Total synthesis of (±) mutisianthol and (±) epi-mutisianthol via intramolecular oxidative Heck cyclization approach Dedicated to the late Professor M. G. Kulkarni, Department of Chemistry, SPPU, Pune for his pioneering work in the field of Wittig olefinat

Article abstract of DOI:10.1016/j.tet.2016.02.057

A simple and straight forward synthesis of (±) mutisianthol and its epimer is described. Implementation of 4-pentenal derivative for palladium catalyzed intramolecular 5-endo-trig Heck cyclization is effective. Other key steps involved are Wittig olefinat

Full text of DOI:10.1016/j.tet.2016.02.057

Accepted Manuscript
Total Synthesis of (±) Mutisianthol and (±) epi-Mutisianthol via Intramolecular
Oxidative Heck Cyclization Approach
Shashikant B. Bhorkade, Kishor B. Gavhane, Vaishali S. Shinde
PII:
S0040-4020(16)30119-3
10.1016/j.tet.2016.02.057
TET 27527
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 February 2016
Accepted Date: 25 February 2016
Please cite this article as: Bhorkade SB, Gavhane KB, Shinde VS, Total Synthesis of (±) Mutisianthol
and (±) epi-Mutisianthol via Intramolecular Oxidative Heck Cyclization Approach, Tetrahedron (2016),
doi: 10.1016/j.tet.2016.02.057.
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ACCEPTED MANUSCRIPT
Total Synthesis of (±) Mutisianthol and (±) epi-Mutisianthol via
Intramolecular Oxidative Heck Cyclization Approach
Shashikant B. Bhorkade*, Kishor B. Gavhane, Vaishali S. Shinde
Department of Chemistry, Savitribai Phule Pune University, Ganeshkhind, Pune-411007, India.
*corresponding author sb.bhorkade@gmail.com
(Dedicated to the late Prof. M. G. Kulkarni, Department of Chemistry, SPPU, Pune for his pioneering work in the
field of Wittig olefination–Claisen rearrangement protocol.)
Graphical abstract
Abstract
A simple and straight forward synthesis of (±) mutisianthol and its epimer is described.
Implementation of 4-pentenal derivative for palladium catalyzed intramolecular 5-endo-trig
Heck cyclization is effective. Other key steps involved are Wittig olefination with
allyloxymethylenetriphenylphosphorane, [3,3] sigmatropic rearrangement and chemoselective
reduction of double bond.
Keywords
Wittig olefination, Claisen rearrangement, Oxidative coupling, Heck reaction, Stereoselective
hydrogenation, chemoselective reduction.
1. Introduction
Palladium catalyzed oxidative Heck reaction is an effective tool for carbon-carbon bond
forming reactions since its discovery1 and its intramolecular version was found to be more useful
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in the synthesis of natural products and pharmaceutically important bioactive compounds
including different types of carbacycles, O-heterocycles and N-heterocycles.2 Indane or indanone
carbacycles are the important motifs because of their presence in many natural products (Figure
1) and due to their great medicinal significance such as antitumour,3 antiviral,4 and anti-
inflammatory5 properties. Various methods are available for the construction of indane
framework.6 In the recent years many research groups have implemented intramolecular
oxidative Heck coupling reaction strategy for synthesis of various indane scaffolds.7 Although
the synthesis of substituted indanes remains challenging task.
Figure 1: Some natural indane representatives.
The phenolic sesquiterpene mutisianthol (1) having trans 1,3 disubstituted
benzocyclopentyl (indane) unit was first isolated in 1979 from the roots of Mutisia homoeantha
by Bohlmann’s group.8 The initial stereochemistry was assigned as cis for two substituents on
five membered ring of mutisianthol (1). In the early of 1997, Ho and co-workers accomplished
the first total synthesis of mutisianthol (1) and revised its structure by assigning the relative
stereochemistry to trans for two substituents on five membered ring of mutisianthol.9
Later, very few research groups have worked on synthetic study of mutisianthol (figure
1). Ferraz et al achieved the total synthesis of mutisianthol exploiting thallium mediated ring
contraction strategy for 1,2-dihydronaphthalene derivative.10 Same group later also accomplished
its enantioselective synthesis through asymmetric hydrogenation and thallium mediated ring
contraction of thus generated tetralin motif.11 Very recently, Dethe et al reported the total
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synthesis of mutisianthol employing the Lewis acid catalyzed Nazarov type cyclization.12
However, use of intramolecular Heck cyclization remains untouched in the synthesis of this
natural indane which initiate us to embark on its total synthesis.
Scheme 1: Summery of the reported strategies for mutisianthol.
Since two decades, our group has been involved in the Wittig olefination on a range of
aldehydes followed by Claisen rearrangement of resulted allyl vinyl ether (I) strategy and their
exploration to the target-oriented synthesis with maximum use of resultant functionalized 4-
pentenal derivatives II (Scheme 2).13
Scheme 2: Outline for generation of 4-pentenal derivative.
In continuation of our these efforts, herein, we report a simple and efficient synthetic
method for indane natural product mutisianthol (1), by the use of thus generated 4-pentenal
derivative for oxidative 5-endo-trig Heck cyclization resulting into indene framework.
2. Result and discussion
2.1 Retrosynthetic analysis
Synthetic plan towards mutisianthol (1) is outlined in Scheme 3. Intramolecular Heck
cyclization reaction of triflate 8 and subsequent regio and stereoselective olefine hydrogenation
of 7 could be the key steps for the final construction of the target molecule 1. We envisaged that
substitution pattern in triflate 8 would be obtained from allyl vinyl ether 9 through sequence of
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reactions such as Claisen rearrangement and olefination. The allyl vinyl ether 9 in turn could be
prepared from appropriately substituted benzaldehyde 10 by using Wittig reaction with
allyloxymethylenetriphenylphosphorane 15. The required substitution in aldehyde 10 could be
easily prepared from known 2,4-dihydroxy toluene 11.
Scheme 3: Retrosynthetic plan for mutisianthol.
2.2 Synthesis of precursor aldehyde 14 with appropriate substitution.
Synthesis of required aldehyde 14 commenced from 2,4-dihydroxytoluene 11. Under
standard Vilsmeier-Haack condition (POCl3/DMF), compound 11 provided coressponding
aldehyde 12 with poor reaction yield.14 However, more than 90% yield of 12 obtained when this
reaction was carried out in acetonitrile instead of DMF itself. The regioselective protection of
hydrogen bonding free hydroxyl group of 12 as methyl ether 13 was achieved by dimethyl
sulphate and K2CO3. Subsequent, protection of remaining hydroxyl group as methoxy methyl
ether provided coressponding fully protected benzaldehyde 14 in 94% yield.
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Scheme 4: Reagents and conditions: (i) POCl3, DMF, MeCN, 0 ºC to rt, 5 h, 93%; (ii)
Dimethylsulphate, K2CO3, MeCN, rt, 12 h, 95%; (iii) MOMCl, NaH, THF, 0 ºC, 30 min, 94%.
2.3 Wittig olefination followed [3,3]-sigmatropic rearrangement strategy for the synthesis
of triflate 8.
The Wittig reaction of 14 with allyloxymethylenetriphenylphosphorane (15)15 was
performed using standard reaction condition previously developed in our lab,13b, 13c to provide
allyl vinyl ether 16 with E/Z ratio 1:1.5 in 72% yield (Scheme 5). The solvent free [3,3]-
sigmatropic rearrangement was then effected by heating 16 neat at 180 ºC for 5 min, to produce
the 4-pentenal derivative 17, which was directly used for next step without purification by
treating it with isopropyltriphenylphosphorane at -10 ºC gave dialkene derivative 18 in excellent
yield. Deprotection of MOM ether in 18 by catalytic HCl in MeOH and subsequent treatment of
thus generated phenol 19 with trifluoromethanesulphonic anhydride, triethylamine and catalytic
DMAP afforded triflate 8 in 82% yield.
t
Scheme 5: Reagents and conditions: (i) Ph3PCH2OCH2CH=CH2Cl, BuOK, THF, 0 ºC, 20 min,
72% ; (ii) Neat, 180 ºC, 5 min, 100%; (iii) iPrPPh3Br, n-BuLi, THF, -10 ºC, 1 h, 80%; (iv) 2
drops conc. HCl, MeOH , 1 h, 87%; (v) Tf2O, TEA, DMAP, DCM, 0 ºC, 5 min, 82%.
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2.4 The key intramolecular oxidative Heck cyclization reaction and synthesis of indene
derivative 7.
After having triflate 8 in hand, we next performed the key palladium catalyzed intramolecular
oxidative Heck cyclization reaction. To our disappointment, treatment of triflate 8 under various
known Heck coupling conditions generated inseparable reaction products mixture containing 20
as one of the product, though appeared as homogeneous on TLC.16 After lot of frustrating and
unanticipated efforts to separate these different products, we decided to use this mixture as such
for the next step. Accordingly, this mixture was treated with excess ethyl mercaptan and sodium
hydride in dry DMF at 130-140 ºC for 20-24 h followed by careful column chromatographic
purification, mainly afforded desired indene 5-ol derivative 7 and deoxygenated compound 21 in
56% and 14% yields respectively (Scheme 6).
Scheme 6: Reagents and conditions: (i) Pd(PPh3)4, TEA, LiCl, DMF, 110 ºC, 20 h; (ii) EtSH,
NaH, DMF, 130-140 ºC, 24 h, 56% (7) and 14% (21) over two steps.
2.5 Completion of total synthesis of (±) mutisianthol and (±) epi-mutisianthol.
The regioselective hydrogenation of benzylic exocyclic double bond of 7 by H2, Pd/C
under controlled condition (pressure and time) exclusively generated the cis isomer 22 in good
yield (Scheme 7). The same result was observed by Dethe et al during the synthesis of jungianol
(2).17 The confirmation for cis stereochemistry was given by comparing the spectral data of 22
with those of reported for epi-mutisianthol.12 Finally, the required stereochemistry for
mutisianthol was obtained by giving temporary protection to the hydroxyl group of 7 as MOM
ether followed by chemoselective reduction with Li/liq. NH3 that resulted in 1:1 mixture of 1 and
22 after deprotection of MOM ether. The formation of cis and trans isomers in equal proportion
during Li/liq. NH3 reduction may possibly be attributed to protonation of the generated tertiary
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planar radical species from both sides. The spectral data of 1 (NMR, IR, HRMS) were well
accordance with the reported data for natural mutisianthol.
Scheme 7: Reagents and conditions: (i) H2 (balloon), 10% Pd/C, MeOH, rt, 1 h, 84%; (ii) (a)
MOMCl, DIPEA, DCM, 0 ºC to rt, 12 h, 86%; (b) Li, liq. NH3, THF -78 ºC, 12 h, then 6 N HCl,
40% (1) and 40% (22).
3. Conclusion
In conclusion, we have developed the strategy for the construction of substituted indane
framework in which intramolecular oxidative Heck cyclization was the key step. Strategy was
successfully applied for the total synthesis of mutisianthol and its epimer. Synthesis was
accomplished in 11 linear steps with an overall yield of 6.57% for mutisianthol and in 10 steps
with overall yield of 16.05% for epi-mutisianthol. By the use of same strategy we are now
working on the syntheses of other indanes.
4. Experimental
4.1 General
All moisture sensitive reactions were carried out under nitrogen atmosphere using oven
dried glassware unless otherwise noted. Dichloromethane, dimethylformamide and acetonitrile
were distilled over CaH2. THF was distilled over Na/benzophenone. Commercial reagents and
solvents were used as received without further purification. All the reactions were monitored by
thin layer chromatography (TLC)-Merck 0.25 mm silica gel 60 F254. TLC plates were visualized
by exposure to ultraviolet light (UV, 254 nm) and/or exposure to an aqueous solution of
potassium permanganate (KMnO4), an acidic solution of anisaldehyde or a solution of ninhydrin
in ethanol followed by heating on hot plate. Flash Chromatography was performed using silica
gel (100-200 mesh) with EtOAc/pet ether solvent system distilled prior to use. Melting points
1
were recorded with Thomas Hoover melting point apparatus and are uncorrected. H NMR
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13
spectra were recorded at 200, 300, 500 MHz and C NMR spectra 50, 75, 126 MHz in CDCl3
solution unless otherwise mentioned, chemical shifts are in ppm downfield from
tetramethylsilane and coupling constants (J) are reported in hertz (Hz). High resolution mass
spectra (HRMS) were recorded on Bruker impact HD ESI source. IR spectra were recorded on a
Shimadzu FTIR-8400 series instrument. All the spectral analysis (IR, NMR, HRMS) were
performed at CIF (Central Instrumentation Facility), Savitribai Phule Pune University, Pune.
4.2 Experimental procedures
4.2.1. 2,4-dihydroxy-5-methylbenzaldehyde (12)
To the stirred solution of 2,4-dihydroxytoulene 11 (5 g, 40.28 mmol) and DMF (6.3 ml,
80.56 mmol) in acetonitrile (70 mL) was added phosphorous oxychloride (4.6 mL, 48 mmol)
dropwise over a period of 15 min at 0 ºC. The resulting yellow coloured solution was further
stirred for 3 h at rt. The yellow solid obtained was then filtered, washed with cold acetonitrile 2-3
times, dissolved in hot water and heated at 50 ºC for 30 min. The red coloured liquid was then
kept for overnight at room temperature and the precipitate obtained was then filtered, dried to
give a brown coloured solid (5.69 g, 37.40 mmol, 92.87%). Rf (20% EtOAc in pet ether) 0.6
1
M.p. 143-147 ºC. IRʋmax (KBr) 3510, 3410, 2955, 2874, 1492, 1410, 1080, 995 cm-1. H NMR
(200 MHz, CDCl3) δ 11.2 (s, 1 H), 9.51 (s, 1 H), 7.20 (s, 1 H), 6.25 (s, 1 H), 5.81 (s, 1 H), 2.16
(s, 3 H). 13C NMR (50 MHz, CDCl3) δ 193.2, 163.8, 161.9, 134.6, 117.4, 113.6, 101.4, 14.7.
HRMS (ESI) m/z calcd for C8H8O3Na [M++Na]: 175.0371; found: 175.0383.
4.2.2. 2-hydroxy-4-methoxy-5-methylbenzaldehyde (13)
Dimethyl sulphate (3.12 mL, 32.86 mmol) was added to the stirred suspension of 2,4-
dihydroxy-6-methylbenzaldehyde 12 (5 g, 32.8 mmol) and K2CO3 (4.5 g, 32.86 mmol) in
acetonitrile (100 mL). The reaction mixture was then stirred for 12 h at room temperature. After
completion of reaction, the reaction was quenched with 2 N HCl (100 mL) and extracted with
ethyl acetate (3x50 mL). Combined organic solution was dried over magnesium sulphate, filtered
and solvent was removed under reduced pressure. The residue was purified by column
chromatography (5% EtOAc in pet ether) to yield 13 as a colorless solid (5.18 g, 31.17 mmol,
94.86%). M. P. 71-74 ºC. Rf (8% EtOAc in pet ether) 0.5. IRʋmax (KBr) 3400, 3010, 2880, 1510,
1
1490, 1070, 990 cm-1. H NMR (200 MHz, CDCl3) δ 11.46 (s, 1H), 9.70 (s, 1H), 7.24 (s, 1H),
6.41 (s, 1H), 3.89 (s, 3H), 2.16 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 194.3, 164.9, 163.2, 134.3,
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119.2, 114.1, 98.4, 55.8, 15.3. HRMS (ESI) m/z calcd for C9H10O3Na [M++Na]: 189.0528;
found: 189.0521.
4.2.3. 4-methoxy-2-(methoxymethoxy)-5-methylbenzaldehyde (14)
NaH (1.47 g, 61.38 mmol, 60% in mineral oil) was suspended in dry THF (25 mL) at 0
ºC. To this mixture was slowly added Phenol 13 (5.1 g, 30.69 mmol) in dry THF (20 mL) at 0 ºC
and reaction mixture was stirred for 10 min. Then it was treated with chloromethyl methoxy
ether (3.2 mL, 39.90 mmol) at 0 ºC and stirred for another 30 min at the same temperature. After
completion of reaction as monitored by TLC, saturated NH4Cl solution was added to quench the
reaction and extracted with ethyl acetate (3x50 mL). The combined organic extract was dried
over magnesium sulphate, filtered and concentrated under vacuum. The solid obtained was
recrystallized from methanol to yield 14 as yellow solid (6.06 g, 28.83 mmol, 93.92%). M. P. 37-
40 ºC. Rf (5% EtOAc in pet ether) 0.3. IRʋmax (KBr) 3055, 2935, 2873, 2773, 1606, 1581, 1396,
1209, 1116, 1057, 993 cm-1. 1H NMR (300 MHz, CDCl3) δ 10.30 (m, 1H), 7.60 (s, 1H), 6.65 (s,
13
1H), 5.27 (s, 2H), 3.87 (s, 3H), 3.51 (s, 3H), 2.13 (s, 3H). C NMR (75 MHz, CDCl3) δ 188.4,
163.8, 160.5, 129.6, 120.8, 118.1, .97.1, 95.0, 56.4, 55.7, 15.3. HRMS (ESI) m/z calcd for
C11H14O4Na [M++Na]: 233.0790; found: 233.0792.
4.2.4. (E/Z)-1-(2-(allyloxy)vinyl)-4-methoxy-2-(methoxymethoxy)-5-methylbenzene (16)
To a suspension of 14 (5 g, 23.78 mmol) and allylo xymethylenetriphenylphosphonium
chloride14 (11.40 g, 30.92 mmol) in dry THF (70 mL), THF solution of potassium tert-butoxide
(5.34 g, 47.57 mmol) was added over the period of 20 minutes at 0 ºC. The reaction was stirred
for another 30 minute at the same temperature. After the completion of reaction (monitored by
TLC), water (150 mL) was added and extracted with ethyl acetate (3 x 100 mL). The combined
organic extracts was washed with water, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude product was purified by silica gel column chromatography
(3% EtOAc in pet ether), gave pure allyl vinyl ether 16 (E/Z=3:2) as colourless thick liquid (4.52
g, 17.10 mmol, 71.91%). Rf (5% EtOAc in hexane) 0.5. IRʋmax (neat) 2935, 1693, 1630, 1097,
927 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.02 (s, 2H), 6.97 – 6.88 (m, 2H), 6.65 (s,
2H), 6.16 (d, J = 7.2 Hz, 1H), 6.10 – 5.90 (m, 4H), 5.58 (d, J = 7.2 Hz, 1H), 5.44 – 5.23 (m, 6H),
5.17 (d, J = 2.6 Hz, 5H), 4.39 (ddt, J = 15.9, 5.4, 1.5 Hz, 7H), 3.82 (dd, J = 7.1, 1.7 Hz, 10H),
3.51 (d, J = 1.1 Hz, 9H), 2.19 – 2.11 (m, 10H). 13C NMR (75 MHz, CDCl3) δ 158.1, 153.9,
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152.7, 151.1, 150.0, 144.1, 143.9, 135.8, 132.0, 122.2, 118.1, 118.0, 103.5, 103.4, 102.2, 101.7,
99.2, 98.4, 89.3, 78.1, 77.2, 55.7, 55.2, 16.6. HRMS(ESI) m/z calcd for C15H20O4Na [M++Na]:
287.1259; found: 287.1268.
4.2.5. 1-methoxy-5-(methoxymethoxy)-2-methyl-4-(6-methylhepta-1,5-dien-4-yl)benzene (18)
To a stirred suspension of (CH3)2CHPPh3Br (4.45 g, 13 mmol) in anhydrous THF (30
mL) under nitrogen, was added dropwise n-BuLi (1.11 g, 17.40 mmol, 15% in hexanes) at 0 ºC.
The resulting orange coloured solution was stirred for 20 min at 0 ºC to give
isopropylphosphorane.
Meanwhile, the allyl vinyl ether 16 (2.30 g, 8.7 mmol) was heated neat at 180 ºC for 5
min affording corresponding aldehyde 17 (2.30 g, 8.7 mmol). After cooling to room temperature,
the aldehyde was dissolved in dry THF (10 ml) and added to above stirred red solution of
isopropylphosphorane. The mixture was stirred for another 1 h at 0 ºC. The reaction was
quenched with H2O (25 mL) and extracted with Et2O (3x50 mL). The organic phase was washed
with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure,
giving pale yellow liquid, which was purified by silica gel column chromatography (2% EtOAc
in pet ether as an eluent), afforded colorless liquid as 18 (2.03 g, 6.99 mmol, 80.33%). Rf (5%
1
EtOAc in hexane) 0.3. IRʋmax (neat) 2950, 2910, 2870, 1620, 1510, 1120, 980 cm-1. H NMR
(500 MHz, CDCl3) δ 6.97 (s, 1H), 6.70 (s, 1H), 5.83 – 5.73 (m, 1H), 5.37 – 5.32 (m, 1H), 5.24 –
5.18 (m, 2H), 5.07 – 4.95 (m, 2H), 3.98 (dd, J = 15.8, 8.5 Hz, 1H), 3.84 (s, 3H), 3.54 (s, 3H),
2.49 – 2.34 (m, 2H), 2.19 (s, 3H), 1.71 (dt, J = 12.5, 6.2 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ
137.6, 131.0, 129.4, 128.3, 125.9, 119.6, 115.1, 98.5, 95.1, 55.8, 55.4, 40.6, 36.7, 25.8, 18.1,
15.6. HRMS(ESI) m/z calcd for C18H27O3 [M++H]: 291.1882; found: 291.1883.
4.2.6. 5-methoxy-4-methyl-2-(6-methylhepta-1,5-dien-4-yl)phenol (19)
To the stirred solution of 18 (2 g, 6.89 mmol) in MeOH (25 mL) was added 2-3 drops of
conc. HCl. The reaction mixture was then refluxed for 1 hour (monitored by TLC), quenched
with saturated sodium bicarbonate solution (15 mL). MeOH was removed under reduced
pressure and the crude product was extracted with EtOAc (3x30 mL). The combined organic
extract was dried over anhydrous MgSO4, filtered and solvent was removed under reduced
pressure giving pale green coloured viscous liquid. The liquid was redissolved in 10% aq. NaOH
solution (100 mL) and washed with ether (3x25 mL). The aqueous layer was acidified with 2N
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HCl (100 mL) and extracted with ethyl acetate (3x70 mL). The combined organic phase was
dried over anhydrous MgSO4, filtered and concentrated to provide 19 as a thick gel (1.48 g, 6.01
mmol, 87.23%), which was used directly for next step without further purification. Rf (15%
1
EtOAc in pet ether) 0.5. IRʋmax (neat) 3405, 2935, 2860, 1660, 1480, 1070, 695 cm-1. H NMR
(500 MHz, CDCl3) δ 6.98 (s, 1H), 6.69 (s, 1H), 5.81-5.72 (m, 1H), 5.31 (d, J = 8.4 Hz, 1H),
5.21-5.07 (m, 2H), 4.03-3.91 (m, 1H), 3.89 (s, 3H), 2.50-2.31 (m, 2H), 2.29 (s, 3H), 1.75-1.68 (d,
10.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 156.4, 146.6, 136.2, 132.3, 130.2, 129.0, 127.4,
126.2, 116.4, 102.0, 54.4, 41.3, 37.0, 26.1, 21.0, 18.5. HRMS (ESI) m/z calcd for C16H22O2K
[M++K]: 285.1257; found: 285.1255.
4.2.7. 5-methoxy-4-methyl-2-(6-methylhepta-1,5-dien-4-yl)phenyl trifluoromethanesulfonate (8)
Triflic anhydride (1.48 mL, 8.83 mmol) was added to the stirred mixture of 19 (1.45 g,
5.89 mmol), TEA (1.6 mL, 11.77 mmol) and DMAP (143 mg, 1.18 mmol) in 30 mL DCM at 0
ºC. Upon completion of reaction (5 min), diluted with water (50 mL), extracted with DCM (3x50
mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The
crude product was purified by silica gel column chromatography (1% EtOAc in pet ether as an
eluent) to yield 8 as a colorless liquid (1.83 g, 4.84 mmol, 82.16%). Rf (3% EtOAc in pet ether)
0.6. IRʋmax (neat) 2930, 2835, 1680, 1440, 1090, 1075, 693 cm-1. 1H NMR (500 MHz, CDCl3) δ
7.11 (s, 1H), 6.67 (s, 1H), 5.80–5.66 (m, 1H), 5.30–5.20 (d, 1H), 5.09–4.93 (m, 2H), 3.95 (m,
1H), 3.85 (s, 3H), 2.46–2.28 (m, 2H), 2.22 (s, 3H), 1.75–1.55 (m, 6H). 13C NMR (126 MHz,
CDCl3) δ 156.3, 144.9, 136.0, 133.2, 129.9, 127.3, 126.2, 119.8, 116.3, 102.9, 41.0, 36.6, 25.8,
18.0, 16.0. HRMS (ESI) m/z calcd for C17H21F3O4SNa [M++Na]: 401.1011; found: 401.1012.
4.2.8. Mixture containing 5-methoxy-6-methyl-1-methylene-3-(2-methylprop-1-en-1-yl)-2,3-
dihydro-1H-indene 20 (IM)
The mixture of 8 (300 mg, 0.792 mmol), TEA (0.32 mL, 2.386 mmol) and LiCl (33.61
mg, 0.792 mmol) in DMF (5 mL) was degased by passing argon gas for 15 min. The Pd(PPh3)4
o
(183 mg, 0.158 mmol, 20 mol%) was added and the reaction mixture was heated at 100-110 C
for 20 h. The reaction mixture was diluted with diethyl ether (10 mL) and filtered through celite
bed, washed the bed with ether (3x10 mL). The combined filtrate was washed with brine solution
(20 mL) followed by water (20 mL). The ether layer was dried over MgSO4, filtered and
concentrated to give crude reaction mixture. The crude reaction mixture was then diluted with
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hexane (100 mL) and filtered through long silica bed. The bed was successively washed with
hexane (3x100 mL). The combined hexane layer was then concentrated under reduced pressure
to provide inseparable products mixture IM (152 mg) Rf (pet ether) 0.4, though appeared
homogeneous on TLC. This mixture was as such used for next step.
4.2.9. 6-methyl-3-methylene-1-(2-methylprop-1-en-1-yl)-2,3-dihydro-1H-inden-5-ol (7) and 2-
methyl-4-(6-methylhepta-1,5-dien-4-yl)phenol (21)
NaH (788 mg, 32.85 mmol, 60% in mineral oil) was washed with anhydrous pet ether
under nitrogen atmosphere and suspended in anhydrous DMF (3 mL). To this mixture was
slowly added a solution of EtSH (1.22 g, 19.71 mmol) in anhydrous DMF (1 mL) at 0 ºC, and
the resulting solution was stirred for 30 minute at rt. A solution of IM (150 mg) in anhydrous
DMF (1 mL) was then added dropwise, and the resulting mixture was stirred for 24 h at 130 °C.
The mixture was cooled to rt, and a saturated solution of NH4Cl was added. The mixture was
extracted with Et2O (3x20 mL), and the organic phase was washed with H2O and brine followed
by drying over anhydrous Na2SO4. Evaporation of the solvent and purification of the residue by
silica gel column chromatography (2-3% EtOAc in pet ether) furnished compound 7 (95 mg,
0.443 mmol, 55.91% from 8) as colourless thick gel, Rf (10% EtOAc in pet ether) 0.5 and 21 (24
mg, 0.110 mmol, 14% from 8) as colourless oil, Rf (10% EtOAc in pet ether) 0.5 as two distinct
products. Spectral data for 7: IRʋmax (neat) 3396, 2929, 2844, 1669, 1439, 1074, 697 cm-1. 1H
NMR (500 MHz, CDCl3) δ 7.10 (s, 1H), 6.68 (s, 1H), 5.24 (d, J = 8.4 Hz, 1H), 5.06 (m, 2H),
3.97-3.86 (m, 1H), 2.56-2.38 (m, 2H), 2.21 (s, 3H), 1.74 (s, 3H), 1.68 (s, 3H). 13C NMR (126
MHz) δ 156.7, 145.0, 143.2, 136.4, 133.5, 130.1, 127.5, 126.4, 115.9, 110.4, 44.3, 39.8, 26.0,
18.1, 5.9. HRMS (ESI) m/z calcd for C15H20OK [M++K]: 253.0996; found: 253.0988. Spectral
data for 21: 1H NMR (500 MHz, CDCl3) δ 7.10-6.97 (m, 2H), 6.7 (d, 7.8 Hz, 1H), 5.81-5.73 (m,
1H), 5.63 (d, J = 8.2 Hz, 1H), 5.20-5.08 (m, 2H), 4.02-3.92 (m, 1H), 2.49-2.31 (m, 2H), 2.21 (s,
3H), 1.70 (s, 6H). 13C NMR (126 MHz) δ 156.2, 133.5, 133.1, 132.1, 128.9, 128.1, 127.0, 124.3,
117.1, 116.0, 49.6, 37.1, 25.8, 18.1, 16.0.
4.2.10. (±) epi-Mutisianthol (22)
To a solution of Compound 7 (20 mg, 0.093 mmol) in MeOH (2 mL)was added
palladium on activated carbon (2.2 mg, 20 mol%). The reaction was stirred under hydrogen
atmosphere at room temperature for two hour, whereupon TLC showed the reaction was
12

ACCEPTED MANUSCRIPT
complete. The solid was filtered off. Evaporation of the solvent and purification of the residue on
silica gel column chromatography (3% EtOAc in pet ether) furnished the product 22 as a white
solid (17 mg, 0.078 mmol, 84.21%). M. P. 65-73 ºC. Rf (7-8% EtOAc in pet ether) 0.4. IRʋmax
1
(KBr) 3404, 2952, 2929, 2870, 1490, 1454, 1420, 1375, 1284, 1180, 1154, 1054, 995 cm-1. H
NMR (500 MHz, CDCl3) δ 6.80 (s, 1H), 6.63 (s, 1H), 5.10 (d, J = 8.4 Hz, 1H), 4.57 (s, 1H), 3.85
- 3.77 (m, 1H), 3.12 - 3.02 (m, 1H), 2.50 - 2.39 (m, 2H), 2.23 (s, 3H), 1.80 (s, 3H), 1.78 (s, 3H),
1.28 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 152.6, 147.4, 139.1, 132.3, 128.5,
125.9, 121.2, 109.6, 44.2, 42.5, 38.1, 25.8, 19.1, 18.1, 15.7. HRMS (ESI) m/z calcd for
C15H20ONa [M++Na]: 239.1412; found: 239.1413.
4.2.11. (±) Mutisianthol (1)
To the cooled solution of compound 7 (30 mg, 0.140 mmol) and DIPEA (0.05 mL, 0.280
mmol) in dichloromethane (5 mL) at 0 ºC was added chloromethyl methoxy ether (0.015 mL,
0.181 mmol). Reaction mixture slowly warmed to rt and stirred for 12 h. Upon completion, 5%
aq. NaOH solution (10 mL) was added and reaction mixture was extracted with dichloromethane
(3x10 mL). The combined organic extract was dried over anhydrous MgSO4, filtered and
concentrated to dryness afforded MOM ether 23 (31 mg, 0.119 mmol, 85.71%) Rf (5% EtOAc in
pet ether) 0.6 enough pure for next step.
Lithium metal (4 mg, 0.580 mmol) was added to the stirred solution of anhydrous
ammonia (25 mL) at -78 ºC. To this mixture was added a solution of 23 (30 mg, 0.116 mmol) in
dry THF (6 mL) at the same temperature followed by stirring for 30 min and quenching with
methanol. The ammonia was evaporated and 20 mL of 6 N methanolic HCl was added and
stirred for another 90 min. Solvent was removed under reduced pressure and crude was purified
by column chromatography (2-3% EtOAc in pet ether) to end up with compound 1 as a white
solid (10 mg, 0.046 mmol, 39.82%) and compound 22 as a white solid (10 mg, 0.046 mmol,
o
39.82%). Spectral data for compound 1: M.P. 97-100 C. Rf (7-8% EtOAc in pet ether) 0.4.
IRʋmax (KBr) 3332, 2955, 2929, 2857, 1620, 1495, 1446, 1375, 1295, 1189, 1166, 881, 861 cm-1.
1H NMR (500 MHz, CDCl3) δ 6.81 (s, 1H), 6.61 (s, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.58 (s, 1H),
3.99-3.92 (m, 1H), 3.20 (m, 1H), 2.21 (s, 3H), 2.00-1.88 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H), 1.20
(d, J = 7.0 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 152.7, 147.8, 138.6, 131.3, 128.6, 126.3,
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121.6, 110.1, 42.4, 41.6, 37.9, 25.6, 20.9, 18.1, 15.9. HRMS (ESI) m/z calcd for C15H21O
[M++H]: 217.1514; found: 217.1517.
Acknowledgment
SB and KG thank Council of Scientific and Industrial Research, New Delhi for the award
of research fellowship.
Notes and References
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16. Optimization of reaction condition for Heck reaction
Catalyst
Base
Additive Solvent Time(h)
MeCN 20
IM(%)a
1 Pd(OAc)2 TEA
-
Complex TLC
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2 Pd(PPh3)4 TEA
3 Pd(PPh3)4 K2CO3
4 Pd(PPh3)4 DIPEA LiCl
5 Pd(PPh3)4 TEA
6 Pd(PPh3)4 TEA
-
-
MeCN
DMF
DMF
DMF
DMSO
12
20
15
20
20
41
Complex TLC
83b
87
LiCl
LiCl
82
IM- inseparable mixture, a isolated yield-calculated by considering IM as product 20,
b reaction proceeded well in the presence of additive (LiCl).
17. Dethe, D. H.; Murhade, G. M. Org. Lett., 2013, 15, 429.
16