Radical induced fragmentation in a benzoxocane ring system: Application to the synthesis of elvirol and a formal synthesis of 7,8-dihydroxycalamenene

Article abstract of DOI:10.1016/j.tet.2012.05.041

A novel radical induced fragmentation in a benzoxocane ring system has been employed for a synthesis of elvirol 8 and an advanced intermediate in the synthesis of 7,8-dihydroxycalamenene 20. The coumarins 9, 22 were taken through a sequence of reactions t

Full text of DOI:10.1016/j.tet.2012.05.041

Tetrahedron 68 (2012) 6575e6580
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical induced fragmentation in a benzoxocane ring system: application
to the synthesis of elvirol and a formal synthesis of 7,8-dihydroxycalamenene
,
Amalesh Roy a, Kazi Tuhina b, Bidyut Biswas a, Ramanathapuram V. Venkateswaran a
*
a Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kollkata 700 032, India
b Department of Chemistry, B.S. College, S-24 P.G.S., Canning 743329, WB, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel radical induced fragmentation in a benzoxocane ring system has been employed for a synthesis
of elvirol 8 and an advanced intermediate in the synthesis of 7,8-dihydroxycalamenene 20. The cou-
marins 9, 22 were taken through a sequence of reactions to the benzoxocanols 16, 30, which when
subjected to Barton’s deoxygenation conditions involving conversion to the corresponding thionocar-
bonates 17, 31 followed by exposure to tri-n-butyltin hydride, underwent a radical induced fragmenta-
tion to furnish elvirol 8 and the curcuphenol derivative 32, which was converted to the dimethoxy
Received 8 February 2012
Received in revised form 7 May 2012
Accepted 10 May 2012
Available online 29 May 2012
Keywords:
compound 33. This had served as an advanced intermediate in
a previous synthesis of
Barton deoxygenation
Radical induced fragmentation
Elvirol
dihydroxycalamenene.
Ó 2012 Elsevier Ltd. All rights reserved.
7,8-Dihydroxycalamenene
1. Introduction
induced fragmentation in a strategically placed oxygenated ring
system where the generated radical undergoes fragmentation
resulting in a phenoxy radical (Scheme 1).
During the last three decades, radical induced carbonecarbon
bond formation processes have revolutionised preparative organic
synthesis.1 This has resulted in the development of novel meth-
odologies with vast potential in the synthesis of complex natural
products. An important but still somewhat less well-exploited area
of radical chemistry is the radical induced bond cleavage processes
in cyclic systems. Such cleavages have been encountered in car-
bocyclic systems and their utility demonstrated by application to
generate complex carbocyclic frameworks towards natural product
synthesis.2 There have been only limited examples of similar
fragmentations extending to heterocyclic systems and these have
been only in the cases of epoxides.3
HO
OH
S
O
1
nBu3SnH,
AIBN
CS2, NaH,
MeI,THF
R
R
R
OH
OH
O
SMe
O
O
4 R = H
5 R = OMe
6 R = H
2 R = H
7 R = OMe
3 R = OMe
Scheme 1. Radical induced fragmentation.
In connection with our synthesis of heliannuol A 1 the primary
constituent of allelochemicals from cultiver sun flowers, we had
disclosed the first case of a radical induced fragmentation in
a benzoxocane system.4 This arose out of our efforts to carry out
a deoxygenation of an alcohol employing the celebrated Bar-
toneMcCombie reaction.5 Thus, the heliannuol derivatives 2 and 3
on conversion to the corresponding thionocarbonates 4 and 5 fol-
lowed by exposure to radical formation conditions resulted in the
heterocyclic ring cleavage to furnish the curcuphenols 6 and 7, re-
spectively. Formation of curcuphenols represented a novel radical
To demonstrate further the utility of this fragmentation process,
we have applied the sequence of reactions to a synthesis of elvirol 8
and a formal synthesis of 7,8-dihydroxycalamenene 20 and the
details are presented below.
2. Results and discussion
2.1. Synthesis of elvirol
Elvirol 8 is a bisabolene sesquiterpene metabolite, isolated from
Elvira biflora.6 Although 8 has been assigned a terpenoid basis, it is
* Corresponding author. E-mail addresses: ocrvv@iacs.res.in, ocrvv@mahen-
dra.iacs.res.in (R.V. Venkateswaran).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.041

6576
A. Roy et al. / Tetrahedron 68 (2012) 6575e6580
unique in that it does not conform to the isoprene rule that goes to
make up all the terpene constituents. Enantiomeric nature of elvirol
has not been referred to in its isolation and as such no information
is available on its possible biological activity. Interestingly, its better
known structural sibling curcuphenol displays interesting bi-
ological activities of both its enantiomers.7,8 Synthesis of elvirol
both as racemate as well as enantiomers has also been disclosed.9
In view of our interest to illustrate the utility of the new frag-
mentation process as above encountered by us, we decided to
employ the methodology for a synthesis of this curcuphenol con-
gener. The synthesis began with 4,6-dimethyl coumarin 9 and es-
sentially followed the same schematic pathway as applied for the
synthesis of curcuphenol.4 This coumarin was transformed to the
styrenol 10 following the reported method.10 The styrenol 10 was
subjected to a Bargellini reaction11 involving interaction with
chloroform in presence of powdered sodium hydroxide in refluxing
acetone and furnished the gem-dimethyl carboxylic acid 11 in 61%
yield. This acid could be smoothly reduced in very good yield to the
corresponding alcohol 12 with lithium aluminium hydride. Taking
cue from our previous experience,4 when this alcohol was sub-
jected to oxidation with PCC, it afforded the benzoxopinenone 13 in
a moderate yield following a two-step procedure involving an
intramolecular aldo-ene cyclisation and reoxidation.
OH
8
a
b
O
9
O
OH
10
O
11
CO2H
c
e
d
O
O
O
O
CH2OH
O
14
13
12
f
g
S
h
OH
O
SMe
O
O
O
O
16
17
15
i
The benzoxopinenone 13 was subjected to ring expansion to the
eight-membered benzoxocane 15 following previous procedure.4
Thus, treatment of 13 with diazomethane in the presence of cata-
lytic amount of palladium acetate furnished the cyclopropyl ketone
14 in very good yield (85%). Catalytic hydrogenation of this cyclo-
propyl ketone 14 resulted in the expected regioselective cleavage of
the central bond revealing the benzoxocanone 15 in excellent yield.
Reduction of this ketone 15 with sodium borohydride proceeded in
a stereocontrolled fashion yielding the alcohol 16 although the
resultant stereochemistry was not quite relevant. This alcohol was
transformed to the thionocarbonate 17 through interaction with
carbon disulfide and methyl iodide in presence of sodium hydride.
Treatment of this thionocarbonate with tri-n-butyltin hydride5 in
toluene under reflux effected the anticipated fragmentation of the
eight-membered ring and furnished elvirol 8 in an overall yield of
52% from the alcohol 16 (Scheme 2). The spectroscopic data [1H
NMR and 13C NMR] of our synthetic 8 were fully consistent with the
reported values.7,8
8
Scheme 2. Reagents and conditions: (a) KOH, ethylene glycol, 2 h, reflux, 60%; (b) (i)
CHCl3, NaOH, acetone, 5 h, reflux, 61%; (ii) CH2N2, ether, 61%; (c) LiAlH4, ether, 4 h,
reflux, 86%; (d) PCC, DCM, 24 h, 40%; (e) CH2N2, diethyl ether, Pd(OAc)2 (cat), 4 h, 0 ꢀC,
85%; (f) H2/Pd/C, 6 h, 94%; (g) NaBH4, MeOH, 4 h, rt, 90%; (h) NaH, THF, CS2, MeI, NH4Cl,
20 h, 70%; (i) Tri-n-butyltin hydride, AIBN, toluene, 4 h, reflux, 74%.
OH
OH
OH
OH
OH
OH
OH
OH
21
18
19
20
Fig. 1. Calamenenes.
The synthesis relied essentially on some of the key sequences as
for the synthesis of elvirol. The properly anointed 4,7-dimethyl-8-
methoxy coumarin 2215 was employed as the starting material.
This was subjected to decarboxylative hydrolysis by refluxing in
ethylene glycol in presence of added potassium hydroxide and fur-
2.2. Synthesis of 7,8-dihydroxycalamenene
Hoffmann et al. isolated two o-catechol derivatives, along with
other components from Guardia platyphylla. These two catechols
were isolated as a mixture and identified as (1S,4S)-7,8-dihydroxy-
11,12-dehydro calamenene 18 and (1S,4R)-7,8-dihydroxy-
11,12-dehydro calamenene 19 (Fig. 1).12 These were found to be
antiinfective and inhibited the in vitro growth of Staphylococcus
aureusUA 9-29, Bacillus subtilis UA 2-27, Klebsiella pneuoniea UA 3-9
and Candida albicans UA 97. These were highly unstable and sub-
sequently it was found that the corresponding dihydro derivatives 20
and 21 also showed the same activity (Fig.1).12 However, the activity
was dependent on the type of hydroxyl protection function. Thus, the
corresponding acetates and dimethyl ethers were devoid of any ac-
tivityandthemono-methyl derivatives showed loss of gram negative
activity. In view of the reported instability of these catechols and the
similar activity profile of the dihydro derivatives, synthetic efforts
have been directed to the latter compounds.13,14
nished the styrenol 23, in 50% yield. Alkylation of this with methyl a-
bromopropionate in presence of potassium carbonate afforded the
styrenecarboxylate 24 in a yield of 87%. Reaction of this ester with
LDA followed by treatment of the resultant enolate with methyl
iodide provided the gem-dimethyl incorporated ester 25 in excellent
yield. Alkaline hydrolysis of the ester delivered the carboxylic acid
26. Intramolecular acylation of this acid was carried out by refluxing
a benzene solution with added thionyl chloride and furnished the
benzoxepinenone 27 in a satisfactory yield (Scheme 3).
This was converted to the cyclopropyl ketone 28 by exposing to
diazomethane in presence of palladium acetate. As in previous
cases,4 catalytic hydrogenation proved to be highly regioselective
leading to the eight-membered ketone 29 in excellent yield. Re-
duction of this ketone with sodium borohydride furnished a single
alcohol 30 and based on previous analogy4 could be assigned the cis
configuration, although the stereochemical outcome of this re-
ductionwas not material to the next course of reactions. This alcohol
was converted to the thionocarbonate 31 by sequential treatment
with carbon disulfide and methyl iodide in presence of sodium hy-
dride. Exposure of this to tri-n-butyltin hydride as per earlier con-
ditions for radical formation resulted in the expected fragmentation
Concurrent to the synthesis of elvirol 17, it was of interest to
extend the sequence of reactions to a formal synthesis of dihy-
droxycalamenene 20. This emanated from the synthesis by Kraus
et al., where the curcuphenol analogue 33, had served as an ad-
vanced intermediate.14 Hence, a synthesis of this curcuphenol
should constitute a formal synthesis of 20.

A. Roy et al. / Tetrahedron 68 (2012) 6575e6580
6577
tubes in a sulfuric acid bath and are uncorrected. Dry solvents and
reagents were prepared from reagent grade materials by conven-
tional methods. Petroleum ether refers to the fraction of bp
60e80 ꢀC. The purity of the products was routinely monitored by
TLC. Drying of organic layers was done with sodium sulfate. 1H NMR
spectra were recorded at 60 or 300 MHz in CCl4 (for 60 MHz) or
CDCl3 solutions. 13C NMR spectra were recorded in CDCl3 solutions
at 75 MHz. Peak positions are indicated in parts per million
downfield from internal TMS standard. IR spectra of liquid products
were recorded in thin films or in CHCl3 solution. IR spectra of solids
were recorded as KBr pellets. Elemental analyses were recorded in
PerkineElmer (CHN Analyzer) 2400 series-2. High-resolution mass
spectra (HRMS) were measured in QTOF I (quadrupole-hexapole-
TOF) mass spectrometer with an orthogonal Z-spray-electrospray
interface on Micro (YA-263) mass spectrometer.
a
b
O
O
OH
OMe
23
O
CO2Me
OMe
22
OMe
24
c
e
d
O
O
CO2Me
O
CO2H
O
OMe
27
OMe
OMe
26
25
Scheme 3. Reagents and conditions: (a) KOH, ethylene glycol, reflux, 2 h, 50%; (b)
K2CO3, CH3CH(Br)COOMe, acetone, reflux, 5 h, 87%; (c) LDA, THF, MeI, ꢁ20 ꢀC to rt, 2 h,
90%; (d) 10% NaOH, MeOH, 50 ꢀC, 1 h, 94%; (e) SOCl2, benzene, reflux, 3 h, 68%.
to finally deliver the curcuphenol derivative 32 in very good yield.
Brief treatment of this styrenol with methyl iodide in presence of
sodium hydride furnished the desired dimethoxy compound 33
(Scheme 4), the advanced intermediate in the synthesis of 20 by
Kraus et al.14 The spectral features were fully consistent with those
reported for the same. Since this has been transformed to the
dihydroxycalamenene 20 in two further steps, the present study
concluded a formal synthesis of this bioactive catechol derivative.
3.2. 2-(2-Isopropenyl-4-methyl-phenoxy)-2-methyl-
propionic acid (11)
Isopropenyl cresol 10 (3.2 g, 21.6 mmol) in acetone (30 mL) was
taken in a three-necked flask with a dropping funnel and a con-
denser. Powdered sodium hydroxide (5.3 g,132.5 mmol) was added
in small portions with stirring. The warm mixture was cooled to
room temperature and chloroform (2.4 mL) was added within
15 min. Then the mixture was refluxed for 5 h, cooled and diluted
with water, acidified with cold HCl (6 N) and thoroughly extracted
with ether. The combined organic extract was washed with brine,
dried and concentrated to afford the gem-di-methyl incorporated
carboxylic acid 11 (3.1 g, 61%) as a semi solid residue. 1H NMR
b
a
27
O
O
O
O
OMe
OMe
(60 MHz, CCl4):
d 6.94e6.96 (m, 3H), 5.15 (br s, 1H), 5.05 (br s, 1H),
28
29
3.51 (s, 1H), 2.35 (s, 3H), 2.21 (s, 3H), 1.25 (s, 6H).
c
3.3. 2-Methyl-2-(4-methyl-2-vinyl-phenoxy)-propan-1-ol (12)
To a magnetically stirred slurry of lithium aluminium hydride
(1 g, 240 mmol) in dry ether (120 mL) was added dropwise to
a solution of the acid 11 (3 g, 13 mmol) in dry ether (40 mL). After
the addition was complete, the mixture was refluxed for 4 h, cooled
and decomposed with cold saturated aqueous Na2SO4 solution. The
ether layer was separated and the aqueous layer was extracted with
ether. The combined ether extract was washed with brine, dried
and concentrated to furnish the alcohol 12 as a colourless liquid. It
was subjected to column chromatography over silica gel. Elution
with ethyl acetate (1:9) furnished the pure alcohol (2.5 g, 86%).
d
S
OH
O
O
SMe
O
OMe
OMe
30
31
e
nmax/cmꢁ1 (thin film) 3440. 1H NMR (60 MHz, CCl4):
d 7.07 (d,
32, R = H
J¼8.1 Hz, 1H), 6.85 (m, 2H), 5.18 (br s, 1H), 5.04 (br s, 1H), 3.52 (s,
2H), 2.31 (s, 3H), 2.10 (s, 3H), 1.27 (s, 6H). Found C, 76.14; H, 9.12%.
C14H20O2 requires C, 76.32; H, 9.15%.
f
33,
R = Me
OR
OMe
Scheme 4. Reagents and conditions: (a) Pd(OAc)2, CH2N2, ether, 0 ꢀC, 3 h, 72%; (b) H2,
Pd/C, EtOH, 2 h, 90%; (c) NaBH4, MeOH, 0 ꢀC, 95%; (d) NaH, CS2, MeI, 0 ꢀC to rt, 8 h, 92%;
(e) TBTH, AIBN, toluene, reflux, 3 h, 90%; (f) MeI, K2CO3, acetone, reflux, 4 h, 97%.
3.4. (Z)-2,2,5,7-Tetramethylbenzo[b]oxepin-3(2H)-one (13)
To a magnetically stirred suspension of pyridinium chlor-
ochromate (3.67 g, 17 mmol) in dichloromethane (100 mL) was
added the styrene alcohol 12 (2.5 g, 11.4 mmol) in dichloromethane
(50 mL) in one portion. After stirring for 24 h, dry ether (50 mL) was
added and the supernatant liquid was decanted from the black
gummy residue. This residue was washed thoroughly with ether
(20 mL) for at least 3e4 times. The combined ether extract was
concentrated and the residual oil was purified by column chro-
matography over silica gel. Elution with ethyl acetate (1:49) affor-
In summary, we have demonstrated the utility of the novel
radical induced fragmentation in an eight-membered oxygenated
ring system by application to the synthesis of a curcuphenol ana-
logue elvirol and a formal synthesis of an antiinfective compound
7,8-dihydroxycalamenene. It is expected that this observation will
find more such applications in organic synthesis.
3. Experimental
3.1. General
ded benzoxepinenone 13 (980 mg, 40%) as a colourless liquid. nmax
cmꢁ1 1649. 1H NMR (300 MHz, CDCl3):
7.16 (br s, 1H), 7.05 (d,
J¼8.1 Hz, 1H), 6.91 (d, J¼8.1 Hz, 1H), 6.2 (s, 1H), 2.27 (s, 3H), 2.24 (s,
3H), 1.24 (s, 6H). 13C NMR (CDCl3, 75 MHz):
203.93, 152.06, 146.94,
134.10, 131.95, 130.99, 129.97, 128.97, 124.24, 87.56, 25.57, 24.65,
/
d
All non aqueous reactions were carried out under an inert at-
mosphere (argon). Melting points were taken in open capillary
d

6578
A. Roy et al. / Tetrahedron 68 (2012) 6575e6580
21.34. Found: C, 77.81; H, 7.35%. C14H16O2 requires C, 77.75; H,
7.46%.
room temperature for 2 h. Carbon disulfide (4.5 mL, 75 mmol) and
methyl iodide (0.55 mL, 9 mmol) were added consecutively and the
mixture was stirred for 20 h. Next day saturated aqueous solution
of NH4Cl was added to decompose. Ether of 10 mL was added and
stirred for 15 min, the ether layer was separated and the aqueous
layer was extracted exhaustively with ether. The combined ether
layer was washed with brine, dried and concentrated to afford
a yellow oil, which was purified by column chromatography over
silica gel. Elution with ethyl acetate in petroleum ether (1:99) fur-
nished the S-methylthionocarbonate 17 (670 mg, 70%). 1H NMR
3.5. 3,3,7,8b-Tetramethyl-1a,8b-dihydro-1H-4-oxa-benzo[a]
cyclopropa[c]cyclohepten-2-one (14)
To a stirred solution of the above unsaturated ketone 13
(670 mg, 3.1 mmol) in dry ether (6 mL) in presence of Pd(OAc)2
(8 mg), a large excess of ethereal diazomethane solution was added
dropwise at 0 ꢀC and the resulting mixture was stirred continu-
ously at room temperature for 4 h. Then it was filtered through
a short column of silica gel to afford a yellow coloured liquid, which
was subjected to column chromatography over silica gel. Elution
with ethyl acetate in petroleum ether (1:49) furnished pure
cyclopropyl ketone 14 (610 mg, 85%) as a colourless oil. nmax/cmꢁ1
(300 MHz, CDCl3):
d
6.9 (s, 1H), 6.84 (d, J¼8.4 Hz, 1H), 6.75 (d,
J¼8.1 Hz, 1H), 5.25 (d, J¼9 Hz, 1H), 3.227e3.29 (m, 2H), 2.45 (s, 3H),
2.19 (s, 3H), 2.08e2.14 (m, 2H), 1.68e1.75 (m, 2H), 1.42 (s, 3H), 1.26
(s, 3H), 1.19 (d, J¼6 Hz, 3H).
A solution of above S-methylthionocarbonate 17 (670 mg,
2 mmol) in dry toluene (20 mL) was heated under reflux with tri-n-
butyltin hydride (0.892 mL, 3.1 mmol) and 2,2-azobisbutyronitrile
(AIBN) (5 mg) for 4 h. Toluene was removed under pressure and
saturated aqueous solution of potassium fluoride (2 mL) was added
and stirred at room temperature for 5 h. The precipitated solid was
filtered off and the filtrate was extracted with ether. The ethereal
extract was washed with brine, dried and solvent was removed to
afford a deep yellow coloured liquid. This was subjected to column
chromatography using silica gel. Elution with ethyl acetate in pe-
troleum ether (1:19) furnished elvirol 8 as a colourless oil (340 mg,
1680. 1H NMR (300 MHz, CDCl3):
d
7.07 (br s, 1H), 6.84 (d, J¼8 Hz,
1H), 6.69 (d, J¼7.9 Hz, 1H), 2.99 (t, J¼5.2 Hz, 1H), 2.22 (s, 3H), 2.03
(m, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.15 (s, 3H), 1.12 (m, 1H). 13C NMR
(CDCl3, 75 MHz):
d 211.00, 150.82, 135.43, 134.67, 129.60, 127.96,
124.97, 88.28, 39.18, 27.91, 27.62, 26.30, 23.37, 21.82, 21.44. Found C,
78.19; H, 7.81%. C15H18O2 requires C, 78.23; H, 7.88%.
3.6. 10-Methoxy-2,2,6,9-tetramethyl-5,6-dihydro-4H-benzo
[b]oxocin-3-one (15)
The cyclopropyl ketone 14 (610 mg, 2.6 mmol) in double dis-
tilled ethanol (6 mL) was hydrogenated by using Pd/C (10%, 100 mg)
as a catalyst at room temperature and atmospheric pressure. After
complete consumption of hydrogen gas the solution was filtered.
The solvent was removed and the residual oil was purified by col-
umn chromatography using silica gel. Elution with ethyl acetate in
petroleum ether (1:99) afforded the cyclic ketone 15 (610 mg, 94%)
as a colourless oil. nmax/cmꢁ1 1712. 1H NMR (300 MHz, CDCl3):
74%). nmax/cmꢁ1 3372. 1H NMR (300 MHz, CDCl3):
d 6.86 (s, 1H), 6.78
(d, J¼8.1 Hz, 1H), 6.58 (d, J¼8.1 Hz, 1H), 5.07 (t, J¼6.9 Hz, 1H), 4.56
(s, 1H), 2.84e2.94 (m, 1H), 2.19 (s, 3H), 1.83e1.91 (m, 2H), 1.59 (s,
3H), 1.56e1.58 (m, 2H), 1.46 (s, 3H), 1.16 (d, J¼6 Hz, 3H). 13C NMR
(75 MHz, CDCl3):
d 149.74, 131.78, 131.02, 128.95, 126.56, 126.00,
123.57, 114.25, 36.23, 30.60, 25.06, 24.70, 19.97, 19.70, 16.64. Found:
C, 82.32; H, 10.31%. C15H22O requires C, 82.51; H, 10.16%.
d
6.89 (s, 1H), 6.85 (d, J¼8.8 Hz, 1H), 6.75 (d, J¼8 Hz, 1H), 3.02e3.09
3.9. 6-Isopropenyl-2-methoxy-3-methyl-phenol (23)
(m, 1H), 2.14e2.43 (m, 2H), 2.21 (s, 3H), 1.92 (m, 1H), 1.50e1.62 (m,
1H), 1.42 (s, 3H), 1.37 (s, 3H), 1.25 (d, J¼7 Hz, 3H). 13C NMR (CDCl3,
4,7-Dimethyl-8-methoxy coumarin 22 (13 g, 74.7 mmol) was
added portion wise to a solution of KOH (18 g, 321 mmol) in water
(8 mL) and ethylene glycol (120 mL). The reaction mixture was
refluxed for 2 h. It was cooled and poured into crushed ice and
extracted with ether. The organic layer was washed with saturated
brine and dried. The residue after removal of solvent was distilled
to afford the styrenol 23 (5.72 g, 50%). This styrenol 23 displayed
a tendency to rapidly polymerise and hence only 1H NMR was
recorded and taken to the next step. 1H NMR (300 MHz, CDCl3):
75 Hz):
d 213.25, 151.18, 139.40, 135.07, 128.58, 127.57, 86.50, 36.43,
35.07, 34.54, 24.90, 23.81, 21.82, 21.44. Found: C, 77.59; H, 8.62%.
C15H20O2 requires C, 77.55; H, 8.68%.
3.7. 2,2,6,8-Tetramethyl-3,4,5,6-tetrahydro-2H-benzo[b]
oxocin-3-ol (16)
The above ketone 15 (610 mg, 2.5 mmol) in methanol (20 mL)
was cooled at 0 ꢀC and sodium borohydride (185 mg, 5 mmol) was
added portion wise to the cold mixture with stirring for 4 h. The
methanol was evaporated, excess sodium borohydride was
quenched with cold water and extracted with ether (3ꢂ15 mL). The
combined ether extract was washed with water, dried and con-
centrated to afford a light yellow coloured liquid. This was purified
by column chromatography (petroleum ether/EtOAc 19:1) to fur-
d
6.88 (d, J¼7.8 Hz, 1H), 6.66 (d, J¼7.8 Hz, 1H), 5.98 (br s, 1H), 5.23 (s,
2H), 3.83 (s, 3H), 2.22 (s, 3H), 2.14 (s, 3H).
3.10. 2-(6-Isopropenyl-2-methoxy-3-methyl-phenoxy)-
propionic acid methyl ester (24)
nish the alcohol 16 as a colourless dense liquid (550 mg, 90%). nmax
/
A mixture of the styrenol 23 (2 g, 13.5 mmol), methyl a-bro-
cmꢁ1 3458. 1H NMR (300 MHz, CDCl3):
d
7.00 (br s, 1H),
mopropionate (2.44 g, 13.5 mmol), anhydrous K2CO3 (3.73 g,
27 mmol) and KI (20 mg) in dry acetone (60 mL) was heated under
reflux with stirring for 5 h. It was then concentrated to one-third of
the volume, diluted with water and extracted with ether
(3ꢂ40 mL). The combined organic layer was washed with cold 5%
NaOH solution and water. Then it was dried and concentrated. The
residual oil was passed through a short column of alumina and
eluted with petroleum ether to afford the alkylated product 24
6.96e6.81(m, 2H), 3.64 (s, 1H), 3.36 (d, J¼9 Hz, 1H), 3.21e3.23 (m,
1H), 2.33 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.29 (d, J¼7 Hz, 3H). 13C
NMR (CDCl3, 75 MHz):
d 150.74, 141.06, 134.11, 127.03, 126.86,
124.91, 83.37, 75.86, 36.68, 32.66, 26.11, 23.32, 21.51, 21.41. Found C,
77.12; H, 9.45%. C15H22O2 requires C, 76.88; H, 9.46%.
3.8. 2-(1,5-Dimethyl-hex-4-enyl)-1-methoxy-4-methyl-
benzene, elvirol (8)
(2.6 g, 87%). 1H NMR (300 MHz, CDCl3):
d 6.89 (s, 2H), 5.11 (s, 1H),
5.05 (s, 1H), 4.66 (q, J¼6.7 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.25 (s,
Preparation of the S-methylthionocarbonate (17). To a stirred
suspension of sodium hydride (0.43 g, 9 mmol, 50% dispersion in
oil) in dry THF (10 mL) was added a solution of the alcohol 16
(700 mg, 3 mmol) in dry THF (7 mL) and the mixture was stirred at
3H), 2.15 (s, 3H), 1.47 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
172.7, 151.5, 148.3, 144.0, 136.7, 131.6, 126.0, 124.2, 115.5, 77.7, 60.5,
52.0, 23.7, 18.6, 15.9; HRMS (ESþve) calcd for C15H20O4Na [MþNa]þ
287.1259, found 287.1253.

A. Roy et al. / Tetrahedron 68 (2012) 6575e6580
6579
3.11. 2-(6-Isopropenyl-2-methoxy-3-methyl-phenoxy)-2-
methyl-propionic acid methyl ester (25)
excess of ethereal diazomethane solution was added dropwise at
0 ꢀC and the resulting mixture was stirred continuously at room
temperature for 3 h. The oil after removal of ether was purified by
column chromatography over silica gel (petroleum ether/ethyl ac-
etate 49:1) to furnish the cyclopropyl ketone 28 as a colourless solid
(760 mg, 72%). It was crystallized from ether/petroleum ether; mp
60e62 ꢀC. nmax/cmꢁ1 (thin film) 1678. 1H NMR (300 MHz, CDCl3):
To a well stirred solution of LDA [prepared from n-butyllithium
(1.4 mL of 1.6 M solution in hexane, 2.24 mmol) and diisopropyl-
amine (0.32 mL, 2.3 mmol)] in THF at ꢁ20 ꢀC, a solution of the ester
24 (530 mg, 2.00 mmol) in THF (2 mL) was added dropwise under
cold condition (ꢁ40 ꢀC). After 30 min, methyl iodide (0.15 mL,
2.4 mmol) was added and stirred for another 2 h at ꢁ20 ꢀC and then
allowed to attain room temperature and stirred at this temperature
for 30 min. The reaction mixture was then quenched with saturated
solution of ammonium chloride in water and extracted with ether.
The combined ethereal extract was washed with water, brine, dried
and the solvent was removed under reduced pressure. The residual
oil was purified by column chromatography over silica gel and
eluted with ethyl acetate in petroleum ether (1:20) to furnish the
methylated ester 25 (510 mg, 90%). 1H NMR (300 MHz, CDCl3):
d
7.00 (d, J¼8.1 Hz, 1H), 6.90 (d, J¼8.1 Hz, 1H), 3.84 (s, 3H), 3.09 (t,
J¼4.5 Hz, 1H), 2.15 (s, 3H), 2.08 (dd, J¼8.7, 5.9 Hz, 1H), 1.56 (s, 3H),
1.51 (s, 3H), 1.32e139(m, 1H), 1.25 (s, 3H); 13C NMR (75 MHz,
CDCl3):
d 211.28, 152.6, 146.17, 134.7, 130.4, 126.3, 122.9, 89.0, 60.4,
39.0, 27.8, 27.3, 26.2, 22.29, 21.6, 15.98; HRMS (ESþve) calcd for
C16H20O3Na [MþNa]þ 283.1310, found 283.1314.
3.15. 10-Methoxy-2,2,6,9-tetramethyl-5,6-dihydro-4H-benzo-
[b]oxocin-3-one (29)
d
6.87 (d, J¼7.8 Hz, 1H), 6.82 (d, J¼7.8 Hz, 1H), 5.09 (s, 1H), 4.97 (s,
1H), 3.80 (s, 3H), 3.68 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H), 1.41 (s, 6H);
13C NMR (75 MHz, CDCl3):
174.27, 152.9, 145.9, 145.0, 138.81,
The cyclopropyl ketone 28 (200 mg, 0.77 mmol) in distilled
ethanol (3 mL) was hydrogenated using Pd/C (10%, 50 mg) as cat-
alyst at room temperature and atmospheric pressure. After 2 h the
mixture was filtered and the solvent was removed under reduced
pressure to furnish a colourless oil, which was purified by column
chromatography over silica gel (petroleum ether/ethyl acetate
49:1) to afford the cyclic ketone 29 (180 mg, 90%) as a colourless oil.
d
130.98, 126.4, 124.06, 115.44, 81.23, 60.23, 52.19, 25.03, 23.64, 15.9;
HRMS (ESþve) calcd for C16H22O4Na [MþNa]þ 301.1416, found
301.1411.
3.12. 2-(6-Isopropenyl-2-methoxy-3-methyl-phenoxy)-2-
methyl-propionic acid (26)
nmax/cmꢁ1 (thin film) 1715. 1H NMR (300 MHz, CDCl3):
d 6.95 (d,
J¼3.9 Hz, 1H), 6.85 (d, J¼3.9 Hz,1H), 3.85e3.88 (m, 1H), 3.79 (s, 3H),
3.07 (m,1H), 2.42 (td, J¼11.8, 4.2 Hz,1H), 2.25 (s, 3H), 2.02e2.16 (m,
2H), 1.55 (s, 3H), 1.44 (s, 3H), 1.27 (d, J¼6.9 Hz, 3H); 13C NMR
To a stirred solution of the ester 25 (510 mg, 1.8 mmol) in
methanol (0.3 mL) 10% NaOH solution (in water) was added. The
reaction mixture was heated at 50 ꢀC for 1 h. After cooling the re-
action mixture was acidified by cold dil HCl (6 N) and extracted
with ether (3ꢂ20 mL). The combined ether layer was washed with
a saturated aqueous NaHCO3 solution. The alkali part was then
acidified with cold dil HCl and extracted with ether (3ꢂ20 mL). The
combined ether layer was washed with water, brine, dried and
concentrated over vacuum to afford the pure acid 26 as colourless
(75 MHz, CDCl3):
d 211.89, 152.58, , 146.47, 139.11, 129.94, 127.04,
121, 87.76, 59.54, 35.40, 34.83, 31.78, 24.12, 22.1, 20.09,16.06; HRMS
(ESþve) calcd for C16H22O3Na [MþNa]þ 285.1466, found 285.1469.
3.16. 10-Methoxy-2,2,6,9-tetramethyl-3,4,5,6-tetrahydro-2H-
benzo[b]oxocin-3-ol (30)
The ketone 29 (550 mg, 2.1 mmol) in methanol (10 mL) was
cooled to 0 ꢀC (ice bath) and NaBH4 (220 mg, 4.2 mmol) was added
portion wise with stirring for 2 h. The methanol was evaporated,
excess sodium borohydride was quenched with cold water and
extracted with ether (3ꢂ15 mL). The combined ethereal extract was
washed with water, dried and concentrated. The residual oil was
purified by column chromatography (petroleum ether/ethyl acetate
gummy liquid (470 mg, 94%). 1H NMR (300 MHz, CDCl3):
d 10.5 (br
s, 1H), 6.82 (d, J¼7.8 Hz, 1H), 6.76 (d, J¼7.8 Hz, 1H), 5.07 (s, 1H), 4.94
(s 1H), 3.70 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H), 1.38 (s, 6H); 13C NMR
(75 MHz, CDCl3):
123.5, 115.1, 81.7, 59.7, 23.6, 22.5, 14.9.
d 176.7, 151.2, 143.87, 143.77, 137.6, 129.7, 125.9,
3.13. (Z)-9- Methoxy-2,2,5,8-tetramethylbenzo[b]oxepin-
3(2H)-one (27)
19:1) to afford the alcohol 30 (526 mg, 95%) as a colourless oil. nmax
/
cmꢁ1 (thin film) 3432. 1H NMR (300 MHz, CDCl3):
d
6.91 (d,
J¼7.8 Hz, 1H), 6.82 (d, J¼7.8 Hz, 1H), 3.77 (s, 3H), 3.49 (m, 1H), 3.26
To a stirred solution of acid 26 (200 mg, 1.70 mmol) in dry
benzene (10 mL) was added freshly distilled SOCl2 (0.28 mL,
3.9 mmol). The reaction mixture was heated under reflux for 3 h. It
was then cooled and excess SOCl2 was removed by azeotropic
distillation under vacuum with fresh addition of dry benzene
(3ꢂ5 mL). The residual mass was decomposed by crushed ice and
extracted with ether (3ꢂ15 mL). The combined ether layer was then
washed with saturated aqueous NaHCO3 solution, water, brine and
then dried. Elution with ethyl acetate/petroleum ether (1.5%) fur-
nished the ketone 27 as colourless oil (120 mg, 68%). nmax/cmꢁ1
(m, 1H), 2.23 (s, 3H), 2.11 (m, 2H), 1.82 (m, 2H), 1.29 (s, 6H), 1.25 (d,
J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 152.7, 147.08, 140.1,
129.25, 126.21, 120.74, 116.29, 85.5, 76.73e76.89, 59.47, 35.18, 31.76,
27.07, 25.74, 23.0, 21.05, 16.0; HRMS (ESþve) calcd for C16H24O3Na
[MþNa]þ 287.1623, found 287.1625.
3.17. S-Methylthionocarbonate (31)
To a stirred suspension of sodium hydride (0.25 g, 1.04 mmol,
50% dispersion in oil) in dry THF (10 mL) was added a solution of
the alcohol 30 (260 mg, 0.9 mmol) in dry THF (4 mL) and the
mixture was stirred at room temperature for 2 h. Carbon disulfide
(1.5 mL, 24.6 mmol) and methyl iodide (0.2 mL, 3 mmol) were
added consecutively and the mixture was stirred for 8 h. The re-
action mixture was quenched by saturated solution of NH4Cl. Ether
of 10 mL was added and stirred for 15 min. The ether layer was
separated and the aqueous layer was extracted exhaustively with
ether. The combined ether layer was washed with brine, dried and
concentrated to afford yellow oil, which as then purified by column
chromatography over silica gel. Elution with petroleum ether in
pentane (50:50) furnished the S-methylthionocarbonate 31
1648. 1H NMR (300 MHz, CDCl3):
J¼8.1 Hz, 1H), 6.19 (s, 1H), 3.78 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.3
(s, 6H); 13C NMR (75 MHz, CDCl3):
203.4, 152.0, 147.4, 146.7, 134.4,
d
7.02 (d, J¼8.1 Hz, 1H), 6.9 (d,
d
130.5, 128.1, 125.9, 122.5, 87.6, 60.5, 25.3, 23.6, 16.3; HRMS (ESþve)
calcd for C15H18O3Na [MþNa]þ 269.1154, found 269.1156.
3.14. 5-Methoxy-3,3,6,8b-tetramethyl-1a,8b-dihydro-1H-4-
oxa-benzo[a]cyclopropa[c]cyclohepten-2-one (28)
To a stirred solution of the above unsaturated ketone 27 (1 g,
4.06 mmol) and Pd(OAc)2 (10 mg) in dry ether (15 mL), a large

6580
A. Roy et al. / Tetrahedron 68 (2012) 6575e6580
(310 mg, 92%). nmax/cmꢁ1 (thin film): 1730. 1H NMR (300 MHz,
CDCl3):
and extracted with ether (3ꢂ10 mL). The combined organic layer
was washed with cold 5% aqueous NaOH solution and water. Then it
was dried and concentrated to afford the dimethyl ether 33
d
6.94 (d, J¼7.8 Hz, 1H), 6.84 (d, J¼7.8 Hz, 1H), 5.4 (d,
J¼9.7 Hz, 1H), 3.79 (s, 3H), 3.48 (m, 1H), 2.63 (s, 3H), 2.24 (s, 3H),
2.07e2.15(m, 2H), 1.70e1.76 (m, 2H), 1.36 (s, 3H), 1.25 (d, J¼6.9 Hz,
(49.6 mg, 94%). 1H NMR (300 MHz, CDCl3):
d
6.8 (d, J¼7.9 Hz, 1H),
3H); 13C NMR (75 MHz, CD Cl3):
d
215.7, 152.5, 146.8, 140.3, 129.3,
6.75 (d, J¼7.9 Hz, 1H), 5.04 (t, J¼6 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H),
3.05 (m, 1H), 2.16 (s, 3H), 1.76e1.95 (m, 3H), 1.59 (s, 3H), 1.46 (s, 3H),
126.6, 120.5, 88.1, 83.7, 59.5, 35.4, 26.6, 23.3, 22.6, 20.5, 20.3, 19.0,
16.1; HRMS (ESþve) calcd for C18H26O3S2Na [MþNa]þ 377.1221,
found 377.1224.
1.11 (d, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 151.41, 150.93,
139.47, 131.46, 129.47, 125.75, 124.80, 121.61, 60.78, 60.05, 37.94,
31.83, 26.55, 25.85, 22.13, 17.78, 15.81; HRMS (ESþve) calcd for
C17H26O2Na [MþNa]þ 285.1830, found 285.1831.
3.18. 6-(1,5-Dimethyl-hex-4-enyl)-2-methoxy-3-methyl-
phenol (32)
References and notes
A
solution of above S-methylthionocarbonate 31 (90 mg,
0.25 mmol) in dry toluene (5 mL) was heated under reflux with tri-
n-butyltin hydride (0.087 mL, 0.31 mmol) and 2,2-
1. (a) Rowlands, G. J. Tetrahedron 2010, 66, 1593e1636; (b) Rowlands, G. J. Tetra-
hedron 2009, 65, 8603e8655.
azobisbutyronitrile (AIBN) (0.5 mg) for 4 h. Toluene was removed
under reduced pressure and saturated aqueous solution of potas-
sium fluoride (2 mL) was added and stirred at room temperature
for 6 h. The precipitated solid was filtered off and the filtrate was
extracted with ether. The ethereal extract was washed with brine,
dried and solvent was removed to afford a deep yellow coloured
liquid. This was then subjected to column chromatography using
silica gel. Elution with petroleum ether in pentane (1:1) furnished
the cleaved product 32 as a colourless oil (50 mg, 90%). 1H NMR
2. (a) Goto, M.; Miyoshi, I.; Ishii, Y.; Ogasawara, Y.; Kakimoto, Y. I.; Nagumo, S.;
Nishida, A.; Kawahara, N.; Nishida, M. Tetrahedron 2002, 58, 2339e2350; (b)
Harrowven, D. C.; L’Helias, N.; Moseley, J. D.; Blumire, N. J.; Flanagan, S. R. Chem.
Commun. 2003, 2658e2659; (c) Ghosh, S.; Sarkar, S. Tetrahedron 1994, 50,
921e930.
3. Rawal, V. H.; Newton, R. C.; Krishnamurthy, V. J. Org. Chem. 1990, 55, 5181e5183.
4. Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V. Chem. Commun. 2002,
634e635.
5. (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975,
€
1574e1585; (b) Barton, D. H. R.; Crich, D.; Lobberding, A.; Zard, S. Z. J. Chem. Soc.
€
, Chem. Commun. 1985, 646e647; (c) Barton, D. H. R.; Crich, D.; Lobberding, A.;
Zard, S. Z. Tetrahedron 1986, 42, 2329e2338; (d) Barton, D. H. R. Half a Century
of Free Radical Chemistry; Cambridge University Press: Cambridge, 1993; (e)
Zard, S. Z. Aust. J. Chem. 2006, 59, 663e668.
6. Bohlmann, F.; Grenz, M. Tetrahedron Lett. 1969, 10, 1005e1006.
7. Wright, A. ,E.; Pomponi, S. ,A.; McConnell, O. J.; Kohomot, S.; McCarthy, P. J. J.
Nat. Prod. 1987, 50, 976e978.
(300 MHz, CDCl3):
d
6.81 (d, J¼7.9 Hz, 1H), 6.65 (d, J¼7.9 Hz, 1H),
5.73 (s, 1H), 5.12 (t, J¼6 Hz, 1H), 3.79 (s, 3H), 3.09 (m, 1H), 2.27 (s,
3H), 1.93 (m, 3H), 1.67 (s, 3H), 1.54 (s, 3H), 1.21 (d, J¼6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3):
d 146.52, 145.22, 131.78, 131.36, 127.47,
124.90, 122.36, 121.75, 60.72, 37.14, 32.36, 26.39, 25.87, 21.03, 17.76,
15.82; HRMS (ESþve) calcd for C16H24O2Na [MþNa]þ 271.1674,
found 271.1671.
8. McEnroe, F. ,J.; Fenical, W. Tetrahedron 1978, 34, 1661e1664.
9. (a) Bohlmann, F.; Kornig, D. Chem. Ber. 1974, 107, 1777e1779; (b) Ho, T.-L.; Ho,
M.-F. J. Chin. Chem. Soc. 2001, 48, 879e881; (c) Singh, V.; Khurana, A.; Kaur, I.;
Sapehiyia, V.; Kad, G. L.; Singh, J. J. Chem. Soc., Perkin Trans. 1 2002, 1766e1768.
10. Dhekne, V. V.; Kulkarni, B. D.; Rao, A. S. Indian J. Chem., Sect. B 1977, 15,
755e756.
11. (a) Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329e339; (b) Biswas, B.; Sen, P. K.;
Venkateswaran, R. V. Tetrahedron 2007, 63, 12026e12036.
12. Wahyouno, S.; Hoffmann, J. J.; Bates, R. B.; McLaughlin, S. P. Phytochemistry
1991, 30, 2175e2182.
3.19. 1-(1,5-Dimethyl-hex-4-enyl)-2,3-dimethoxy-4-methyl-
benzene (33)
A mixture of styrenol 32 (50 mg, 0.2 mmol), MeI (40 mg,
0.2 mmol), anhydrous K2CO3 (125 mg, 1 mmol) and KI (5 mg) in dry
acetone (3 mL) was heated under reflux with stirring for 5 h. It was
then concentrated to one-third of the volume, diluted with water
13. Schmalz, H. G.; Hollander, J.; Arnold, M.; Duerner, G. Tetrahedron Lett. 1993, 34,
6259e6262.
14. Kraus, G. A.; Jeon, I. Org. Lett. 2006, 23, 5315e5316.
15. Mills, D. F. J. Heterocycl. Chem. 1980, 14, 1597e1600.