New syntheses of dillapiol [4,5-dimethoxy-6-(2-propenyl)-1,3-benzodioxole], its 4-methylthio and other analogs

Article abstract of DOI:10.1139/v00-138

Three syntheses of the natural synergist dillapiol from the natural, commercially available sesamol as starting material, are described. A major difference between these is the order of introduction of the additional methoxy and allyl substituents. In one

Full text of DOI:10.1139/v00-138

1345
New syntheses of dillapiol [4,5-dimethoxy-6-(2-
propenyl)-1,3-benzodioxole], its 4-methylthio and
other analogs
Sherry L. Majerus, Najma Alibhai, Sasmita Tripathy, and Tony Durst
Abstract: Three syntheses of the natural synergist dillapiol from the natural, commercially available sesamol as starting
material, are described. A major difference between these is the order of introduction of the additional methoxy and
allyl substituents. In one of the syntheses, a formyl group is introduced at C4 via an electrophilic aromatic substitution
reaction and then converted into the methoxy group using a Baeyer–Villiger reaction and subsequent methylation; in
the other two, a directed ortho-metalation, Baeyer–Villiger, methylation sequence was employed. Various intermediates
along the synthetic route were used to generate more than 30 analogs, including the 4-thiomethyldillapiol, to investi-
gate the structure activity relationships of the pesticide synergism of these compounds. Radio-labeled dillapiol, bearing
14C at the C4 methoxy group was also prepared. Initial screening with mosquito larvae showed that most of the
derivatives prepared in this study had signifacant synergistic activities in combination with the phototoxic larvicide
α-therthiophene.
Key words: dillapiol, insecticide synergists, dillapiol analogs, 4-methylthiodillapiol.
Résumé : On décrit trois synthèses du dillapiol, un produit naturel de synergie, qui ont été réalisées à partir du
sésamol, un produit naturel disponible commercialement. Ces trois ces synthèses diffèrent principalement par l’ordre
d’introduction des substituants méthoxy et alkyles additionnels. Dans l’une de ces synthèses, le groupe formyle est
introduit en C-4 par le biais d’une réaction de substitution aromatique électrophile et elle est ensuite transformée en
groupe méthoxy à l’aide d’une réaction de Baeyer–Villiger et une réaction de méthylation subséquente; dans les deux
autres, on fait appel à la séquence de réaction impliquant une métalation ortho dirigée, une réaction de Baeyer–Villiger
et une méthylation. On a utilisé divers intermédiaires obtenus au cours de ces voies de synthèses pour générer plus de
30 analogues, y compris le 4-thiométhyldillapiol, afin d’en étudier les relations structure-activité de synergie de ces
composés comme pesticide. On a aussi préparé du dillapiol radioactivement marqué par du 14C dans le groupe
méthoxy en C-4. Des évaluations initiales avec des larves de moustiques montrent que la plupart des dérivés préparés
au cours de cette étude présentent des activités importantes de synergie lorsqu’on les utilise en combinaison avec
l’α-therthiophéne, un larvicide phototoxique.
Mots clés : dillapiol, effet de synergie pour les insecticides, analogues de dillapiol, 4-méthylthiodillapiol. Majerus et
al. 1355
Introduction
from the insects. Examples of natural lignans with known
synergistic activity, in addition to the dillapiol, are myris-
ticin (2), safrole (3), and sessamin (4). Piperonyl butoxide
(5) the commonly used commercial synergist for pyrethroids
and carbamates, is also known to inhibit PSMOs.
Dillapiol is a monolignan and a major constituent of the
essential oils of a number of plants, including Indian dill
(Antheum graveolus) (3), and Piper aduncum, (4), a species
in the Piperaceae family. The latter grows as a small shrub in
many tropical areas such as Central America, the West In-
dies, and Southeast Asia. The development of dillapiol for
commercial purposes requires either an inexpensive reliable
natural source or a viable synthetic source. Additionally for
registration purposes both the toxicity to nontarget species
and pharmacokinetics including the nature of the metabolites
need to be known. The latter studies can be carried out best
with isotopically labeled material.
During the past few years we have been involved in a pro-
ject aimed at developing natural insecticides (1). Part of this
includes the use of the naturally occurring synergist dillapiol
(1). Dillapiol is a member of a group of both natural and
synthetic synergists known as polysubstrate mono-oxy-
genase inhibitors (PMSO) whose key structural unit is a ben-
zene ring bearing a methylenedioxy unit (2). This unit binds
strongly to the heme portion of the cytochrome P-450
thereby inhibiting the oxidation of various other substrate
such as insecticides and delaying their rate of elimination
Received October 1, 1999. Published on the NRC Research
Press website on October 16, 2000.
S.L. Majerus, N. Alibhai, S. Tripathy, and T. Durst.1
Departments of Chemistry and Biology, University of Ottawa,
Ottawa, ON KIN 6N5, Canada.
Three syntheses of dillapiol have previously been reported.
3,4,5-Tri-methoxyacetophenone (5), 2-hydroxy-3-methoxyben-
zaldehyde (o-vanillin) (6), and 1,2,3-trimethoxybenzene (7)
were used as starting materials. These syntheses required
1Author to whom correspondence may be addressed.
Telephone: (613) 562-5800 ext. 6072. Fax: (613) 562-5170.
e-mail: tdurst@science.uottawa.ca
Can. J. Chem. 78: 1345–1355 (2000)
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Can. J. Chem. Vol. 78, 2000
Scheme 1. Reagents: (a) K2CO3–CH2=CHCH2Br; (b) N,N-dimethylaniline (180°C); (c) (CH2O)n–SnCl4–Bu3N; (d) CH3I–K2CO3;
(e) MCPBA–CHCl3 (18 h, 0°C); ( f ) LiOH–THF–H2O; (g) CH3I–K2CO3–acetone.
5–7 steps and occurred in 2, 10, and 6% yield, respectively.
None of the three syntheses is efficient or amenable to the
introduction of isotopic carbon in the form of the relative in-
expensive methyl iodide. We therefore decided to investi-
gate several new syntheses which would be not only more
efficient and enable us to introduce the labeled CH3I in the
last synthetic step, but also enable us to generate a family of
derivatives to initiate a structure–activity relationship study.
Finally, access to various intermediates is expected to help
in the identification of metabolites.
tributylamine (8) to afford 8 in 60% isolated yield. Replace-
ment of tributylamine by other tertiary amines such as
triethyl- or trioctylamine either reduces or did not improve
the yield of 8. The variation of other reaction parameters
such as temperature and reaction time also did not result in
yield improvements.
This compound was quantitatively methylated to 9 in
preparation for the Baeyer–Villiger and subsequent hydroly-
sis of the formate ester to form 10. The conversion of 9 to
10 was carried out using 1 equiv. of MCPBA in CHCl3 at
0°C for 18 h and afforded the formyl intermediate in 71%
isolated yield, saponification of which gave 10. Under these
conditions competition by the alkene moiety for the peracid
to give an epoxide was minor; at room temperature the rates
of desired Baeyer–Villiger and the epoxidation were quite
comparable. Finally, methylation of 10 with CH3I–K2CO3 in
acetone afforded pure dillapiol. Replacement of cold methyl
iodide with carbon-14 labeled material afforded radio-
labeled dillapiol, suitable for metabolism studies.
Discussion of results
Three syntheses have been completed starting with
sesamol (6). These are shown in Schemes 1–3. The structure
of the intermediates generated in each sequence were deter-
1
mined mainly by H NMR. The assignments were supported
by 13C NMR, IR, and HRMS data. These are given in the
experimental section.
In the first synthesis, Scheme 1, sesamol (6)2 was con-
verted to the ortho-allylated phenol 7 in 81% overall yield
via O-allylation, followed by a Claisen rearrangement. Intro-
duction of the formyl group into the 4 position in 7 was ac-
complished by treatment with formaldehyde, SnCl4, and
The overall yield of dillapiol from sesamol via Scheme 1,
based on the isolated yields of each intermediate, is more
than 21%. The major shortcomings of this route are the
rather stringent conditions required for the introduction of
the formyl group and the problem of the competing
2 The numbering used throughout this paper is based on the IUPAC numbering of the 1,3-benzodioxole ring system. See structure 6,
Scheme 1.
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Majerus et al.
1347
Scheme 2. Reagents: (a) MOM-Cl–nBuLi; (b) nBuLi, THF, (–78°C), then DMF; (c) MCPBA; (d) 10% KOH; (e) K2CO3 and CH3I;
( f ) CH3CO2H, NaI; (g) K2CO3, CH2=CHCH2Br; (h) N,N-dimethylaniline (180°C); (i ) K2CO3 and CH3I.
epoxidation of the terminal double bond during the Baeyer–
Villiger reaction of 9. These difficulties became more severe
on attempted scale-up.
Considerable effort was expended to avoid the sensitive
Scheme 3. Reagents: (a) nBuLi, THF, (–78°C), then DMF;
(b) MCPBA (25°C), then KOH; (c) N,N-dimethylaniline (180°C);
(d) CH3I, K2CO3, acetone.
reactions and shorten the synthesis by going directly from 7
to the resorcinol 20 and hence to dillapiol. Direct o-hydro-
xylation of 7 using H2O2–AlCl3 according to Kurz and John-
son (9) or by use of oxygen and copper metal in the
presence of CuCl2 as developed by Capdevielle and Maumy
(10) was unsuccessful and gave mainly recovered 7.
In the second synthesis, Scheme 2, the MOM-protected
sesamol 11 was o-metallated (11) and treated with DMF to
produce the aldehyde 12 in 85% yield. The protection of
phenol as a THP derivative, thus avoiding the rather expen-
sive MOM-chloride, was not possible since reaction of 6
with dihydopyran in the presence of acid resulted in the in-
troduction of the THP unit at C6 via an electrophile aro-
matic substitution to afford 16 rather than the desired phenol
protection.
Baeyer–Villiger oxidation followed by basic hydrolysis af-
forded phenol 13 which was methylated to give 14. Removal
of the MOM group set the stage for alkylation and subse-
quent Claisen rearrangement to afford phenol 15,
methylation of which gave dillapiol 1. The overall yield of
dillapiol via Scheme 2 was 19%.
rangement of 19 at 190°C afforded the resorcinol 20 which
was methylated to dillapiol. The overall yield of dillaiol
from sesamol via Scheme 3 is 31%.
Synthesis of dillapiol analogues
After this synthesis was completed we realized that one
might be able to avoid the protection–deprotection sequence
if ortho-directed metallation and subsequent introduction of
the formyl group could be carried out on the allyl ether 17 to
give 18. The conversion of 18 to dillapiol would require first
a Baeyer–Villiger reaction and hydrolysis to the resorcinol
19 and then double methylation to dillapiol. Such a sequence
would save three steps from the synthesis shown in
Scheme 2.
We were concerned that 17 would undergo a 1,2-Wittig
rearrangement rather than the directed ortho-metallation.
Fortunately, this fear was unfounded and reaction of 17 with
1 equiv. of nBuli followed addition of DMF gave 18 in 87%
isolated yield. Conversion to 19 was successful upon stirring
with MCPBA at 0°C for 24 h. The reduced nucleophilicity
of the double bond in 18 relative to 9 allows the Baeyer–
Villiger reaction to proceed without competition from the
epoxidation of the allyl ether. The intermediate formate ester
was hydrolyzed to 19 without purification. Claisen rear-
Several of the intermediates in Schemes 1 and 2 were suit-
able for the preparation of dillapiol analogues. These com-
pounds have been evaluated for their ability to synergize the
insecticidal property of α-terthienyl when determined in the
presence of light (12). For example, ortho-metalation of the
MOM-protected sesamol 11, followed by treatment with
dimethyl disulfide afforded the S-methyl derivative 21 in
91% yield. This compound was converted via 22a into the 3-
thiomethyl analog of dillapiol 23a in four steps in 48% over-
all yield. Oxidation afforded the sulfoxide and sulfone
analogs 24a and 25a, respectively (Scheme 4). A number of
other sulfide, sulfoxide, and sulfone analogs were also pre-
pared in a similar manner simply by replacing dimethyl
disulfide with other disulfides (Scheme 4). Surprisingly, re-
action of the ortho-lithiated allyl ether with dimethyl
disulfide was not nearly as efficient as reaction with DMF
and afforded only about 55% of the desired product. In addi-
tion, a significant amount of a by-product which was diffi-
cult to separate from the desired product was obtained. The
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Can. J. Chem. Vol. 78, 2000
Scheme 4. Reagents: (a) nBuLi, THF, (–78°C), then RSSR; (b) Hcl–MeOH–NaI; (c) allyl bromide – K2CO3 – acetone; (d) N,N-
dimethylaniline (180°C); (e) CH3I–K2CO3–acetone; ( f ) MCPBA (1.1 equiv.); (g) MCPBA (2.2 equiv.).
by-product has not been identified and this route to sulfur
analogues of dillapiol was not pursued further.
The aldehydes 8 and 9 served as a source of a number of
derivatives. Thus, reduction of 8 with NaBH4, or reaction
with n-octylmagnesium iodide, gave the derivatives 26 and
27, respectively.
Similarly, the methoxyaldehyde 9 was reduced to 28, or
converted to 29 upon addition of n-octylmagnesium bro-
mide. Reaction of 9 with methyl (triphenylphosphoranylidene)
acetate resulted in formation of the unsaturated ester 30. The
1H NMR of both 27 and 29 show nonequivalence of each of
the methylene hydrogens both α and β to the chiral benzylic
center. The β methylene hydrogen nonequivalence is some-
what surprising and may be due to a combination of both
steric crowding and intramolecular hydrogen bonding result-
ing in a preferred conformation in which each of these sets
of geminal hydrogens continue to show nonequivalence.
The use of the phenol 10 allowed us to generate ethers
such as 31 and thereby test how increased lipophilicity rela-
tive to dillapiol affects the synergism of these compounds.
Qualitatively, only a few derivatives showed activity compa-
rable to or greater than dillapiol. The most active derivative
was the cinnamate ester 30 with a synergism factor 30%
higher than dillapiol. In the sulfur series the sulfides showed
synergism effects of approximately 1.1–1.3, relative to
dillapiol equals. In contrast the corresponding sulfoxides and
sulfones had effects which were approximately 40–60% of
that observed for dillapiol.
Experimental
General comments
1
Unless stated otherwise, H NMR were obtained at 200 or
500 MHz, and 13C NMR spectra at 125 MHz. Solvents used
in reactions were distilled prior to use. BuLi was purchased
from Aldrich as
a
hexane solution and titrated
[diphenylacetic acid] prior to use. Usual work-up refers to
partitioning of the reaction mixture between an organic sol-
vent such as ether, ethyl acetate, or dichloromethane and wa-
ter or 5% NH4Cl solution, drying of the organic phase with
anhydrous MgSO4, and evaporating the solvents at reduced
pressure. Yields, unless indicated otherwise, refer to
chromatograpically pure fractions.
Biological results
Detailed SAR studies of the compounds described in this
paper and a number of other analogs as synergists for the
light α-terthienyl (α-T) is being published elsewhere (12).
© 2000 NRC Canada

Majerus et al.
1349
101.7, 115.9, 125.2, 132.7, 133.5, 137.0, 141.1, 144.9.
HRMS calcd. for C11H12O4: 208.0736; found: 208.0740.
5-Hydroxy-6-(2-propenyl)-1,3-benzodioxole (7)
This compound was prepared in 81% overall yield follow-
ing the procedure of Grubbs et al. (13). Melting point 74–
76°C, lit. (13) mp 74–76°C.
4,5-Dimethoxy-6-(2-propenyl)-1,3-benzodioxole)(dillapiol)
(1)
4-Formyl-5-hydroxy-6-(2-propenyl)-1,3-benzodioxole (8)
Paraformaldehyde (0.56 g, 18.5 mmol) was added to tolu-
ene (5.6 mL) containing 1.5 g (8.4 mmol) of 7, 0.1 mL
(0.84 mmol) of tin tetrachloride, and 0.8 mL (3.37 mmol) of
tri-n-butylamine. The resulting yellow solution was heated
8 h at 100°C, then cooled, acidified with 2 N HCl to pH 2,
and extracted with ether. Purification by silica gel chroma-
tography (1:1, hexane :CH2Cl2) afforded 1.05 g (60%) of 8
as a bright yellow solid, mp 68–70°C. IR (cm–1): 1658,
A mixture of 10 (100 mg, 0.48 mmol), CH3I (0.28 mL),
and K2CO3 (0.1 g) was stirred at rt for 72 h. The solvent was
evaporated. Usual work-up afforded, after chromatography
(5:1, hexane:EtOAc), 80 mg (78%) of dillapiol. The physical
and spectroscopic properties were identical to those of the
commercial material.
5-(Methoxymethoxy)-1,3-benzodioxole (11)
To a solution of sesamol (5.0 g, 36.2 mmol) in 20 mL of
dry THF at 0°C was added 1 equiv. of BuLi (16.5 mL, 2.2 M).
The reaction mixture was stirred for 30 min and then 1.5 equiv.
of chloromethyl methyl ether (4.4 g, 4.1 mL) was added.
The resulting mixture was stirred at rt for 24 h and then
quenched with 10 mL of saturated NH4Cl. The usual work-
up gave 6.5 g (98%) of 11 as a colorless liquid. The product
was used as such. EI–MS (m/z, %): 182 (M+., 100), 152
1
3215. H NMR δ: 3.27–3.29 (m, 2H), 5.03–5.07 (m, 2H),
5.86–5.94 (m, 1H), 6.00 (s, 2H), 6.87 (s, 1H), 10.09 (s, 1H),
10.65 (s, 1H). 13C NMR δ: 32.8, 102.5, 106.7, 116.0, 117.6,
119.0, 136.1, 140.1, 148.5, 152.3, 191.3. HRMS calcd. for
C11H10O4: 206.0579; found: 206.0568.
4-Formyl-5-methoxy-6-(2-propenyl)-1,3-benzodioxole (9)
Potassium carbonate (1.31 g, 9.45 mmol) and methyl io-
dide (3.92 mL, 63.0 mmol) were added sequentially to a so-
lution of aldehyde 8 (1.30 g, 6.30 mmol) in acetone
(10 mL). The resulting solution was allowed to stir at rt for
48 h, after which time the solvent was evaporated under re-
duced pressure. The remaining K2CO3 was dissolved in wa-
ter and the aqueous phase extracted with ether (3 × 15 mL).
Chromatography (5:1, hexane:EtOAc) of the crude product
gave 1.35 g (97%) of 9 as a pale yellow solid, mp 101–
1
(75), 137 (30). H NMR δ: 3.47 (s, 3H), 5.08 (s, 2H), 5.91
(s, 2H), 6.49 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 6.62 (d, 1H, J =
2.2 Hz), 6.70 (d, 1H, J = 8.4 Hz). 13C NMR δ: 55.9, 95.5,
99.7, 101.2, 108.0, 108.4, 142.5, 148.1, 152.5. HRMS calcd.
for C9H10O4: 182.0579; found: 182.05830.
4-Formyl-5-(methoxymethoxy)-1,3-benzodioxole (12)
BuLi (12.5 mL, 2.2 M) was added to a solution of 5.0 g
(27.5 mmol) of 11 in dry THF (20 mL) at 0°C. The reaction
mixture was stirred for 30 min and 1.5 equiv. of DMF
(3.00 g, 3.18 mL) was added. The resulting mixture was
stirred at room temperature for 4 h and quenched with
10 mL of NH4Cl solution. Work-up gave the crude product
as an orange powder. Purification by flash column chroma-
tography (3:1, hexane:ethyl acetate) gave 12 as pale yellow
crystals (4.9 g, 85%), mp 85–87°C. EI–MS (m/z, %): 210
1
102°C. H NMR δ: 3.32 (dt, 2H, J = 6.4, 1.5 Hz), 3.77 (s,
3H), 5.03–5.08 (m, 2H), 5.86–5.91 (m, 1H), 6.05 (s, 2H),
6.83 (s, 1H), 10.23 (s, 1H). 13C NMR δ: 33.0, 64.1, 102.9,
114.2, 114.7, 116.4, 125.7, 136.5, 144.9, 146.9, 153.6,
188.1. IR (cm–1): 1689. HRMS calcd. for C12H12O4:
220.0736; found: 220.0754.
4-Hydroxy-5-methoxy-6-(2-propenyl)-1,3-benzodioxole
(10)
1
(M+., 92), 178 (53), 164 (82). IR (cm–1): 1687. H NMR δ:
3.48 (s, 3H), 5.17 (s, 2H), 6.09 (s, 2H), 6.58 (d, 1H, J =
8.6 Hz), 6.86 (d, 1H, J = 8.6 Hz), 10.35 (s, 1H). 13C NMR δ:
56.4, 95.7, 102.9, 106.4, 111.7, 113.1, 143.4, 148.1, 153.6,
188.0. HRMS calcd. for C10H10O5: 210.0528; found:
210.05317.
To a cooled (0°C) solution of aldehyde 9 (210 mg,
0.95 mmol) in dry CHCl3 (6 mL) was added in one portion
MCPBA (0.30 g, 0.95 mmol, 55%). After 18 h, the reaction
mixture was allowed to reach rt and washed with sodium
sulfite (sat., 2 × 10 mL), sodium bicarbonate (sat., 1 × 10 mL),
and water (1 × 10 mL). The extract was dried over Na2SO4,
filtered and evaporated to dryness. The resulting oily residue
was purified by flash chromatography (3:1, Hex:EtOAc) to
give the formyl derivative of 10 as a colorless oil (160 mg,
71%). IR (cm–1): 1759. 1H NMR δ: 3.32 (d, 2H, J = 6.5 Hz),
3.69 (s, 3H), 5.03–5.06 (m, 2H), 5.86–5.93 (m, 1H), 5.94 (s,
2H), 6.56 (s, 1H), 8.26 (s, 1H). 13C NMR δ: 33.6, 61.8,
102.3, 107.0, 116.1, 126.3, 126.8, 136.8, 144.6, 144.8, 157.9.
HRMS calcd. for C12H12O5: 236.0685; found: 236.0690.
To a solution of the above formyl derivative (250 mg,
1.06 mmol) in THF (9 mL) was added 1 mL of a 3 N NaOH
solution. The resulting homogeneous solution was stirred at
rt for 1 h and diluted with brine. Usual work-up gave 10
(180 mg, 82%) as a pale yellow solid, mp 61–63°C. IR (cm–
4-Hydroxy-5-(methoxymethoxy)-1,3-benzodioxole (13)
MCPBA (5.30 g, 30.7 mmol) was added in one portion to
a solution of aldehyde 12 (3.00 g, 14. 3 mmol) in dry CHCl3
(25 mL) at 0°C. The reaction mixture was warmed up to rt
and stirred for 24 h, washed with sodium sulfite solution
(sat., 2 × 15 mL), sodium bicarbonate (sat., 2 × 20 mL), and
water (2 × 20 mL). The extract was dried over anhyd.
MgSO4, filtered, and evaporated to dryness. The resulting
oily residue was purified by flash column chromatography
(5:1, hexane:ethyl acetate) affording the expected formate
ester as a pale yellow liquid (2.76 g, 91%). EI–MS (m/z, %):
1
226 (M+., 6), 45 (100). IR (cm–1): 1752. H NMR δ: 3.45 (s,
3H), 5.06 (s, 2H), 5.96 (s, 2H), 6.64 (d, 1H, J = 8.6 Hz),
6.62 (d, 1H, J = 8.6 Hz), 8.24 (s, 1H). 13C NMR δ: 56.2,
96.2, 102.3, 105.5, 108.5, 124.1, 139.8, 143.9, 144.6, 157.7.
HRMS calcd. for C11H10O6: 226.077; found: 226.04806.
1
1): 3523. H NMR δ: 3.31 (dt, 2H, J = 6.5, 1.4 Hz), 3.73 (s,
3H), 5.03–5.07 (m, 2H), 5.50 (s, 1H), 5.87–5.93 (m, 1H),
5.90 (s, 2H), 6.25 (s, 1H). 13C NMR δ: 33.6, 61.8, 101.0,
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Can. J. Chem. Vol. 78, 2000
To the above compound (20 mg, 0.94 mmol) in 5 mL of
extract was acidified with conc. HCl and extracted with
ether (3 × 15 mL). The crude residue obtained after work-up
was purified by flash column chromatography (9:1, hex-
ane:ethyl acetate) to give 15 as pale yellowish liquid
(400 mg, 87%). EI–MS (m/z,%): 208 (M+., 100). IR (cm–1):
THF was added 25% NaOH solution (2 mL). The reaction
mixture was stirred for 4 h at rt and extracted with water
(4 × 5 mL). The resulting oily residue, obtained after usual
work-up was purified using flash chromatography (9:1, hex-
ane:ethyl acetate). Phenol 13 was obtained as a pale yellow
liquid, (11 mg, 59%). EI–MS (m/z, %): 198 (M+., 100), 166
1
926, 987. H NMR δ: 3.30 (d, 2H, J = 6.6 Hz), 4.03 (s, 3H),
5.00–5.11 (m, 2H), 5.43 (s, 1H), 5.84 (s, 2H), 5.85–6.02 (m,
1H), 6.33 (s, 1H). 13C NMR δ: 33.7, 59.9, 100.9, 102.8,
115.4, 117.5, 131.1, 143.2, 136.7, 139.9, 141.6. HRMS
calcd. for C11H12O4: 208.0736; found: 208.0731.
1
(29), 153 (33). IR (cm–1): 3540. H NMR δ: 3.51 (s, 3H),
5.07 (s, 2H), 5.92 (s, 1H), 6.20 (s, 1H), 6.30 (d, 1H, J =
8.4 Hz), 6.54 (d, 1H, J = 8.4 Hz, the OH proton was not
located). 13C NMR δ: 56.5, 97.6, 99.2, 101.7, 109.4, 132.3,
134.5, 141.5, 144.5. HRMS calcd. for C9H10O5: 198.0528;
found: 198.05296.
4,5-Dimethoxy-6-(2-propenyl)-1,3-benzodioxole (1)
The phenol 15 (140 mg, 0.70 mmol), K2CO3 (140 mg,
0.10 mmol), and 0.50 mL (0.8 mmol) of methyl iodide was
reacted in 5 mL of acetone as with 9. Work-up and chroma-
tography gave 130 mg (80%) of 1.
5-Hydroxy-4-methoxy-1,3-benzodioxole (14)
Phenol 13 (4.9 g, 24.7 mmol) was O-methylated following
the procedure for formation of 9. The yield of 4-methoxy-5-
methoxymethyl-1,3-benzodioxole, a pale yellow liquid, was
5.05 g, (96%). EI–MS (m/z, %): 212 (M+., 100), 182 (89),
5-Allyloxy-4-formyl-1,3-benzodioxole (18)
1
167 (69). H NMR δ: 3.49 (s, 3H), 3.99 (s, 3H), 5.08 (s,
To a solution of compound 17 (0.3 g, 1.68 mmol) in
anhyd. THF (5 mL), n-BuLi (1.35 mL, 2.01 mmol, 1.5 mo-
lar solution in hexane) was added dropwise at 78°C. The re-
sulting yellow solution was allowed to stir for 45 min and
then N,N-dimethylformamide (0.26 mL, 3.37 mmol) was
added. After 30 min, the reaction mixture was quenched
with sat. NH4Cl solution and extracted with ether. Flash col-
umn chromatography of the crude ether extracts using ethyl
acetate:hexane (1:5) furnished the aldehyde 18 (302 mg,
2H), 5.88 (s, 2H), 6.41 (d, 1H, J = 8.4 Hz), 6.57 (d, 1H, J =
8.6 Hz). 13C NMR δ: 56.1, 60.1, 96.6, 101.2, 101.4, 110.1,
135.4, 137.7, 144.1, 144.2. HRMS calcd. for C10H12O5:
212.0685; found: 212.0709.
The above compound (4.86 g, 22.9 mmol) in acetone
(15 mL) containing 5.15 g, (34.3 mmol) of NaI was stirred
for 30 min. 3 N Methanol HCl (40 mL) was added and the
resulting reaction mixture stirred for 4 h. Most of the solvent
was evaporated and the crude residue dissolved in water
(10 mL). The aqueous phase was extracted with ether (3 ×
15 mL) and the combined organic extracts were then washed
with 10% NaOH solution (3 × 15 mL). The combined aque-
ous phase was acidified using conc. HCl and extracted with
ether (3 × 20 mL). Further work-up afforded 2.81 g (73%)
of 14 as pale orange crystals, mp 53–55°C. EI–MS (m/z, %):
1
87%) as a yellow solid, mp = 98–100°C. H NMR: δ 4.52
(m, 2H), 5.25 – 5.34 (m, 2 H), 6.04 (s, 2H), 5.81–6.11 (m,
1H), 6.27 (d, 1H, J = 8.6 Hz), 6.83 (d, 1H, J = 8.5 Hz),
10.37 (s, 1H). 13C NMR δ: 70.6, 103.5, 104.2, 111.7, 113.5,
118.5, 133.1, 143.2, 148.9 155.7, 188.8. HRMS calcd. for
C11H10O4: 206.0593; found: 206.0581.
1
168 (M+, 100), 153 (76). IR (cm–1): 3541. H NMR δ: 4.02
(s, 3H), 5.43 (s, 1H), 5.87 (s, 2H), 6.39 (s, 2H). 13C NMR δ:
59.9, 101.1, 101.8, 105.9, 131.4, 136.2, 142.1, 142.7. HRMS
calcd. for C8H8O4: 168.0422; found: 168.0408.
5-Allyloxy-4-hydroxy-1,3-benzodioxole (19)
To a solution of aldehyde 18 (0.3 g, 1.45 mmol) in dry
chloroform (5 mL) at 0°C, was added in one portion
MCPBA (0.61 g, 1.74 mmol, 50%). The resulting mixture
was stirred at 0°C for 24 h. The mixture was diluted with
chloroform (20 mL) and was washed with sat. sodium sulfite
(1 × 15 mL), sat. sodium bicarbonate solution (1 × 15 mL)
and water (1 × 15 mL). The crude formate ester (0.25 g,
78%) was obtained as an oil and used for the next reaction
5-Hydroxy-4-methoxy-6-(2-propenyl)-1,3-benzodioxole
(15)
A solution of 14 (2.55 g, 15.2 mmol), allyl bromide
(2.0 mL, 23 mmol), and anhyd. K2CO3 (3.15 g, 23 mmol) in
acetone (15 mL) was refluxed for 30 h. The solvent was re-
moved under reduced pressure and the crude residue was
dissolved in 20 mL water and 10 mL of 10% NaOH solu-
tion. Further work-up gave 5-O-allyl-4-methoxy-1,3-benzo-
dioxole as a yellow liquid (2.72 g, 86%). EI–MS (m/z, %):
1
without any further purification. H NMR δ: 4.45 (m, 2H),
5.25 (m, 2 H), 5.96 (s, 2H), 5.95–6.01 (m, 1H), 6.34 (d, 1H,
J = 8.5 Hz), 6.59 (d, 1H, J = 8.5 Hz), 8.24 (s, 1H). To a so-
lution of the ester (0.25 g, 1.13 mmol) in THF (5 mL), was
added 1 mL of a 3 N NaOH solution. The resulting homoge-
neous solution was stirred at rt for 1 h and was extracted
with water (4 × 10 mL). The aqueous phase was then acidi-
fied with 2 N HCl and was extracted with CH2Cl2 (3 ×
20 mL). Further work-up afforded an oily residue. Purifica-
tion by silica gel flash column chromatography using ethyl
acetate–hexane (1:5) as eluent gave 19 (0.15 g, 70%) as a
1
208 (M+., 39), 167 (100). IR (cm–1): 977, 929.; H NMR δ:
3.97 (s, 3H), 4.47 (dt, 2H, J = 5.4 Hz, 1.4 Hz), 5.22 (ddt,
1H, J = 10.5 Hz, 1.6 Hz, 1.4 Hz), 5.35 (ddt, 1H, J =
17.3 Hz, 1.6 Hz, 1.6 Hz), 5.86 (s, 1H), 6.00–6.06 (m, 1H),
6.32 (d, 1H, J = 8.5 Hz), 6.38 (d, 1H, J = 8.5 Hz). 13C NMR
δ: 60.2, 71.2, 101.1, 101.2, 107.2, 117.5, 133.6, 134.9,
138.1, 143.4, 146.2. HRMS calcd. for C11H12O4: 208.0736;
found: 208.0755.
A solution of the above allyl ether (460 mg, 2.0 mmol) in
5 mL N,N-dimethylaniline was heated at 190°C for 2.5 h.
The solution was cooled, diluted with 7 mL of ether, and
washed several times with 10% NaOH solution. The alkaline
1
yellow liquid. H NMR δ: 4.48 (m, 2H), 5.32 (m, 2H), 5.92
(s, 2 H), 5.90–6.10 (m, 1 H), 6.30 (s, 2 H). 13C NMR δ:
71.6, 99.3, 102.3, 105.3, 119.1, 132.2, 133.5, 137.1, 142.8,
144.0. HRMS calcd. for C10H10O4:194.0593; found:
194.0602.
© 2000 NRC Canada

Majerus et al.
1351
5.05 (s, 2H), 5.93 (s, 2H), 6.63 (d, 1H, J = 8.5 Hz), 6.77 (d,
1H, J = 8.5 Hz), 7.08–7.20 (m, 5H). 13C NMR δ: 56.1, 95.7,
101.6, 104.2, 1007.8 08.8, 125.5, 127.1, 128.7, 136.2, 142.5,
150.4, 152.7. HRMS calcd. for C15H14O4S: 290.0613; found:
290.0600.
4,5-Dihydroxy-6-(2-propenyl)-1,3-benzodioxole (20)
A
solution of 19 (0.15 g, 0.77 mmol) in N,N-
dimethylaniline (2 mL) was heated at 190°C for 1 h and then
was allowed to cool to rt The reaction mixture was extracted
into ethyl acetate and was washed with 1 N HCl solution (3
× 10 mL), brine (2 × 10 mL), followed by water (10 mL).
The crude rearranged product was purified via silica gel
flash chromatography using ethyl acetate–hexane (3:7) as
4-(4′-Methoxyphenylthio)-5-methoxymethoxy-1,3-
benzodioxole (21d)
1
eluent to yield 20 (0.12 g, 79%) as a brown syrup. H NMR
Reaction of 420 mg of 11 with 530 mg of p-meth-
oxyphenyl disulfide gave 250 mg (40%) of 21d as white
crystals, mp 82–84°C. EI–MS (m/z, %): 320 (M+, 8.6), 278
(46), 139 (100). 1H NMR δ: 3.34 (s, 3H), 3.69 (s, 3H), 5.03
(s, 2H), 5.88 (s, 2H), 6.56 (d, 1H, J = 8.5 Hz), 6.68 (d, 1H,
J = 8.5 Hz), 6.74 (d, 2H, J = 8.9 Hz), 7.22 (d, 2H, J =
8.9 Hz). 13C NMR δ: 55.0, 55.9, 95.7, 101.4, 106.3, 107.7,
108.1, 114.2, 126.2, 130.7, 142.3, 149.8, 152.3, 158.3. HRMS
calcd. for C16H16O5S: 320.0718; found: 320.0706.
δ: 3.31 (m, 2 H), 5.44 (m, 2H), 5.87 (s, 2H), 5.85–6.02 (m,
1H), 6.22 (s, 1H). 13C NMR δ: 35.4, 101.82, 102.0, 116.7,
118.4, 129.6, 133.4, 137.1, 138.2, 142.6. HRMS calcd. for
C10H10O4: 194.0579; found 194.5965.
4,5-Dimethoxy-6-(2-propenyl)-1,3-benzodioxole (1)
To a solution of 20 (0.02 g, 0.103 mmol) in acetone
(3 mL), was added sequentially potassium carbonate (28 mg,
0.21 mmol), and methyl iodide (0.10 mL, 0.206 mmol). The
resulting reaction mixture was allowed to stirred at rt for
60 h. Solvent was removed under reduced pressure. The
crude product obtained after the usual work-up was purified
by silica gel flash column chromatography using ethyl ace-
tate–hexane (1:5) as eluent to furnish the dillapiol (1)
(18 mg, 82%) as a yellow liquid.
Removal of the MOM group
General procedure
Each MOM derivative 21 was dissolved in a mixture of
acetone and 3 N methanolic HCl containing NaI. The mix-
ture was stirred for about 4 h and most of the solvent was re-
moved under reduced pressure. The residue was partitioned
between ether and 10% NaOH solution. The basic extracts
were acidified and reextracted with ether. The crude prod-
ucts obtained after further work-up were purified by
recrystallization or chromatography.
Reaction of 11 with disulfides
General procedure
nBuLi (1 equiv.) was added to 1 equiv. of 11 in THF at
0°C. After 30 min, 1.5 equiv. of disulfide was added and the
solution was stirred for 1 h. Further work-up followed by sil-
ica gel chro-matography afforded the desired 4-thio deriva-
tives.
5-Hydroxy-4-methylthio-1,3-benzodioxole
From 4.0 g of 21a and 3.94 g of NaI in 15 mL of acetone
and 40 mL of 3 N methanolic HCl was obtained 2.65 g
(80%) of the title compound as a white powder, mp 51–
53°C. EI–MS (m/z, %): 184 (M+, 100), 169 (30). IR (cm–1):
4-Methylthio-5-methoxymethoxy-1,3-benzodioxole (21a)
This reaction was carried out starting with 5.0 g
(27.5 mmol) of 11. The yield of 21a, a pale yellow liquid,
was 5.70 g (91%). EI–MS (m/z, %): 228 (M+, 100), 198
1
3428. H NMR δ: 2.31 (s, 3H), 5.98 (s, 2H), 6.22 (s, 1H),
6.42 (d, 1H, J = 8.4 Hz), 6.69 (d, 1H, J = 8.4 Hz). 13C
NMR δ: 18.0, 101.6, 103.4, 105.4, 109.4, 140.7, 149.3,
151.2. HRMS calcd. for C8H8O3S: 184.0194; found: 184.0163.
1
(63), 182 (17). H NMR δ: 2.41 (s, 3H), 3.47 (s, 3H), 5.92
(s, 2H), 5.11 (s, 2H), 5.92 (s, 2H), 6.52 (d, 1H, J = 8.6 Hz),
6.59 (d, 1H, J = 8.6 Hz). 13C NMR δ: 16.9, 56.1, 95.9,
101.2, 106.7, 107.8, 108.8, 142.3, 148.5, 151.7. HRMS
calcd. for C10H12O4S: 228.0456; found: 228.04679.
5-Hydroxy-4-phenylmethanethio-1,3-benzodioxole
Reaction of 2.51 g of 21b with 1.86 g of NaI in 50 mL of
acetone–methanol–conc. HCl (1:3:1) for 1 h afforded 1.68 g
(91%) of the deprotected phenol as a yellowish oil. EI–MS
(m/z, %): 260 (M+, 36), 169 (8.2), 91 (100). IR (cm–1): 3434.
1H NMR δ: 3.87 (s, 2H), 5.85 (s, 2H), 6.03 (s, 1H), 6.35 (d,
1H, J = 8.4 Hz), 6.68 (d, 1H, J = 8.4 Hz), 7.10–7.25 (m,
5H). 13C NMR δ: 39.3, 101.0, 101.5, 105.3, 109.8, 127.4,
128.4, 128.7, 137.2, 140.4, 149.8, 151.7. HRMS calcd. for
C14H12O3S: 260.0510; found: 260.0512.
4-Phenylmethanethio-5-methoxymethoxy-1,3-
benzodioxole (21b)
From 3.0 g, (16 mmol) of 11 and 5.35 g (22 mmol) of
benzyl disulfide was obtained 2.37 g (58%) of 21b as yellow
oil. EI–MS (m/z, %): 304 (M+, 29), 259 (18), 182 (26), 91
1
(100). H NMR δ: 3.45 (s, 3H), 4.07 (s, 2H), 5.03 (s, 2H),
5.85 (s, 2H), 6.54 (d, 1H, J = 8.5 Hz), 6.63 (d, 1H, J =
8.5 Hz), 7.20 (s, 5H). 13C NMR δ: 38.0, 56.1, 96.0, 101.2,
106.5, 107.4, 107.9, 126.9, 128.1, 128.8, 138.0, 142.2,
149.5, 152.5. HRMS calcd. for C16H16O4S: 304.0792; found:
304.0758.
5-Hydroxy-4-phenylthio-1,3-benzodioxole
Compound 21c (670 mg, 2.3 mmol), 5.2 g of NaI in
10 mL of acetone and 8 mL of 3 N methanolic HCl was
stirred for 1 h. The yield of the title compound, a white pow-
der, mp 119–122°C, was >99%. EI–MS (m/z, %): 246 (M+,
4-Phenylthio-5-methoxymethoxy-1,3-benzodioxole (21c)
Reaction of 1.50 g (8.0 mmol) of 11 (1.5 g, 8.0 mmol)
and 1.80 g (8.0 mmol) of diphenyl disulfide gave 0.67 g
(30%) of 21c as white crystals, mp 67–69°C. EI–MS (m/z, %):
1
100), 162 (23), 140 (49). IR (cm–1): 3441. H NMR δ: 5.96
(s, 2H), 6.18 (s, 1H), 6.52 (d, 1H, J = 8.5 Hz), 6.81 (d, 1H,
J = 8.6 Hz), 7.12–7.26 (m, 5H). 13C NMR δ (ppm): 99.5,
101.9, 105.9, 110.8, 126.5, 127.0, 129.3, 134.2, 141.0,
1
290 (M+, 51), 260 (25), 91 (50). H NMR δ: 3.33 (s, 3H),
© 2000 NRC Canada

1352
Can. J. Chem. Vol. 78, 2000
150.1, 151.9. HRMS calcd. for C13H10O3S: 246.0351; found:
246.0334.
8.5 Hz), 6.75 (d, 1H, J = 8.5 Hz), 7.07–7.22 (m, 5H).
13C NMR δ: 70.3, 101.6, 103.5, 104.9, 108.4, 117.2, 125.4,
127.3, 128.6, 132.8, 136.2, 141.7, 150.5, 145. HRMS calcd.
for C16H14O3S: 286.0664; found: 286.0649.
5-Hydroxy-4-(4′-methoxyphenylthio)-1,3-benzodioxole
Compound 21d (250 mg, 0.78 mmol) in acetone (10 mL)
and 8 mL of 3 N methanolic HCl containing 180 mg NaI
was stirred for 2 h. The yield of the above phenol (mp 82–
83°C) was 180 mg (83%). EI–MS (m/z, %): 276 (M+,100),
5-Allyoxy-4-(4′-methoxyphenylthio)-1,3-benzodioxole
Reaction of the phenol, series d (1.10 g, 4.0 mmol),
anhyd. K2CO3 (0.83 g, 6.0 mmol) and 0.41 mL of allyl bro-
mide in acetone (15 mL) at reflux for 23 h gave 0.96 g
(76%) of the expected product as a clear oil. EI–MS (m/z, %):
1
162 (18), 140 (44). IR (cm–1): 3443. H NMR δ: 3.74 (s,
3H), 5.94 (s, 2H), 6.31 (s, 1H), 6.47 (d, 1H, J = 8.5 Hz),
6.75 (d, 1H, J = 8.4 Hz), 6.79 (d, 1H, J = 6.9 Hz), 7.20 (d,
1H, J = 7.6 Hz). 13C NMR δ: 55.3, 101.5, 101.7, 105.8,
110.4, 114.9, 124.5, 130.4, 140.9, 149.8, 151.6, 159.0. HRMS
calcd. for C14H12O4S: 276.0456; found: 276.0466.
1
316 (M+., 32), 275 (30), 149 (100). IR (cm–1): 931, 953. H
NMR δ: 3.72 (s, 3H), 4.43 (dt, 2H, J = 5.1 Hz, 1.5 Hz), 5.18
(ddt, 1H, J = 12 Hz, 1.6 Hz, 1.5 Hz), 5.31 (ddt, 1H, J =
18 Hz, 1.7 Hz, 1.6 Hz), 5.90 (s, 2H), 5.83–5.97 (m, 1H),
6.30 (d, 1H, J = 8.5 Hz), 6.67 (d, 1H, J = 8.5 Hz), 6.75 (d,
2H, J = 9.0 Hz), 7.26 (d, 2H, J = 9.0 Hz). 13C NMR δ: 55.1,
70.3, 101.4, 104.8, 105.6, 107.8, 114.2, 117.2, 126.3, 131.0,
132.9, 141.6, 149.9, 153.7, 158.4. HRMS calcd. for
C17H16O4S: 316.0770; found: 316.0766.
Allylation of the 4-thio-5-hydroxy derivatives
General procedure
The above phenols were dissolved in acetone containing
about 10–20% excess of anhydrous potassium carbonate.
The mixture was refluxed for up to 24 h. The solvent was
evaporated under reduced pressure and the residue was parti-
tioned between ether and 10% NaOH solution. Further pro-
cessing of the ether phase gave the desired product.
Claisen rearrangement of the 5-allyl ethers
General procedure
The 5-allyl ethers obtained as described above were dis-
solved in a small quantity of N,N-dimethylaniline and heated
to 190°C for 1–3 h. The cooled reaction mixture was diluted
with ether and extracted with 10% NaOH solution. The com-
bined basic extracts were acidified and extracted with ether.
Further work-up and purification yielded the desired Claisen
rearrangement products.
5-Allyoxy-4-methylthio-1,3-benzodioxole
From 1.89 g of 5-hydroxy derivative, series a, 2.13 g of
potassium carbonate and 0.90 mL of allyl bromide in 15 mL
acetone was obtained after 23 h of reflux, 2.03 g (88%) of
the desired product as a clear liquid. EI–MS (m/z, %): 224.1
(M+., 100), 184 (13), 137 (98). 1H NMR δ: 2.46 (s, 1H), 4.53
(dt, 2H, J = 5.1 Hz, 1.4 Hz), 5.28 (dd, 1H, J = 10.5 Hz,
1.5 Hz), 5.44 (dd, 1H, J = 17.0 Hz, 1.6 Hz), 5.97 (s, 2H),
6.00–6.09 (m, 1H), 6.31 (d, 1H, J = 8.5 Hz), 6.63 (d, 1H, J =
8.5 Hz). 13C NMR δ: 16.9, 70.3, 101.2, 104.5, 106.4, 117.4,
133.1, 133.8, 141.5, 148.7, 153.3. HRMS calcd. for
C11H12O3S: 224.0507; found: 224.0533.
5-Hydroxy-4-methylthio-6-(2-propenyl)-1,3-benzodioxole
(22a)
Allyl ether, series a (1.0 g, 4.0 mmol) when heated in
5 mL of N,N-dimethylaniline (5 mL) at 190°C for 2.5 h,
gave 0.87 g (87%)of 22a as a colourless liquid. EI–MS (m/z, %):
224 (M+., 100), 197 (9), 176 (18). IR (cm–1): 927, 953, 3425.
1H NMR δ (ppm): 2.31 (s, 3H), 3.32 (dt, 2H, J = 6.8 Hz,
1.4 Hz), 5.01–5.11 (m, 2H), 5.95 (s, 2H), 5.88–6.02 (m, 1H),
6.40 (s, 1H), 6.62 (s, 1H).13C NMR δ: 18.0, 34.4, 101.3,
102.9, 110.4, 115.5, 117.1, 136.6, 140.3, 147.5, 148.2. HRMS
calcd. for C11H12O3S: 224.0507; found: 224.0493.
5-Allyoxy-4-phenylmethanethio,3-benzodioxole
A solution of the 5-phenol, series b (1.68 g, 6.5 mmol),
anhyd. K2CO3 (1.10 g, 8.0 mmol and 0.63 mL of allyl bro-
mide in 15 mL of acetone when refluxed for 23 h, yielded
1.39 g (83%) of the desired allyl ether as a clear oil. EI–MS
(m/z, %): 300 (M+, 30), 259 (38), 91 (100). IR (cm–1): 953,
5-Hydroxy-4-phenylmethanethio-6-(2-propenyl)-1,3-
benzodioxole (22b)
1
995. H NMR δ: 4.09 (s, 2H), 4.46 (d, 2H, J = 5.1 Hz), 5.27
(dd, 1H, J = 10.5 Hz, 1.5 Hz), 5.43 (dd, 1H, J = 15.6 Hz,
1.6 Hz), 5.84 (s, 2H), 5.95–6.11 (m, 1H), 6.30 (d, 1H, J =
8.4 Hz), 6.62 (d, 1H, J = 9.2 Hz), 7.21 (s, 5H). 13C NMR δ:
37.9, 70.3, 101.1, 104.6, 105.5, 107.1, 117.3, 126.8, 128.1,
128.8, 133.1, 138.0, 141.3, 149.7, 153.9. HRMS calcd. for
C17H16O3S: 300.0821; found: 300.0820.
Allyl ether, series b (4.30 g, 14.0 mmol) when treated as
above gave 0.42 g (98%) of 22b as a colourless oil. EI–MS
(m/z, %): 300 (M+, 48), 224 (91), 209 (28), 176 (48). IR
1
(cm–1): 954, 997, 1638, 3429. H NMR δ: 3.25 (d, 2H, J =
6.4 Hz), 3.87 (s, 2H), 4.93–5.04 (m, 2H), 5.82–5.96 (m, 1H),
5.83 (s, 2H), 6.18 (s, 1H), 6.61 (s, 1H), 7.08–7.25 (m, 5H).
13C NMR δ: 34.4, 39.4, 100.6, 101.2, 10.9, 115.3, 116.9,
127.4, 128.5, 128.7, 136.6, 137.2, 140.1, 148.0, 148.8.
HRMS calcd. for C17H16O3S: 300.0821; found: 300.08240.
5-Allyoxy-4-phenylthio-1,3-benzodioxole
A mixture of phenol, series c (1.62 g, 6.6 mmol), anhyd.
K2CO3 (1.10 g, 8.0 mmol), and 0.63 mL of allyl bromide
when refluxed for 23 h in acetone (15 mL) gave 1.25 g
(84%) of the expected allyl ether. EI–MS (m/z, %): 268
5-Hydroxy-4-phenylthio-6-(2-propenyl)-1,3-benzodioxole
(22c)
From 1.5 g of allyl ether, series c, was obtained 550 mg
(37%) of 22c as a pale yellow oil. EI–MS (m/z, %): 286
(M+, 100), 162 (8). IR (cm–1): 953, 997, 1638, 3443.
1H NMR δ: 3.35 (dt, 2H, J = 6.4 Hz, 1.4 Hz), 5.05–5.09
1
(M+., 52), 245 (52), 91 (100). IR (cm–1): 943, 996. H NMR
δ: 4.44 (dt, 2H, J = 5.0 Hz, 1.6 Hz), 5.15 (ddt, 1H, J =
10.5 Hz, 1.6 Hz, 1.5 Hz), 5.25 (ddt, 1H, J = 17.0 Hz, 1.7 Hz,
1.6 Hz), 5.76–5.95 (m, 1H), 5.93 (s, 2H), 6.35 (d, 1H, J =
© 2000 NRC Canada

Majerus et al.
1353
(m, 2H), 5.92 (s, 2H), 5.93–5.99 (m, 1H), 6.31 (s, 1H), 6.73
(s, 1H), 7.13–7.23 (m, 5H). 13C NMR δ: 34.4, 99.0, 101.5,
111.9, 115.7, 117.6, 126.5, 127.0, 129.3, 134.3, 136.5, 40.6,
148.3, 148.9. HRMS calcd. for C16H14O3S: 286.0664; found:
286.0641.
5-Methoxy-4-(4′-methoxyphenylthio)-6-(2-propenyl)-1,3-
benzodioxole (23d)
Phenol 22d (170 mg) was converted in 96% yield into
23d as a pale yellow oil. EI–MS (m/z, %): 330 (M+., 100),
1
176 (21), 121 (68). IR (cm–1): 949, 995, 1638. H NMR δ:
3.34 (dt, 2H, J = 6.5 Hz, 1.5 Hz), 3.73 (s, 3H), 3.75 (s, 3H),
5.03–5.07 (m, 2H), 5.87 (s, 2H), 5.88–5.94 (m, 1H), 6.63 (s,
1H), 6.77 (d, 2H, J = 8.9 Hz), 7.24 (d, 2H, J = 8.9 Hz).
13C NMR δ: 34.1, 55.2, 62.0, 101.5, 109.7, 109.8, 114.5,
115.9, 126.0, 126.3, 130.7, 137.1, 143.6, 148.1, 152.7,
158.5. HRMS calcd. for C18H18O4S: 330.0926; found:
330.0942.
5-Hydroxy-4-(4′-methoxyphenylthio)-6-(2-propenyl)-1,3-
benzodioxole (22d)
The allyl ether from series d (310 mg, 0.9 mmol) when
heated for 2.5 h in 3 mL of N,N-dimethylaniline gave 0.29 g
(97%) of 22d as pale yellow oil. EI–MS (m/z, %): 316 (M+,
100), 208 (22), 180 (47). IR (cm–1): 949, 995, 1638, 3440.
1H NMR δ: 3.32 (d, 2H, J = 6.5 Hz), 3.74 (s, 3H), 5.02 (s,
1H), 5.05 (d, 2H, J = 6 Hz), 5.91 (s, 2H), 5.89–5.97 (m, 1H),
6.42 (s, 3H), 6.67 (s, 1H), 6.78 (d, 2H, J = 8.7 Hz), 7.19 (d,
2H, J = 8.7 Hz). 13C NMR δ: 34.5, 55.4, 101.1, 101.5, 111.5,
114.9, 115.6, 117.5, 124.7, 130.4, 136.6, 140.6, 148.0, 148.7,
159.0. HRMS calcd. for C17H16O4S: 316.0770; found:
316.0749.
Oxidation of the sulfides (23) to sulfoxides (24) and
sulfones (25)
General procedures
For the oxidation to the sulfoxides, a solution of the sul-
fide in ethyl acetate was cooled to approx. –40°C and 1.2 equiv.
of MCPBA was added. The reaction mixture was allowed to
warm to rt and stirred for 24 h. Work-up consisted of wash-
ing first with sat. sodium bisulfite solution, then with sat.
sodium bicarbonate, and finally with water. The organic sol-
uble product was purified by column chromatography.
The oxidation to sulfones was carried out with 3–4 equiv.
of MCPBA in ethyl acetate at rt for 24 h. The work-up of
the reaction mixture was similar to that of the sulfoxides.
Methylation of phenols (22)
These reactions were carried out in the same manner as
the conversion 8 to 9.
5-Methoxy-4-methylthio-6-(2-propenyl)-1,3-benzodioxole
(23a)
Phenol 22a (400 mg, 1.8 mmol), was converted in 87%
yield (372 mg) to 23a. EI–MS (m/z, %): 238 (M+,100), 223
(13), 176 (41). IR (cm–1): 949, 996. 1H NMR δ: 2.45 (s, 3H),
3.30 (dt, 2H, J = 6.5 Hz, 1.4 Hz), 3.75 (s, 3H), 5.01–5.05
(m, 2H), 5.93 (s, 2H), 5.84–5.92 (m, 1H), 6.53 (s, 1H).
13C NMR δ: 16.9, 34.0, 61.4, 101.3, 108.2, 112.3, 115.7,
125.8, 137.1, 143.4, 146.8, 151.8. HRMS calcd. for
C12H14O3S: 238.0664; found: 238.0682.
5-Methoxy-4-methylsulfinyl-6-(2-propenyl)-1,3-
benzodioxole (24a)
Sulfide 23a (100 mg, 0.42 mmol) was reacted with
0.5 mmol of MCPBA in 6 mL of ethyl acetate to afford
67 mg (63%) of 24a as a pale yellowish liquid. EI–MS (m/z, %):
254 (M+., 83), 237 (100). IR (cm–1): 942, 994, 1050.
1H NMR δ: 3.01 (s, 3H), 3.16 (dd, 2H, J = 6.4 Hz, 1.5 Hz),
3.78 (s, 3H), 5.03–5.09 (m, 2H), 5.84–5.89 (m, 1H), 6.06
(s, 2H), 6.74 (s, 1H). 13C NMR δ: 33.1, 39.7, 63.4, 102.7,
112.3, 116.5, 120.8, 126.1, 136.3, 145.0, 145.5, 149.1.
HRMS calcd. for C12H14O4S: 254.0613; found: 254.0607.
5-Methoxy-4-phenylmethanethio-6-(2-propenyl)-1,3-
benzodioxole (23b)
Phenol 22b (420 mg, 1.4 mmol) was converted into
5-Methoxy-4-methylsulfonyl-6-(2-propenyl)-1,3-
benzodioxole (25a)
0.420 mg (96%) of 23b. EI–MS (m/z, %): 314 (M+., 72), 223
1
(11), 91 (100). IR (cm–1): 950, 994, 1638. H NMR δ: 3.30
Oxidation of 50 mg, (0.21 mmol) of sulfide 23a afforded
45 mg (80%) of sulfone 25a as a pale yellow solid. EI–MS
(m/z, %): 270 (M+., 100). IR (cm–1): 950, 993, 1136, 1316.
1H NMR δ: 3.26 (s, 3H), 3.54 (d, 2H, J = 6.5 Hz), 3.84
(s, 3H), 5.06–5.13 (m, 2H), 5.84–5.92 (m, 1H), 6.05 (s, 2H),
6.83 (s, 1H). 13C NMR δ: 32.1, 44.8, 63.8, 102.8, 113.9,
117.0, 118.1, 127.0, 135.9, 145.0, 145.2, 149.2. HRMS
calcd. for C12H14O5S: 270.0562; found: 270.0541.
(dt, 2H, J = 6.4 Hz, 1.5 Hz), 3.65 (s, 3H), 4.12 (s, 2H),
4.96–5.07 (m, 2H), 5.88 (s, 2H), 5.83–5.95 (m, 1H), 6.55
(s, 1H), 7.17–7.24 (m, 5H). 13C NMR δ: 34.0, 37.9, 61.6,
101.3, 108.9, 109.9, 115.7, 125.7, 127.0, 128.3, 128.9,
137.2, 138.0, 43.2, 147.6, 152.5. HRMS calcd. for
C18H18O3S: 314.0977; found: 314.0953.
5-Methoxy-4-phenylthio-6-(2-propenyl)-1,3-benzodioxole
(23c)
5-Methoxy-4-phenylmethanesulfinyl-6-(2-propenyl)-1,3-
benzodioxole (24b)
The title compound 23c was obtained as a yellowish oil in
87% yield starting with 550 mg of 22c. EI–MS (m/z, %):
300 (M+., 100), 176 (48), 162 (15). IR (cm–1): 948, 995,
From 110 mg, (0.4 mmol) of 23b was obtained 70 mg
(61%) of sulfoxide 24b as a yellowish oil. EI–MS (m/z, %):
330 (M+., 21), 283 (47), 91 (100). IR (cm–1): 951, 992, 1049,
1
1639. H NMR δ: 3.35 (dt, 2H, J = 6.4 Hz, 1.4 Hz), 3.73 (s,
1
3H), 5.02–5.11 (m, 2H), 5.91 (s, 2H), 5.86–6.05 (m, 1H),
6.71 (s, 1H), 7.10–7.22 (m, 5H). 13C NMR δ: 34.2, 62.2,
101.6, 107.6, 110.4, 116.0, 125.6, 126.2, 127.1, 128.9,
136.2, 137.1, 143.7, 148.6, 153.2. HRMS calcd. for
C17H16O3S: 300.0821; found: 300.0802.
1071. H NMR (500 MHz) δ: 3.24 (d, 2H, J = 6.3 Hz), 3.56
(s, 3H), 4.34 (d, 1H, J = 12.5 Hz), 4.45 (d, 1H, J = 12.5 Hz),
5.00–5.06 (m, 2H), 5.82 (d, 1H, J = 1.34), 5.90 (d, 1H, J =
1.4 Hz), 5.81–5.87 (m, 1H), 6.67 (s, 1H), 7.10–7.24 (m, 5H).
13C NMR δ: 33.0, 59.2, 63.0, 102.6, 112.3, 116.3, 118.6,
© 2000 NRC Canada

1354
Can. J. Chem. Vol. 78, 2000
125.8, 128.1, 128.4, 130.2, 130.3, 136.4, 145.2, 145.8,
149.4. HRMS calcd. for C18H18O4S: 330.0926; found:
330.0910.
3H), 4.99–5.07 (m, 2H), 5.75–5.83 (m, 1H), 6.05 (s, 2H),
6.92 (s, 1H), 6.84 (d, 2H, J = 8.9 Hz), 7.93 (d, 2H, J =
8.9 Hz). 13C NMR δ: 33.1, 55.5, 63.6, 102.7, 113.7, 113.9,
116.9, 126.9, 129.8, 134.4, 136.0, 144.9, 145.1, 149.2,
163.4. HRMS calcd. for C18H18O6S: 362.0824; found:
362.0821.
5-Methoxy-4-phenylmethanesulfonyl-6-(2-propenyl)-1,3-
benzodioxole (25b)
Oxidation of 80 mg (0.25 mmol) of sulfide 23b in 6 mL
of ethyl acetate gave 40 mg (45%) of sulfone 25b as a white
solid, mp 133–136°C. EI–MS (m/z, %): 346 (M+., 34), 139
5-Hydroxy-4-hydroxymethyl-6-(2-propenyl)-1,3-
benzodioxole (26)
To a solution of the aldehyde 8 (238 mg, 1.15 mmol) in
2.5 mL of ethanol was added 44 mg of sodium borohydride.
The solution was stirred for 40 min, diluted with 2 mL of
water, and then acidified with 2 N HCl. Work-up afforded
1
(16), 91 (100). IR (cm–1): 1149, 1320. H NMR δ: 3.35 (d,
2H, J = 6.4 Hz), 3.88 (s, 3H), 4.57 (s, 2H), 5.05–5.15 (m,
2H), 5.82 (s, 2H), 5.88–5.93 (m, 1H), 6.77 (s, 1H), 7.20–
7.24 (m, 5H). 13C NMR δ: 33.2, 62.2, 63.9, 102.6, 114.1,
116.8, 126.7, 128.1, 128.3, 128.5, 130.9, 133.9, 144.9,
146.3, 1494. HRMS calcd. for C18H18O5S: 346.0875; found:
346.0852.
256 mg of crude product which was purified by chromatog
-
raphy to yield 198 mg (83%) of 26 as a white solid, mp 82–
84°C. EI–MS (m/z, %): 208 (M+., 26), 190 (100), 189 (50).
1
IR (cm–1): 3404, 3587. H NMR δ: 2.55 (s, 1H), 3.28 (dt, J
= 6.5, 1.4 Hz), 4.81 (s, 2H), 5.05–5.10 (m, 2H), 5.83 (s,
2H), 5.91–5.96 (m, 1H), 6.53 (s, 1H), 6.85 (s, 1H). 13C
NMR δ: 34.2, 57.8, 101.0, 108.9, 115.7, 118.3, 136.9, 140.4,
143.3, 148.8. HRMS calcd. for C11H12O4: 208.0736; found:
208.0736.
5-Methoxy-4-lphenylsulfinyl-6-(2-propenyl)-1,3-
benzodioxole (24c)
Sulfide 23c (100 mg, 0.30 mmol) was oxidized to
sulfoxide 24c, mp 83–87°C, in 76% yield. EI–MS (m/z, %):
316 (M+., 39), 299 (100), 190 (59). IR (cm–1): 948, 994,
1
1054,1639. H NMR δ: 3.29 (d, 2H, J = 6.4 Hz), 3.85 (s,
3H), 5.00–5.07 (m, 2H), 5.82 (s, 1H), 5.82–5.88 (m, 1H),
5.97 (s, 1H), 6.68 (s, 1H), 7.24–7.71 (m, 5H). 13C NMR δ:
33.0, 63.2, 102.6, 112.4, 116.5, 124.3, 125.8, 128.8, 130.3,
136.2, 143.8, 145.4. HRMS calcd. for C17H16O4S: 316.0770;
found: 316.0766.
5-Hydroxy-4-(1-hydroxyoctyl)-6-(2-propenyl)-1,3-
benzodioxole (27)
A solution of 300 mg (1.45 mmol) of aldehyde 8 in 2 mL
of ether was added to a freshly prepared solution (approx.
3 mmol) of n-octylmagnesium bromide in 3 mL of ether.
The reaction mixture was refluxed for 45 min and quenched
with sat. NH4Cl solution. Work-up afforded 108 mg (25%)
of 27, mp 91–93°C. EI–MS: (m/z, %): 320 (M+.-H2O, 100),
191 (53). IR (cm–1): 3372, 3586. 1H NMR δ: 0.86 (t, 3H, J =
6.7 Hz), 1.24–1.33 (m, 11H), 1.41–1.46 (m, 1H), 1.75–1.81
(m, 1H), 1.85–1.91 (m, 1H), 2.54 (s, 1H), 3.23–3.33 (m,
2H), 5.02–5.07 (m, 3H), 5.79 (d, 1H, J= 1.3 Hz), 5.83 (d,
1H, J = 1.4 Hz), 5.91–5.99 (m, 1H), 6.52 (s, 1H), 7.65 (d,
1H, J = 4.5 Hz). 13C NMR δ: 14.1, 22.6, 25.5, 29.2, 29.3,
29.5, 31.8, 33.9, 36.6, 70.4, 100.8, 108.4, 111.4, 115.4,
119.0, 137.1, 139.8, 142.6, 147.8. HRMS calcd. for
C19H28O4: 320.1998; found: 320.1998.
5-Methoxy-4-phenylsulfonyl-6-(2-propenyl)-1,3-
benzodioxole (25c)
Oxidation of 90 mg (0.21 mmol) of sulfide 23c in ethyl
acetate (6 mL) with 2 equiv. of MCPBA for 24 h provided
the sulfone 25c as a white solid, mp 86–88°C, in 71% yield.
EI–MS (m/z, %): 332 (M+., 100), 176 (34). IR (cm–1): 992,
1
953, 1148, 1319. H NMR δ: 3.23 (dt, 2H, J = 6.4 Hz,
1.5 Hz), 3.80 (s, 3H), 5.03–5.07 (m, 2H), 5.77–5.82 (m, 1H),
6.08 (s, 2H), 6.78 (s, 1H), 7.41–7.57 (m, 5H). 13C NMR δ:
33.0, 63.6, 102.8, 114.0, 116.9, 118.7, 126.9, 127.5, 128.7,
133.2, 136.0, 142.6, 145.0, 145.4, 149.3. HRMS calcd. for
C17H16O5S: 332.0719; found: 332.0699.
4-Hydroxymethyl-5-methoxy-6-(2-propenyl)-1,3-
benzodioxole (28)
5-Methoxy-4-(4′-methoxyphenylsulfinyl)-6-(2-propenyl)-
1,3-benzodioxole (24d)
The aldehyde 9 (350 mg) was reduced with NaBH4 fol-
lowing the procedure for 8 to give 28 as an oil in 75% puri-
Sulfide 23d (140 mg) was oxidized to give 100 mg (68%)
of sulfoxide 25c as a pale yellow oil. EI–MS (m/z, %): 330
(M+., 60), 190 (28), 121 (100). IR (cm–1): 949,
993,1044,1639. 1H NMR δ: 3.27 (dt, 2H, J = 6.4 Hz,
1.4 Hz), 3.77 (s, 3H), 3.82 (s, 3H), 4.99–5.06 (m, 2H), 5.81–
5.84 (m, 1H), 5.87 (s, 1H), 5.98 (s, 1H), 6.66 (s, 1H), 6.92
(d, 2H, J = 8.9 Hz), 7.64 (d, 2H, J = 8.9 Hz). 13C NMR δ:
33.1, 55.4, 63.2, 102.6, 112.1, 114.4, 116.5, 122.1, 125.9,
126.4, 135.4, 136.4, 144.7, 145.5, 149.2, 161.5. HRMS
calcd. for C18H18O5S: 346.0875; found: 346.0875.
1
fied yield. IR (cm–1): 3598. H NMR δ: 2.45 (s, 1H), 3.30
(dt, 2H, J = 6.5, 1.4 Hz), 3.72 (s, 3H), 4.68 (s, 2H).
13C NMR δ: 33.6, 55.7, 62.5, 101.4, 108.9, 115.9, 116.4,
125.4, 137.2, 143.7, 144.7, 150. EI–MS (m/z, %): 222 (M+., 100).
HRMS calcd. for C12H14O4: 222.0892; found: 222.0906.
4-(1-Hydroxyoctyl)-5-methoxy-6-(2-propenyl)-1,3-
benzodioxole (29)
This compound was prepared in 68% yield in a manner
similar to the preparation of 27. The yield of 29, a clear yel-
lowish oil, was 65%. EI–MS (m/z, %): 334 (M+., 5), 316
5-Methoxy-4-(4′-methoxyphenylsulfonyl)-6-(2-propenyl)-
1,3-benzodioxole (25d)
1
(100), 190 (42), 43 (75). IR (cm–1): 3588. H NMR δ: 0.84–
Sulfide 23d (90 mg) was oxidized to sulfone 25d, mp 82–
0.87 (m, 3H), 1.24–1.30 (m, 11H), 1.45–1.50 (m, 1H), 1.76–
1.78 (m, 1H), 1.90–1.91 (m, 1H), 3.31 (dd, 2H, J = 6.4,
1.0 Hz), 3.70 (s, 3H), 4.88 (s, 1H), 5.02–5.06 (m, 2H), 5.87–
5.93 (m, 1H), 5.91 (s, 2H), 6.56 (s, 1H). 13C NMR δ: 14.1,
85°C, in 71% yield. EI–MS (m/z, %): 362 (M+., 38), 300
1
(100), 176 (52). IR (cm–1): 953, 992, 1145, 1315. H NMR
δ: 3.22 (dt, 2H, J = 6.4 Hz, 1.4 Hz), 3.80 (s, 3H), 3.81 (s,
© 2000 NRC Canada

Majerus et al.
1355
22.6, 26.1, 29.2, 29.5, 29.7, 31.9, 33.7, 37.6, 62.5, 68.3,
101.3, 108.4, 115.9, 120.8, 125.5, 137.2, 143.6, 143.9,
149.7. HRMS calcd. for C20H30O4: 334.2145; found:
334.2157.
Acknowledgements
Funding was provided by Natural Sciences and Engi-
neering Research Council of Canada (NSERC) (Strategic
Program). S.L. Majerus was the recipient of an NSERC PGS
A scholarship.
Cinnamate ester (30)
Methyl (triphenylphosphoranylidene)acetate (0.16 g,
0.47 mmol) was added to a solution of aldehyde 24
(85.5 mg, 0.39 mmol) in toluene (2 mL) and the mixture
was refluxed for 22 h. After this time, the mixture was
cooled to rt and the solvent was removed under vacuum. Pu-
rification by flash chromatography (5:1, hexane–ethyl ace-
tate) afforded the desired product 30 as a pale yellow solid,
mp 76–78°C, (98.4 mg, 91%). EI–MS (m/z, %): 276 (M+.,
100), 245 (41). IR (cm–1): 1713 1H NMR δ: 3.32 (dt, 2H, J =
6,5, 1.4 Hz), 3.69 (s, 3H), 3.79 (s, 3H), 5.03–5.07 (m, 2H),
5.87–5.93 (m, 1H), 6.00 (s, 2H), 6.66 (s, 1H), 6.78 (d, 1H,
J = 16.3 Hz), 7.81 (d, 1H, J = 16.3 Hz). 13C NMR δ: 33.6,
51.6, 62.7, 101.8, 110.7, 112.3, 116.0, 121.8, 125.5, 135.0,
137.0, 143.9, 145.6, 151.2, 167.9. HRMS calcd. for
C15H16O5: 276.0998; found: 276.0999.
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5-Methoxy-4-octyloxy-6-(2-propenyl)-1,3-benzodioxide (31)
A solution of phenol 10 (88 mg), K2CO3 (90 mg), and
octyl bromide (0.09 mL) in 6 mL of acetone was refluxed
for 64 h. The acetone was evaporated and the residue parti-
tioned between water and ether. The yield of 31, a yellow
oil, was 60%. EI–MS (m/z, %): 320 (M+., 64), 208 (74), 84
1
(62), 49 (100). H NMR δ: 0.87 (t, 3H, J = 6.8 Hz), 1.24–
1.32 (m, 8H), 1.42–1.45 (m,2H), 1.72–1.75 (m, 2H), 3.29
(dt, 2H), J = 6.6, 1.1 Hz), 3.75 (s, 3H), 4.16 (t, 2H, J =
6.7 Hz), 5.00–5.04 (m, 2H), 5.85 (s, 2H), 5.87–5.93 (m, 1H),
6.33 (s, 1H). 13C NMR δ: 14.1, 22.6, 25.8, 29.2, 29.3, 30.1,
31.8, 34.0, 61.2, 72.6, 101.0, 102.7, 115.4, 126.0, 136.3,
136.9, 137.5, 144.4, 144.7. HRMS calcd. for C19H28O4:
320.1988; found: 320.1984.
13. R.H. Grubbs, O. Fu, and G.C. Fu. J. Org. Chem. 59, 4029
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© 2000 NRC Canada