2941m, 2840w, 1721m, 1646w,
1598m, 1588m, 1489s, 1475s, 1442m, 1361w, 1321w, 1304w, 1272s, 1249s, 1207m, 1183m, 1092s, 1076s,
1029m. 1H-NMR (300 MHz, CDCl3): 6.89 (t, J ¼ 8.3, HꢀC(8)); 6.67 – 6.61 (m, HꢀC(7), HꢀC(9));
4.41 – 4.26 (m, HaꢀC(4), HaꢀC(2)); 4.16 – 4.09 (m, HbꢀC(4), HꢀC(3), HbꢀC(2)); 3.86 (s, MeO); 2.01
(br. s, OH). 13C-NMR (75 MHz, CDCl3): 152.3 (C(6)); 151.9 (C(9a)); 140.8 (C(5a)); 122.9 (C(8)); 113.7
(C(9)); 107.0 (C(7)); 75.2 (C(2)); 74.9 (C(4)); 69.7 (C(3)); 56.3 (MeO). EI-MS: 196 (100, Mþ), 177 (1),
165 (9), 151 (38), 140 (25), 125 (15), 110 (11), 107 (26), 95 (21), 93 (17), 81 (4), 77 (5), 68 (2), 66 (2), 6.3
(3), 57 (4), 55 (4), 51 (10).
6-Methoxy-2H-1,5-benzodioxepin-3(4H)-one (13). As described in Exper. 4, with 27b (0.40 g,
2.04 mmol). The obtained yellow resin was bulb-to-bulb distilled at 658/0.2 Torr: 13 (0.34 g, 87%). Clear
crystals.
9. Benzodioxepinone 14 by Procedure A. 2,2’-[1,2-Phenylenebis(oxy)]bis[acetic Acid] Dimethyl
Ester (10c). As described in Exper. 3 (conventional method), with 9c (0.50 g, 4.54 mmol). Bulb-to-bulb
distillation (1808/0.05 Torr) performed twice afforded 10c (1.01 g, 88%). White solid. M.p. (pentane) 44 –
488. The microwave procedure provided 10c in 48% yield. IR (KBr): 3012w, 2961m, 1752s, 1708w, 1596m,
1507s, 1456m, 1434m, 1372m, 1334m, 1275m, 1233s, 1197s, 1180s, 1163m, 1138s, 1088w, 1068m, 1020w.
1H-NMR (300 MHz, CDCl3)1): 6.94 – 6.86 (m, HꢀC(3’), HꢀC(4’), HꢀC(5’), HꢀC(6’)); 4.71 (s,
CH2(1’’), CH2(2)); 3.77 (s, Me(3)O, Me(3’’)O). 13C-NMR (75 MHz, CDCl3)1): 169.3 (C(1)O, C(2’’)O);
147.9 (C(1’), C(2’)); 122.6 (C(4’), C(5’)); 115.3 (C(3’), C(6’)); 66.5 (CH2(1’’), CH2(2)); 52.1 (Me(3)O,
Me(3’’)O). EI-MS: 254 (32, Mþ), 222 (2), 193 (10), 162 (33), 149 (3), 135 (14), 121 (29), 107 (2), 95 (10),
77 (16), 63 (8), 52 (10), 45 (100).
Methyl 3,4-Dihydro-3-oxo-2H-1,5-benzodioxepine-2-carboxylate (11c). As described in Exper. 3,
with 10c (3.65 g, 14.37 mmol): 11c (2.78 g, 87%). Pale brown oil. IR (neat): 3472m, 2956m, 1746s, 1682m,
1634w, 1594m, 1494s, 1456m, 1439s, 1396w, 1338m, 1273s, 1250m, 1228s, 1157m, 1106m, 1081m, 1025m.
1H-NMR (300 MHz, CDCl3): 7.11 – 6.95 (m, HꢀC(6), HꢀC(7), HꢀC(8), HꢀC(9)); 5.36 (s, HꢀC(2));

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Helvetica Chimica Acta – Vol. 90 (2007)
4.82 (d, J ¼ 16.8, HaꢀC(4)); 4.60 (d, J ¼ 16.8, HbꢀC(4)); 3.85 (s, MeO). 13C-NMR (75 MHz, CDCl3):
199.3 (C(3)); 165.2 (CO2); 147.2 (C(5a)); 147.0 (C(9a)); 125.0 (C(7)); 123.6 (C(9)); 121.4 (C(8)); 120.5
(C(6)); 81.8 (C(2)); 76.8 (C(4)); 52.9 (MeO). EI-MS: 222 (99, Mþ), 190 (6), 163 (17), 146 (3), 135 (100),
121 (61), 107 (24), 92 (4) 91 (4), 80 (52), 77 (38), 69 (11), 65 (26), 63 (26), 52 (41), 43 (30).
2H-1,5-Benzodioxepin-3(4H)-one (14). As described in Exper. 3, with 11c (0.65 g, 2.93 mmol) in
EtOH/CH2Cl2 2 :1. The obtained yellow-brown semi-solid 14 (0.45 g, 94%) was triturated with CH2Cl2:
14 (0.05 g, 10%). White crystalline solid. M.p. (CH2Cl2) 64 – 658. IR (KBr): 3408w, 2957m, 1741s, 1631m,
1
1586w, 1495s, 1459w, 1303m, 1263s, 1181w, 1153w, 1097m, 1052s, 1025m. H-NMR (300 MHz, CDCl3):
6.90 (s, HꢀC(6), HꢀC(7), HꢀC(8), HꢀC(9)); 4.08 (s, CH2(2), CH2(4)). 13C-NMR (75 MHz,
(CD3)2CO): 204.3 (C(3)); 152.2 (C(5a), C(9a)); 124.9 (C(7), C(8)); 122.7 (C(6), C(9)); 79.4 (C(2),
C(4)). EI-MS: 164 (100, Mþ), 136 (2), 121 (27), 108 (10), 94 (3), 80 (75), 63 (13), 52 (27), 32 (22).
10. Benzodioxepinone 18 by Procedure B. 3,4-Dihydro-3-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-1,5-
benzodioxepine (26c). As described in Exper. 4, with 9c (0.50 g, 4.54 mmol): 26c (0.99 g, 87%). Yellow-
brown viscous oil. IR (neat): 3436 (br.), 3069w, 3036w, 2942s, 2871m, 2852m, 2741w, 2661w, 2223w, 1932w,
1737w, 1600w, 1583m, 1492s, 1464m, 1455m, 1442w, 1403w, 1379w, 1356w, 1303s, 1258s, 1248s, 1202w,
1181w, 1160m, 1122m, 1104m, 1074s, 1043s, 1022s. 1H-NMR (300 MHz, CDCl3): 7.01 – 6.86 (m, HꢀC(6),
HꢀC(7), HꢀC(8), HꢀC(9)); 4.74 (t, J ¼ 3.6, HꢀC(2’)); 4.45 – 4.10 (m, CH2(2), HꢀC(3), CH2(4));
3.94 – 3.87 (m, HaꢀC(6’)); 3.57 – 3.50 (m, HbꢀC(6’)); 1.89 – 1.50 (m, CH2(3’), CH2(4’), CH2(5’)).
13C-NMR (75 MHz, (CD3)2CO): 150.0 (C(5a), C(9a)); 124.0 (C(8)); 122.9 (C(7)); 121.5 (C(6)); 120.8
(C(9)); 98.5 (C(2’)); 74.4 (C(3)); 73.1 (C(2)); 72.0 (C(4)); 62.7 (C(6’)); 30.8 (C(3’)); 25.3 (C(5’)); 19.4
(C(4’)). EI-MS: 250 (43, Mþ), 222 (2), 194 (2), 166 (18), 148 (23), 135 (7), 121 (37), 109 (5), 107 (1), 103
(1), 99 (5), 91 (4), 85 (100), 77 (7), 67.1 (15), 57 (18), 55 (11).
3,4-Dihydro-2H-1,5-benzodioxepin-3-ol (27c). As described in Exper. 4, with 26c (0.82 g,
3.28 mmol). The obtained clear oil partially solidified to a white semi-solid upon cooling. Evaporative
crystallization from Et2O/pentane gave 27c (0.49 g, 91%). Clear crystals. M.p. (pentane) 48 – 508. IR
(KBr): 3266 (br.), 2964w, 2917w, 2856w, 1594w, 1579w, 1523w, 1494m, 1455w, 1402w, 1375w, 1261s, 1182w,
1
1132m, 1098m, 1040s, 1019s. H-NMR (300 MHz, CDCl3): 7.04 – 6.94 (m, HꢀC(6), HꢀC(7), HꢀC(8),
HꢀC(9)); 4.31 – 4.26 (m, HaꢀC(4), HaꢀC(2)); 4.12 – 4.07 (m, HbꢀC(4), HꢀC(3), HbꢀC(2)); 2.61 (br.
s, OH). 13C-NMR (75 MHz, CDCl3): 151.1 (C(5a), C(9a)); 124.0 (C(7), C(8)); 121.6 (C(6), C(9)); 74.8
(C(2), C(4)); 69.7 (C(3)). EI-MS: 166 (100, Mþ), 147 (3), 135 (19), 122 (26), 121 (77), 110 (30), 109
(12), 95 (15), 81 (9), 77 (14), 63 (13), 52 (9).
2H-1,5-Benzodioxepin-3(4H)-one (14). As described in Exper. 4, with 27c (0.39 g, 2.35 mmol). The
obtained pale yellow oil was purified by CC (silica gel (short column), CH2Cl2): 14 (0.23 g, 60%). White
crystalline solid. M.p. (CH2Cl2) 64 – 658.
11. Benzodioxepinone 15 by Procedure A. 2,2’-[(4-Nitro-1,2-phenylenebis(oxy)]bis[acetic Acid]
Dimethyl Ester (10d). As described in Exper. 3 (microwave procedure), with 9d (0.50 g, 3.22 mmol).
Purification by vacuum CC (silica gel (short column), pentane, then AcOEt/pentane 1:9 ! 3 :7
gradient), followed by bulb-to-bulb distillation (2158/0.1 Torr) provided 10d (0.71 g, 74%). Bright yellow
solid. The conventional method provided 10d in 53% yield. M.p. (pentane) 84 – 868. IR (KBr): 3087w,
2960w, 1757s, 1590w, 1520m, 1505m, 1437w, 1373w, 1347m, 1309w, 1286m, 1242w, 1207s, 1174m, 1145w,
1
1109m, 1085m, 1062m. H-NMR (300 MHz, CDCl3)1): 7.93 – 6.85 (m, HꢀC(3’), HꢀC(5’), HꢀC(6’));
4.83 (s, CH2(2)); 4.80 (s, CH2(1’’)); 3.82 (s, Me(3)O); 3.81 (s, Me(3’’)O). 13C-NMR (75 MHz, CDCl3)1):
168.3 (C(1)O); 168.1 (C(2’’)O); 153.0 (C(1’)); 147.4 (C(2’)); 142.2 (C(4’)); 118.7 (C(6’)); 113.0 (C(5’));
109.8 (C(3’)); 66.1 (CH2(2)); 66.0 (CH2(1’’)); 52.5 (Me(3)O); 52.4 (Me(3’’)O). EI-MS: 299 (22, Mþ), 267
(10), 240 (10), 207 (5), 194 (8), 180 (15), 166 (16), 151 (3), 135 (5), 120 (6), 107 (5), 92 (3), 79 (17), 63
(9), 51 (13), 45 (100), 30 (3).
Methyl 3,4-Dihydro-7-nitro-3-oxo- and 3,4-Dihydro-8-nitro-3-oxo-2H-1,5-benzodioxepine-2-carbox-
ylate (11d). As described in Exper. 3, with 10d (0.71 g, 2.37 mmol): crude 11d (0.43 g, 68%). Bright red/
yellow oil as a complex mixture. IR (neat): 3413m, 2924s, 2725w, 2255w, 2128w, 1740m, 1645m, 1590w,
1519m, 1460s, 1376m, 1342m, 1278m, 1051s, 1026s, 1005s. EI-MS: 267 (100, Mþ), 235 (11), 207 (22), 194
(6), 180 (8), 166 (29), 162 (10), 149 (8), 134 (66), 119 (21), 107 (24), 101 (7), 92 (16), 79 (53), 77 (18), 75
(32), 69 (19), 65 (11), 63 (31), 59 (32), 53 (23), 51 (48), 45 (38), 39 (14).

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7-Nitro-2H-1,5-benzodioxepin-3(4H)-one (15). As described in Exper. 3, with 11d (0.81 g,
3.03 mmol) for 2.5 h. The obtained brown semi-solid (0.28 g) was purified by semi-prep. HPLC
(tR 11.7 min; lmax 239 and 311 nm): 15 (16 mg, 2%). Orange oil. IR (KBr): 3452w, 3080w, 2925w, 2853w,
1801w, 1736s, 1587m, 1517s, 1491m, 1429w, 1346s, 1315m, 1274s, 1176w, 1122w, 1098w, 1080w, 1036m.
1H-NMR (300 MHz, CDCl3): 8.03 – 7.11 (m, HꢀC(6), HꢀC(8), HꢀC(9)); 4.98 (s, CH2(2)); 4.91 (s,
CH2(4)). 13C-NMR (75 MHz, CDCl3): 202.1 (C(3)); 153.7 (C(9a)); 147.9 (C(5a)); 143.3 (C(7)); 121.3
(C(9)); 119.8 (C(8)); 117.6 (C(6)); 76.3 (C(2)); 75.3 (C(4)). EI-MS: 209 (100, Mþ), 193 (2), 167 (4), 166
(3), 163 (3), 151 (14), 135 (15), 120 (4), 107 (55), 105 (8), 90 (3), 79 (37), 77 (12), 75 (14), 63 (12), 51
(23). HR-ESI-MS: 209.0325 (C9H7O5Nþ, Mþ; calc. 209.0324).
12. Benzodioxepinone 15 by Procedure B. 3,4-Dihydro-7-nitro-3-[(tetrahydro-2H-pyran-2-yl)oxy]-
2H-1,5-benzodioxepine (26d). As described in Exper. 4, with 9d (0.50 g, 3.22 mmol): 26d (0.81 g, 85%).
Deep orange viscous oil. IR (neat): 3428 (br.), 3081w, 2945s, 2870m, 2605w, 2243w, 1994w, 1809s, 1720w,
1586m, 1520s, 1494m, 1463w, 1424w, 1347s, 1322m, 1281s, 1265s, 1202w, 1182w, 1159w, 1123s, 1073s, 1033s.
1H-NMR (300 MHz, CDCl3): 7.80 – 7.77 (m, HꢀC(8), HꢀC(6)); 7.00 – 6.97 (m, HꢀC(9)); 4.71 (ꢀtꢁ,
HꢀC(2’)); 4.54 – 4.27 (m, CH2(2), HꢀC(3), CH2(4)); 3.92 – 3.84 (m, HaꢀC(6’)); 3.57 – 3.50 (m,
HbꢀC(6’)); 1.86 – 1.51 (m, CH2(3’), CH2(4’), CH2(5’)). 13C-NMR (75 MHz, CDCl3): 155.5 (C(9a)); 149.5
(C(5a)); 142.6 (C(7)); 120.8 (C(9)); 118.8 (C(8)); 116.9 (C(6)); 98.9 (C(2’)); 74.4 (C(3)); 73.0 (C(2));
72.1 (C(4)); 62.8 (C(6’)); 30.6 (C(3’)); 25.1 (C(5’)); 19.4 (C(4’)). EI-MS: 295 (11, Mþ), 211 (19), 193 (19),
180 (1), 166 (12), 147 (3), 134 (1), 120 (4), 107 (2), 91 (3), 85 (100), 79 (5), 67 (10), 63 (3), 57 (11), 55
(4), 51 (3).
3,4-Dihydro-7-nitro-2H-1,5-benzodioxepin-3-ol (27d). As described in Exper. 4, with 26d (0.76 g,
2.57 mmol). The obtained yellow resin was crystallized from Et2O: 27d (0.28 g, 52%). Pale yellow solid.
M.p. (Et2O) 74 – 788. IR (KBr): 3453 (br.), 3105w, 3076w, 2953w, 1802w, 1721w, 1587w, 1518s, 1496m,
1
1466w, 1422w, 1351s, 1325m, 1283s, 1270m, 1186w, 1126w, 1103w, 1077m, 1020m. H-NMR (300 MHz,
CDCl3): 7.87 – 7.82 (m, HꢀC(6), HꢀC(8)); 7.05 (d, J ¼ 8.7, HꢀC(9)); 4.36 – 4.21 (m, CH2(2), HꢀC(3),
CH2(4)); 2.12 (br. s, OH). 13C-NMR (75 MHz, CDCl3): 155.9 (C(9a)); 150.1 (C(5a)); 143.2 (C(7)); 121.5
(C(9)); 119.4 (C(8)); 117.5 (C(6)); 74.9 (C(2)); 74.6 (C(4)); 69.0 (C(3)). EI-MS: 211 (100, Mþ), 192 (2),
180 (14), 167 (11), 166 (11), 155 (9), 152 (4), 137 (12), 134 (5), 121 (11), 107 (20), 94 (4), 91 (6), 79 (15),
77 (4), 75 (4), 65 (16), 63 (16), 57 (15), 51 (13).
7-Nitro-2H-1,5-benzodioxepin-3(4H)-one (15). At ꢀ 788 under N2, DMSO (0.42 g, 5.37 mmol) in
CH2Cl2 (5 ml) was added dropwise over 20 min to oxalyl chloride (0.34 g, 2.68 mmol) in CH2Cl2 (40 ml),
and the mixture was stirred for 15 min. Then 27d (0.25 g, 1.18 mmol) in CH2Cl2 (5 ml) was added
dropwise over 30 min followed by stirring at ꢀ 788 for 90 min. Et3N (0.68 g, 6.72 mmol) was then added
dropwise over 15 min, and the soln. was stirred for a further 2 h at ꢀ 788. THF/H2O 1:1 (10 ml) was
added while maintaining the temp. of the mixture below ꢀ 608. The soln. was then allowed to reach 08
followed by addition of CH2Cl2 (40 ml). The org. mixture was washed with 2m HCl (2 ꢂ 60 ml), dried
(MgSO4), and concentrated and the crude resin crystallized from MeCN: 15 (0.21 g, 84%). Bright yellow
semi-solid. M.p. (MeCN) 110 – 1128.
13. Benzodioxepinone 16 by Procedure A. 2,2’-[(4-Formyl-1,2-phenylene)bis(oxy)]bis[acetic Acid]
Dimethyl Ester (10e). As described in Exper. 3 (microwave procedure), with 9e (1.00 g, 7.24 mmol).
Purification by bulb-to-bulb distillation (2108/0.1 Torr) gave 10e (1.61 g, 79%). White solid. The
conventional method gave 10e in 55% yield. M.p. (pentane) 84 – 868. IR (KBr): 2957w, 1765m, 1751s,
1682m, 1598m, 1588m, 1520m, 1442m, 1428m, 1404w, 1392w, 1380w, 1340m, 1332m, 1290m, 1218s, 1175m,
1133s, 1080w, 1060m. 1H-NMR (300 MHz, CDCl3)1): 9.83 (s, CHO); 7.50 – 6.91 (m, HꢀC(3’), HꢀC(5’),
HꢀC(6’)); 4.81 (s, CH2(1’’)); 4.78 (s, CH2(2)); 3.80 (s, Me(3)O, Me(3’’)O). 13C-NMR (75 MHz, CDCl3)1):
190.4 (CHO)); 168.4 (C(1)O, C(2’’)O); 152.8 (C(1’)); 148.1 (C(2’)); 131.0 (C(4’)); 126.9 (C(5’)); 113.3
(C(6’)); 112.6 (C(3’)); 65.9 (CH2(1’’), CH2(2)); 52.3 (Me(3)O, Me(3’’)O). EI-MS: 282 (38, Mþ), 250 (11),
223 (7), 193 (4), 177 (5), 163 (18), 149 (35), 135 (4), 119 (8), 105 (5), 95 (6), 77 (11), 63 (8), 51 (10), 45
(100).
Methyl 7-Formyl-3,4-dihydro-3-oxo- and 8-Formyl-3,4-dihydro-3-oxo-2H-1,5-benzodioxepine-2-car-
boxylate (11e). As described in Exper. 3, with 10e (0.30 g, 1.06 mmol): crude 11e (0.13 g, 50%). Yellow oil
as a complex mixture. IR (neat): 3425m, 2956m, 2361w, 1742s, 1688m, 1599m, 1509m, 1440m, 1276s,

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Helvetica Chimica Acta – Vol. 90 (2007)
1212s, 1163m, 1130m, 1063m. EI-MS: 178 (56), 149 (100), 121 (25), 103 (1), 91 (6), 79 (6), 63 (14), 51
(12), 42 (8).
3,4-Dihydro-3-oxo-2H-1,5-benzodioxepine-7-carboxaldehyde (16). As described in Exper. 3, with
11e (0.17 g, 0.68 mmol). Extraction was performed without NaHCO3 neutralization: yellow oily 16
(0.11 g, 85%). The sample was purified by semi-prep. HPLC (tR 7.8 min, lmax 270 nm): 16 (12 mg, 11%).
Yellow semi-solid. IR (KBr): 3437 (br.), 3041w, 2923w, 2852w, 2836w, 2735w, 1802w, 1736s, 1704w, 1683s,
1605w, 1575s, 1508m, 1438w, 1421w, 1383w, 1359w, 1341w, 1314m, 1299m, 1283s, 1269s, 1236w, 1208w,
1162w, 1109w, 1044m, 1027w, 1017w. 1H-NMR (300 MHz, CDCl3): 9.85 (s, CHO); 7.53 – 7.50 (m,
HꢀC(6), HꢀC(8)); 7.10 (d, J ¼ 8.8, HꢀC(9)); 4.79 (s, CH2(2)); 4.71 (s, CH2(4)). 13C-NMR (75 MHz,
CDCl3): 203.0 (C(3)); 190.2 (CHO); 153.5 (C(9a)); 148.6 (C(5a)); 132.4 (C(7)); 126.0 (C(8)); 122.7
(C(9)); 121.6 (C(6)); 76.1 (C(2)); 75.2 (C(4)). EI-MS: 192 (100, Mþ), 163 (81), 149 (6), 135 (13), 121 (5),
108 (15), 91 (4), 79 (26), 63 (12), 51 (19), 42 (6), 39 (5).
14. Preparation of 16 by Procedure B. 3,4-Dihydro-3-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-1,5-
benzodioxepine-7-carboxaldehyde (26e). As described in Exper. 4, with 9e (0.50 g, 3.62 mmol): 26e
(0.74 g, 74%). Caramel brown viscous oil. IR (neat): 3422 (br.), 3063w, 2943m, 2869m, 2733w, 1803w,
1686s, 1601s, 1573m, 1501s, 1432m, 1389w, 1356w, 1316m, 1281s, 1201w, 1158m, 1127s, 1074s, 1033s.
1H-NMR (300 MHz, CDCl3): 9.77 (s, CHO); 7.42 – 6.95 (m, HꢀC(6), HꢀC(8), HꢀC(9)); 4.72 (ꢀtꢁ,
HꢀC(2’)); 4.59 – 4.22 (m, CH2(4), HꢀC(3), CH2(2)); 4.01 – 3.78 (m, HaꢀC(6’)); 3.56 – 3.51 (m,
HbꢀC(6’)); 1.80 – 1.18 (m, CH2(5’), CH2(4’), CH2(3’)). 13C-NMR (75 MHz, CDCl3): 190.6 (CHO); 155.3
(C(9a)); 150.1 (C(5a)); 131.7 (C(7)); 125.2 (C(8)); 121.4 (C(9)); 121.3 (C(6)); 98.7 (C(2’)); 74.0 (C(3));
72.9 (C(2)); 72.0 (C(4)); 62.8 (C(6’)); 30.7 (C(3’)); 25.2 (C(5’)); 19.5 (C(4’)). EI-MS: 278 (22, Mþ), 250
(1), 222 (2), 194 (30), 176 (19), 164 (16), 149 (30), 137 (4), 121 (3), 119 (4), 113 (3), 109 (2), 105 (1), 103
(1), 99 (1), 93 (1), 91 (5), 85 (100), 79 (5), 67 (13), 57.1 (14), 55 (7), 51 (3).
3,4-Dihydro-3-hydroxy-2H-1,5-benzodioxepine-7-carboxaldehdye (27e). As described in Exper. 4,
with 26e (0.56 g, 2.01 mmol): 27e (0.35 g, 89%). Yellow resin. IR (neat): 3440 (br.), 3078w, 2939m,
2856m, 2735w, 2620w, 1794w, 1731m, 1688s, 1599s, 1588m, 1574m, 1505s, 1434s, 1394w, 1359w, 1338w,
1317m, 1280s, 1169m, 1138m, 1099w, 1035m. 1H-NMR (300 MHz, CDCl3): 9.82 (s, CHO); 7.47 – 7.45 (m,
HꢀC(6), HꢀC(8)); 7.06 (d, J ¼ 8.8, HꢀC(9)); 4.32 – 4.14 (m, CH2(2), HꢀC(3), CH2(4)); 2.87 (br. s,
OH). 13C-NMR (75 MHz, CDCl3): 190.6 (CHO); 155.8 (C(9a)); 150.8 (C(5a)); 132.2 (C(7)); 125.7
(C(8)); 122.6 (C(9)); 121.8 (C(6)); 74.7 (C(2)); 74.5 (C(4)); 69.1 (C(3)). EI-MS: 194 (100, Mþ), 175 (3),
163 (17), 149 (65), 137 (21), 121 (13), 119 (6), 109 (6), 105 (3), 95 (6), 91 (5), 79 (8), 77 (8), 65 (9), 63
(11), 57 (7), 51 (9).
3,4-Dihydro-3-oxo-2H-1,5-benzodioxepine-7-carboxaldehyde (16). As described in Exper. 4, with
27e (0.25 g, 1.29 mmol). The crude resin was crystallized from MeCN: 16 (0.13 g, 52%). White solid. M.p.
(MeCN) 110 – 1128.
15. Benzodioxepinone 17 by Procedure A. 2,2’-{[4-(tert-Butyl)-1,2-phenylene]bis(oxy)}bis[acetic
Acid] Dimethyl Ester (10f). As described in Exper. 3 (conventional method), with 9f (1.00 g, 6.02 mmol).
Bulb-to-bulb distillation (1908/0.3 Torr) performed twice afforded 10f (1.40 g, 75%). Clear oil. IR (neat):
2908s, 2956s, 2870m, 2111w, 1762s, 1608m, 1592m, 1583m, 1510s, 1440s, 1414m, 1376m, 1364m, 1294s,
1201s, 1153s, 1110m, 1068s, 1028m, 1005m. 1H-NMR (300 MHz, CDCl3)1): 6.96 – 6.77 (m, HꢀC(3’),
t
HꢀC(5’), HꢀC(6’)); 4.72 (s, CH2(1’’)); 4.68 (s, CH2(2)); 3.78 (s, Me(3)O, Me(3’’)O); 1.26 (s, Bu).
13C-NMR (75 MHz, CDCl3)1): 169.5 (CO(1), CO(2’’)); 147.3 (C(1’)); 145.9 (C(2’), C(4’)); 119.4 (C(5’));
114.9 (C(6’)); 114.2 (C(3’)); 67.2 (CH2(2)); 66.7 (CH2(1’’)); 52.1 (Me(3)O); 52.0 (Me(3’’)O); 34.3
(Me3C); 31.3 (Me3C). EI-MS: 310 (23, Mþ), 295 (100), 222 (2), 205 (1), 191 (1), 177 (4), 163 (11), 149
(3), 133 (5), 121 (2), 117 (2), 105 (4), 91 (6), 77 (5), 65 (2), 59 (2), 51 (1), 45 (32).
Methyl 7-(tert-Butyl)-3,4-dihydro-3-oxo- and 8-(tert-Butyl)-3,4-dihydro-3-oxo-2H-1,5-benzodioxe-
pine-2-carboxylate (11f). As described in Exper. 3, with 10f (2.42 g, 7.81 mmol): 11f (1.89 g, 87%). Clear
brown oil. IR (neat): 3456m, 2958s, 2870s, 2566m, 2085w, 1741s, 1582m, 1504s, 1473m, 1437s, 1414s,
1364m, 1269s, 1206s, 1149s, 1126s, 1102m, 1079m. 1H-NMR (300 MHz, CDCl3): Regioisomer 1: 7.11 – 6.94
(m, HꢀC(6), HꢀC(8), HꢀC(9)); 5.40 (s, HꢀC(2)); 4.82 (d, J ¼ 16.4, HaꢀC(4)); 4.60 (d, J ¼ 16.6,
HbꢀC(4)); 3.87 (s, MeO); 1.28 (s, tBu); Regioisomer 2: 7.11 – 6.94 (m, HꢀC(6), HꢀC(8), HꢀC(9)); 5.36
t
(s, HꢀC(2)); 4.81 (d, J ¼ 17.1, HaꢀC(4)); 4.58 (d, J ¼ 16.8, HbꢀC(4)); 3.86 (s, MeO); 1.28 (s, Bu).
13C-NMR (75 MHz, CDCl3): Regioisomer 1: 199.6 (C(3)); 165.5 (CO2); 148.5 (C(9a)); 146.4 (C(5a));

Helvetica Chimica Acta – Vol. 90 (2007)
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144.5 (C(7)); 120.8 (C(8)); 119.8 (C(9)); 117.5 (C(6)); 81.7 (C(2)), 76.7 (C(4)); 52.9 (MeO); 34.4
(Me3C); 31.3 (Me3C); Regioisomer 2: 199.6 (C(3)); 165.4 (CO2); 147.2 (C(9a)); 145.7 (C(5a)); 144.8
(C(7)); 121.8 (C(8)); 120.6 (C(9)); 118.2 (C(6)); 81.9 (C(4)); 76.8 (C(2)); 52.9 (MeO); 34.2 (Me3C); 31.3
(Me3C). EI-MS: 278 (22, Mþ), 263 (100), 235 (5), 219 (3), 205 (6), 191 (3), 175 (5), 163 (3), 147 (4), 133
(2), 121 (3), 115 (4), 105 (3), 91 (6), 77 (5), 65 (2), 55 (2), 41 (2), 32 (5).
7-(tert-Butyl)-2H-1,5-benzodioxepin-3(4H)-one (17). As described in Exper. 3, with 11f (1.24 g,
4.46 mmol) for 2.5 h, with the aq. workup involving neutralization with aq. NaHCO3 soln. prior to
extraction. The obtained brown oil was bulb-to-bulb distilled at 100 – 1058/0.2 Torr: 17 (0.82 g, 84%).
White crystalline solid. M.p. (pentane) 66 – 688. IR (KBr): 2965s, 2950m, 2901m, 2868m, 1791w, 1742s,
1577m, 1504s, 1477m, 1461m, 1438m, 1424m, 1409m, 1394w, 1367w, 1359w, 1347w, 1300s, 1274s, 1248m,
1
1206m, 1189m, 1127m, 1098w, 1045s. H-NMR (300 MHz, CDCl3): 7.02 – 6.79 (m, HꢀC(6), HꢀC(8),
t
HꢀC(9)); 4.72 (s, CH2(2)); 4.69 (s, CH2(4)); 1.26 (s, Bu). 13C-NMR (75 MHz, CDCl3): 204.9 (C(3));
147.6 (C(9a)); 147.4 (C(5a)); 145.8 (C(7)); 120.7 (C(8)); 120.3 (C(9)); 117.8 (C(6)); 75.7 (C(2)); 75.6
(C(4)); 34.3 (Me3C); 31.3 (Me3C). EI-MS: 220 (26, Mþ), 205 (100), 177 (11), 149 (3), 135 (4), 121 (4),
105 (4), 91 (7), 77 (7), 6.5 (3), 55 (2), 41 (3).
16. Benzodioxepinone 17 by Procedure B. 7-(tert-Butyl)-3,4-dihydro-3-[(tetrahydro-2H-pyran-2-
yl)oxy]-2H-1,5-benzodioxepine (26f). As described in Exper. 4, with 9f (0.5 g, 3.01 mmol): 26f (0.90 g,
98%). Light brown viscous oil. IR (neat): 3435 (br.), 3039w, 2952s, 2870m, 2741w, 2662w, 1727w, 1625w,
1613w, 1574m, 1505s, 1463m, 1455m, 1442w, 1412w, 1393w, 1363w, 1355w, 1306s, 1274m, 1263m, 1239m,
1
1202m, 1185w, 1161w, 1122s, 1097w, 1076s, 1034s, 1023m. H-NMR (300 MHz, CDCl3): 6.96 – 6.86 (m,
HꢀC(6), HꢀC(8), HꢀC(9)); 4.74 (t, J ¼ 2.8, HꢀC(2’)); 4.46 – 4.21 (m, CH2(2), HꢀC(3), CH2(4));
3.95 – 3.86 (m, HaꢀC(6’)); 3.57 – 3.49 (m, HbꢀC(6’)); 1.90 – 1.43 (m, CH2(3’), CH2(4’), CH2(5’)); 1.26 (s,
tBu). 13C-NMR (75 MHz, CDCl3): 147.5 (C(9a)); 146.3 (C(5a), (C(7)); 120.9 (C(8)); 120.1 (C(9)); 119.7
(C(6)); 98.4 (C(2’)); 74.5 (C(3)); 73.0 (C(2)); 71.9 (C(4)); 62.6 (C(6’)); 34.1 (Me3C); 31.3 (Me3C); 30.8
(C(3’)); 25.3 (C(5’)); 19.4 (C(4’)). EI-MS: 306 (77, Mþ), 291 (58), 263 (3), 261 (2), 250 (2), 248 (1), 235
(13), 222 (19), 207 (81), 204 (5), 193 (5), 189 (24), 177 (12), 163 (6), 161 (6), 151 (10), 147 (3), 133 (10),
121 (4), 119 (4), 117 (3), 115 (3), 105 (12), 91 (12), 85 (100), 77 (11), 67 (17), 57 (25), 55 (17), 51 (36).
7-(tert-Butyl)-3,4-dihydro-2H-1,5-benzodioxepin-3-ol (27f). As described in Exper. 4, with 26f
(0.80 g, 2.61 mmol): 27f (0.47 g, 81%). White solid. M.p. (pentane) 48 – 508. IR (KBr): 3459 (br.), 2962m,
2866w, 1578w, 1503s, 1460w, 1447w, 1409m, 1390w, 1364w, 1311s, 1274s, 1252m, 1236s, 1204w, 1184w,
1
1118m, 1090m, 1057m, 1042s, 1022m. H-NMR (300 MHz, CDCl3): 7.04 – 6.95 (m, HꢀC(6), HꢀC(8),
HꢀC(9)); 4.32 – 4.23 (m, HaꢀC(2), HaꢀC(4)); 4.09 – 4.04 (m, HbꢀC(2), HꢀC(3), HbꢀC(4)); 2.70 (ꢀsꢁ,
OH); 1.27 (s, tBu). 13C-NMR (75 MHz, CDCl3): 150.4 (C(9a)); 148.5 (C(5a)); 147.5 (C(7)); 120.9 (C(8));
120.8 (C(9)); 118.6 (C(6)); 74.7 (C(2), C(4)); 69.7 (C(3)); 34.2 (Me3C); 31.3 (Me3C). EI-MS: 222 (29,
Mþ), 207 (100), 163 (4), 151 (9), 133 (5), 123 (5), 105 (7), 91 (5), 77 (6), 65 (2).
7-(tert-Butyl)-2H-1,5-benzodioxepin-3(4H)-one (17). As described in Exper. 4, with 27f (0.41 g,
1.85 mmol). The obtained clear oil was purified by bulb-to-bulb distillation at 100 – 1058/0.2 Torr: 17
(0.30 g, 73%). Crystalline solid M.p. (pentane) 66 – 688.
17. Benzodioxepinone 18 by Procedure A. 2,2’-[Naphthalene-2,3-diylbis(oxy)]bis[acetic Acid]
Dimethyl Ester (10g). As described in Exper. 3 (conventional method), with 9g (2.00 g, 12.49 mmol).
Purification was achieved by continuous trituration with CH2Cl2 until an ivory solid appeared: 10g
(3.56 g, 96%). The microwave procedure gave 10g in 75% yield. M.p. (CH2Cl2) 78 – 808. IR (KBr):
2975w, 2953m, 1751s, 1737s, 1629w, 1603w, 1585w, 1510m, 1488s, 1460m, 1447m, 1436m, 1410w, 1380m,
1339w, 1284s, 1247s, 1228s, 1189m, 1168s, 1123m, 1078w, 1047m, 1034w, 1024m. 1H-NMR (300 MHz,
CDCl3)1): 7.67 (dd, J ¼ 6.1, 3.1, HꢀC(5’), HꢀC(8’)); 7.35 (dd, J ¼ 6.1, 3.5, HꢀC(6’), HꢀC(7’)); 7.12 (s,
HꢀC(1’), HꢀC(4’)); 4.83 (s, CH2(2), CH2(1’’)); 3.82 (s, Me(3)O, Me(3’’)O). 13C-NMR (75 MHz,
CDCl3)1): 169.1 (C(1)O, C(2’’)O); 147.7 (C(2’), C(3’)); 129.5 (C(4a), C(8a)); 126.5 (C(5’), C(8’)); 124.8
(C(6’), C(7’)); 109.6 (C(1’), C(4’)); 66.2 (CH2(2), CH2(1’’)); 52.3 (Me(3)O, MeO(3’’)). EI-MS: 304 (100,
Mþ), 272 (8), 243 (23), 213 (8), 203 (5), 185 (26), 171 (87), 147 (6), 127 (26), 115 (36), 102 (25), 88 (6),
76 (6), 63 (6), 45 (67).
3,4-Dihydro-methyl-3-oxo-2H-naphtho[2,3-b][1,4]dioxepine-2-carboxylate (11g). As described in
Exper. 3, with 10g (1.39 g, 4.57 mmol): 11g (1.16 g, 93%). Caramel brown oil. A portion of this sample was
purified by semi-prep. HPLC (tR 29.9 min, lmax 230 nm): 11g (21 mg, 2%). Light brown oil. IR (KBr):

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3453m, 3056w, 2954w, 1744s, 1635w, 1602w, 1505s, 1469s, 1363m, 1277s, 1225s, 1172s, 1117m, 1072m,
1024m. 1H-NMR (300 MHz, CDCl3): 7.70 (dd, J ¼ 6.0, 3.2, HꢀC(7), HꢀC(10)); 7.54 (s, HꢀC(11)); 7.45
(s, HꢀC(6)); 7.39 (dd, J ¼ 6.7, 3.1, HꢀC(8), HꢀC(9)); 5.41 (s, HꢀC(2)); 4.96 (d, J ¼ 17.1, HaꢀC(4)); 4.81
(d, J ¼ 17.1, HbꢀC(4)); 3.86 (s, MeO). 13C-NMR (75 MHz, CDCl3): 199.5 (C(3)); 165.3 (CO2); 147.2
(C(11a)); 146.5 (C(5a)); 131.0 (C(10a)); 130.0 (C(6a)); 125.7 (C(8)); 125.3 (C(9)); 126.7 (C(10)); 126.8
(C(7)); 118.0 (C(11)); 116.7 (C(6)); 81.7 (C(2)); 76.5 (C(4)); 53.0 (MeO). EI-MS: 272 (3, Mþ), 243 (12),
213 (5), 185 (17), 171 (61), 157 (2), 147 (3), 127 (19), 115 (28), 102 (20), 88 (6), 76 (5), 63 (6), 45 (100).
2H-Naphtho[2,3-b][1,4]dioxepin-3(4H)-one (18). As described in Exper. 3, with 11g (0.33 g,
1.21 mmol) in a minimal amount of EtOH/AcOEt 2 :1 for 2.5 h. Quenching of the reaction soln. in
aq. NaHCO3 soln. and usual workup gave brown semi-solid 18 (0.17 g, 65%). A portion of the sample was
purified by semi-prep. HPLC (tR 15.1 min, lmax 230 nm): 11g (18 mg, 7%). Light brown crystalline solid.
M.p. (MeCN) 70 – 728. IR (KBr): 3442m, 2960s, 2925s, 2854s, 1737m, 1599w, 1504m, 1470m, 1413w,
1363m, 1330w, 1289m, 1262s, 1169w, 1151w, 1098m, 1046s, 1030s. 1H-NMR (300 MHz, CDCl3): 7.51 (dd,
J ¼ 6.4, 3.2, HꢀC(7), HꢀC(10)); 7.19 (dd, J ¼ 6.4, 3.1, HꢀC(8), HꢀC(9)); 7.07 (s, HꢀC(6), HꢀC(11));
4.60 (s, CH2(2), CH2(4)). 13C-NMR (75 MHz, CDCl3): 204.8 (C(3)); 148.2 (C(5a), C(11a)); 130.4 (C(6a),
C(10a)); 126.7 (C(7), C(10)); 125.4 (C(8), C(9)); 117.2 (C(11), C(6)); 75.4 (C(2), C(4)). EI-MS: 214
(100, Mþ), 186 (6), 171 (58), 160 (4), 142 (2), 130 (33), 114 (32), 102 (63), 88 (12), 76 (15), 63 (20), 51
(16), 39 (7). HR-ESI-MS: 215.0715 (C13H10Oþ3 , [M þ 1]þ; calc. 215.0629).
18. Benzodioxepinone 18 by Procedure B. 3,4-Dihydro-3-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-
naphtho[2,3-b][1,4]dioxepine (26g). As described in Exper. 4, with 9g (0.5 g, 3.12 mmol): 26g (0.77 g,
82%). Brown viscous oil. IR (neat): 3331 (br.), 3056w, 2943s, 2870m, 1708m, 1670s, 1631w, 1602w, 1503s,
1
1472s, 1453s, 1386m, 1359m, 1290s, 1260s, 1247s, 1201m, 1172m, 1159m, 1125s, 1074s, 1031s. H-NMR
(300 MHz, CDCl3): 7.67 – 7.61 (m, HꢀC(7), HꢀC(10)); 7.36 (s, HꢀC(6), HꢀC(11)); 7.33 – 7.30 (m,
HꢀC(8), HꢀC(9)); 4.77 (ꢀtꢁ, HꢀC(2’)); 4.51 – 4.30 (m, CH2(2), HꢀC(3), CH2(4)); 4.05 – 3.83 (m,
HaꢀC(6’)); 3.59 – 3.44 (m, HbꢀC(6’)); 1.90 – 1.20 (m, CH2(3’), CH2(4’), CH2(5’)). 13C-NMR (75 MHz,
CDCl3): 151.1 (C(11a)); 150.2 (C(5a)); 130.2 (C(6a), C(10a)); 126.5 (C(7), C(10)); 124.8 (C(8), C(9));
116.9 (C(6), C(11)); 98.5 (C(2’)); 74.6 (C(3)); 73.0 (C(2)); 71.9 (C(4)); 62.7 (C(6’)); 30.7 (C(3’)); 25.3
(C(5’)); 19.4 (C(4’)). EI-MS: 300 (65, Mþ), 272 (14), 244 (8), 216 (31), 198 (17), 185 (10), 181 (2), 171
(44), 169 (14), 160 (18), 141 (9), 131 (11), 128 (11), 127 (14), 115 (22), 114 (17), 102 (22), 85 (100), 77
(4), 76 (4), 67 (18), 57 (28), 55 (11).
3,4-Dihydro-2H-naphtho[2,3-b][1,4]dioxepin-3-ol (27g). As described in Exper. 4, with 26g (0.65 g,
t
2.16 mmol). Crystallization of the residue from BuOMe yielded 27g (0.34 g, 73%). Red solid. M.p.
(tBuOMe) 79 – 808. IR (KBr): 3420 (br.), 3056w, 2925w, 1777w, 1726m, 1627w, 1598m, 1503s, 1474m,
1458w, 1445w, 1432w, 1394w, 1360m, 1341w, 1289m, 1263s, 1173m, 1151w, 1109m, 1069w, 1031s. 1H-NMR
(300 MHz, CDCl3): 7.71 – 7.68 (m, HꢀC(7), HꢀC(10)); 7.46 (s, HꢀC(6), HꢀC(11)); 7.39 – 7.36 (m,
HꢀC(8), HꢀC(9)); 4.41 – 4.36 (m, HaꢀC(2), HaꢀC(4)); 4.14 – 4.09 (m, HbꢀC(2), HꢀC(3), HbꢀC(4));
2.30 (ꢀsꢁ, OH). 13C-NMR (75 MHz, CDCl3): 151.1 (C(5a), C(11a)); 130.7 (C(6a), C(10a)); 126.8 (C(7),
C(10)); 125.3 (C(8), C(9)); 118.1 (C(6), C(11)); 75.3 (C(2), C(4)); 69.8 (C(3)). EI-MS: 216 (100, Mþ),
197 (1), 185 (13), 172 (16), 171 (32), 160 (33), 145 (5), 131 (16), 127 (13), 115 (22), 114 (23), 102 (13), 88
(5), 77 (4), 76 (4), 63 (4).
2H-Naphtho[2,3-b][1,4]dioxepin-3(4H)-one (18). As described in Exper. 4, with 27g (0.31 g,
1.43 mmol): 18 (0.19 g, 61%). Grey-white solid. M.p. (MeCN) 70 – 748.
19. 7-Bromo-8-methyl-2H-1,5-benzodioxepin-3(4H)-one (19). Sodium bromate (2.54 g, 16.83 mmol)
was added to 1 (1.00 g, 5.62 mmol) dissolved in cyclohexane/H2O 4 :3 (70 ml). Then sodium metabisulfite
(0.98 g, 5.15 mmol) in H2O (10 ml) was added dropwise, and the mixture was stirred at 508 for 8 h. The
deep yellow soln. was quenched with ice/H2O (250 ml) and extracted with Et2O (3 ꢂ 100 ml) and the
combined org. phase washed with H2O (2 ꢂ 200 ml), dried (MgSO4), and concentrated: 19 (1.23 g, 85%).
Pale yellow powdery solid. M.p. (pentane) 88 – 908. IR (KBr): 2930w, 2900w, 1737s, 1602w, 1566m, 1480s,
1451m, 1428m, 1416m, 1378w, 1294s, 1266m, 1230w, 1178m, 1152s, 1052s, 1036s. 1H-NMR (300 MHz,
CDCl3): 7.17 (s, HꢀC(6)); 6.87 (s, HꢀC(9)); 4.67 (s, CH2(2)); 4.66 (s, CH2(4)); 2.28 (s, Me). 13C-NMR
(75 MHz, CDCl3): 203.8 (C(3)); 147.3 (C(9a)); 146.6 (C(5a)); 133.3 (C(8)); 124.2 (C(6)); 122.3 (C(9));
117.4 (C(7)); 75.7 (C(2)); 75.5 (C(4)); 21.9 (Me). EI-MS: 258 (89, Mþ), 257 (10), 256 (92), 215 (12), 213

Helvetica Chimica Acta – Vol. 90 (2007)
1027
(12), 202 (3), 200 (4), 174 (25), 172 (28), 149 (30), 135 (5), 121 (6), 105 (3), 93 (100), 77 (18), 65 (14), 51
(12), 39 (10). HR-ESI-MS: 256.9812 (C10H9O3Brþ, Mþ; calc. 256.9813).
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Received January 9, 2007