Bi(OTf)3-catalysed prenylation of electron-rich aryl ethers and phenols with isoprene: A direct route to prenylated derivatives

Article abstract of DOI:10.1039/c1ob05365e

Electron-rich aryl ethers and phenols react with isoprene (2-methylbuta-1,3-diene) in the presence of catalytic Bi(OTf)₃ at 40 °C to afford the corresponding prenylated or 2,2-dimethylchroman products, respectively, in moderate to good yields.

Full text of DOI:10.1039/c1ob05365e

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PAPER
Bi(OTf)3-catalysed prenylation of electron-rich aryl ethers and phenols with
isoprene: a direct route to prenylated derivatives†
Katie E. Judd and Lorenzo Caggiano*
Received 9th March 2011, Accepted 13th April 2011
DOI: 10.1039/c1ob05365e
Electron-rich aryl ethers and phenols react with isoprene (2-methylbuta-1,3-diene) in the presence of
catalytic Bi(OTf)3 at 40 ◦C to afford the corresponding prenylated or 2,2-dimethylchroman products,
respectively, in moderate to good yields. This transformation offers a convenient and expedient entry to
prenylated derivatives of electron-rich aromatics that often display enhanced biological activities. The
methodology has been employed in the efficient synthesis of a biologically active natural product and
related compounds.
and its presence in many biologically active compounds, a number
of chemical syntheses of prenylated phenols have been reported.
Introduction
A large number of biologically active compounds possess one
or more prenyl groups and/or the related 2,2-dimethylchroman
unit.1 Selected examples include novobiocin2 and derrubone 1,3
ortho-Prenylation of phenols has been achieved using various
methods,9 including directed ortho-metallation, metal–halogen
exchange, phenoxide ortho-C-alkylation, Claisen rearrangement,
Friedel–Crafts-like prenylation and conjugate addition to para-
which have anti-tumour activity through the inhibition of heat-
quinone.9a Of particular interest to the present study is the
Bi(OTf)3-catalysed [1,3] rearrangement of aryl prenyl ethers to
afford prenylated phenols and chroman derivatives.9b Chemoen-
zymatic syntheses have also been reported using prenyltranferases
NphB and SCO7190 as biocatalysts.10
shock protein (Hsp90), xanthohumol 2 which displays anti-
inflammatory and anti-cancer activity,4 the antioxidant vitamin
E,5 cytotoxic and antiplasmodial xanthones6 and an antimy-
cobacterial benzofurochroman 37 (selected examples are shown in
Fig. 1).
The isoflavone core of derrubone 4 was achieved in an el-
egant three-step synthesis from commercially available starting
materials in 64% yield, without the need for protecting groups.3b
Unfortunately direct prenylation under various conditions gave
the O-prenyl derivative as the major product. The synthesis of
derrubone 1 was achieved indirectly by: (1) selective MOM-
protection of the isoflavone core at 7-OH, (2) O-allylation at 5-
OH, (3) Claisen rearrangement, (4) cross-metathesis using Grubbs’
second-generation catalyst with 2-methyl-2-butene to provide the
prenyl group and (5) MOM-deprotection in 27% yield over 5 steps
(Scheme 1).
Fig. 1 Selected examples.
Due to a variety of factors, prenylation can often lead to
enhanced biological activities compared to the non-prenylated
precursors,1,8 although the position of substitution is also an
important aspect.1a Owing to the potential for improved activity
Scheme 1 Synthesis of derrubone (R = 3,4-methylenedioxyphenyl).3b
Medicinal Chemistry, Department of Pharmacy and Pharmacology, Uni-
versity of Bath, Claverton Down, Bath, BA2 7AY. E-mail: l.caggiano@
bath.ac.uk; Fax: +44 1225 386114; Tel: +44 1225 385709
† Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data and 1H NMR and 13C NMR spec-
tra, as well as selected 2D NMR data for compound 18. See DOI:
10.1039/c1ob05365e
The reaction of unprotected phenols with isoprene
(2-methylbuta-1,3-diene) affords the corresponding 2,2-
dimethylchromans and has been reported with various Lewis and
Brønsted acids, such as AlCl3,11 phosphoric acid,12 Amberlystꢀ
R
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Table 1 Prenylation of 1,2,3-trimethoxybenzene 5a
Table 2 The effect of additivesa
Isolated yields (%)
Entry
Additive
Time/h
5
6a
6b
1
None
None
20 mL H2O
DTBMP
1.25
1.5
5
0
10
5
62
68
63
7
20
23
13
0
2b
3
4c
6
87
a Reactions were all performed on 2 mmol scale in 10 mL of anhydrous
toluene at 40 ◦C with 2 equiv. isoprene and 10 mol% Bi(OTf)3. b Non-
anhydrous reagent grade toluene used. c 33 mol% DTBMP = 2,6-Di-tert-
butyl-4-methylpyridine was used.
Conversion (%)
Entry
Additive
5
6a
6b
1
2
3
4
5
6
7
8
None
ZrCl4
AlCl3
Yb(OTf)3
Zn(OTf)2
Sc(OTf)3
Bi(OTf)3
BF3·OEt2
100
—
—
Unidentified mixtures
Unidentified mixtures
100
100
58
11
65
—
—
42
70
35
—
—
—
19
—
and Zn(OTf)2; however, Sc(OTf)3 gave some prenylated product
6a but Bi(OTf)3 afforded the best results (entries 4–7). BF3·OEt2
gave the mono-product 6a selectively, although the conversion was
16b
19
lower (entry 8). Both BF3·OEt2 and Sc(OTf)3 have previously
been used in the reaction of isoprene with a phenol but not with
an aryl ether. The prenylated product 6a has also been obtained
by the gold(I)-catalysed reaction of 1,2,3-trimethoxybenzene 5
with dimethylallene in the presence of (4-ClC6H4O)3P(AuCl) and
AgBF4 in 65% yield after 16 h at room temperature.26
a Reactions were performed on 0.5 mmol scale in 2.5 mL of anhydrous
toluene with 2 equiv. isoprene at 20 ◦C for 18 h, with 10 mol% additive
where used. Conversions were determined by 1H NMR of the crude
reaction mixture after it had been passed through a plug of silica gel.
The effect of temperature on the reaction was investigated at
40 ◦C and 60 ◦C, in addition to the results obtained at 20 ◦C
(given in Table 1). It was concluded that the optimum temperature
was 40 ◦C, which was then used throughout.
Bi(OTf)3 could either act as a source of TfOH or as a Lewis
acid. Previous reports that used Bi(OTf)3 have shown that the
15,13 CpMoCl(CO)3,14 ZnCl2/AcOH,15 BF3·OEt2,16 zeolites,17
Ag(OTf),18 Sc(OTf)3–ionic liquid,19 Cu(OTf)2–bipy20 catalysts,
Me3SiI21 and HI.21a In many cases, the ortho-prenylated phenol
initially generated cyclises under the reaction conditions to
afford the chroman. Sartori, however, described the reaction of
phenols and isoprene using a zeolite HSZ-360 catalyst that gave
selectively either the prenylated phenol derivative at 80 ◦C or
˚
addition of 4 A molecular sieves was detrimental to the reaction,
whilst the addition of H2O had little effect, suggesting that TfOH
was the active species.27 Moreover, the addition of a sterically
hindered base (2,6-di-tert-butyl-4-methylpyridine; DTBMP) was
found to inhibit the Bi(OTf)3-catalysed transformation.27a,28 Sim-
ilarly, no difference in reactivity was observed in the Bi(OTf)3-
catalysed Mannich-type reaction between the anhydrous and the
hydrated form (Bi(OTf)3·4H2O) of the catalyst.29 The effect of
these additives were examined in the reaction between 1,2,3-
trimethoxybenzene 5 and isoprene at 40 ◦C and the results are
shown in Table 2.
The use of anhydrous or reagent grade toluene did not affect
the reaction (entries 1 and 2, Table 2); however, with the addition
of H2O, the reaction required 5 h to achieve similar yields (entry
3). The presence of the sterically hindered base DTBMP severely
hindered the reaction (entry 4) and these results are consistent with
previous reports that suggest Bi(OTf)3 is a source of TfOH.27–29
Although TfOH has been suggested as an active catalytic species in
the reaction of phenols with isoprene using AgOTf18 or Cu(OTf)2–
bipy catalyst,20 in both cases the authors suggest the metal also
plays an important role as a Lewis acid.
◦
the corresponding chroman at 120 C.17 Sharma also reported
the selective synthesis of C-prenylated phenols using Me3SiI
generated in situ or HI.21a
Although there are many reports of the reaction of phenols with
isoprene, there are very few examples of the equivalent reaction
with aryl ethers.17,22 The prenylation of aryl ethers with allylic
alcohols or activated derivatives is much more common.9,23 We
now describe the direct prenylation of electron-rich aryl ethers,
phenols and acetates with isoprene under mild reaction conditions,
to afford selectively the corresponding prenylated aryl ether, 2,2-
dimethylchroman and C-prenylated phenol products, respectively.
Results and discussion
During the course of our investigations into the synthesis of bio-
logically active compounds, we discovered that Bi(OTf)3 catalysed
the reaction between electron-rich aryl ethers with isoprene to
generate the prenylated product under mild conditions. Bi(OTf)3
is a commercially available, easy-to-handle Lewis acid that has
been used to catalyse a variety of reactions,24 including aromatic
sulfonation and Friedel–Crafts acylation.24a,25 We examined the
effect of various Lewis acids to catalyse the reaction between 1,2,3-
trimethoxybenzene 5 and isoprene and the results are shown in
Table 1.
Mixtures of mono- and bis-prenylated products were observed,
as the initial mono-prenylated product 6a is more reactive than
the starting material due to increased electron donation. We
investigated the effect of various equivalents of isoprene in the
reaction and the results are shown in Table 3.
There was no observable reaction in the absence of an acid
catalyst (entry 1, Table 1), whilst complicated mixtures of com-
pounds were obtained with either ZrCl4 or AlCl3 (entries 2 and
3). Of the triflate salts, no reaction was observed with Yb(OTf)3
As expected, increased equivalents of isoprene afford more of
the bis-prenylated product 6b. Two equivalents of isoprene gave
complete conversion of the starting material and good levels of
the mono- and bis-prenylated products (entry 3, Table 3), so this
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a
Table 3 The effect of isoprenea
Table 4 Prenylation of various aryl ethers with isoprene and Bi(OTf)3
Isolated yields (%)
Reaction Product(s) (% yield)
time/h
Entry Arene
sm/mono/bisb
Entry
Equiv.
Time/h
5
6a
6b
1c
1.25
—/62 (6a)/20 (6b)
1
1.1
1.5
2
2
22
8
0
50
65
62
41
7
2
20
36
2
1.5
1.25
1.25
3b
4
3
0
a Reactions were all performed on 2 mmol scale in 10 mL of anhydrous
toluene at 40 ◦C with 10 mol% Bi(OTf)3. b Entry 1, Table 2.
2
3
7
5
50/44 (8)/—
85/15 (10)/—
was used with various phenolic ethers and the results are shown
in Table 4.
5-Bromo-1,2,3-trimethoxybenzene 7 was less reactive than
trimethoxybenzene 5 and required 7 h to afford the mono-
prenylated product 8 in 44% yield, together with 50% unreacted
starting material, presumably due to the steric and electronic in-
fluences of the bromo substituent (entry 2, Table 4). The reactivity
was further diminished with a methyl ester substituent, affording
the prenylated ester 10 in only 15% yield and 85% recovered start-
ing material after 5 h (entry 3). 3,4,5-Trimethoxyacetophenone and
3,4,5-trimethoxybenzaldehyde (not shown) only gave unidentified
mixtures of compounds when subjected to the reaction conditions.
The cinnamic methyl ester 11 gave an improved yield, affording
mono-prenylated product 12 in 47% yield after 4 h (entry 4).
An increase in reactivity was observed with the removal of
conjugation, as the dihydrocinnamic methyl ester 13 gave both
the mono- and bis-prenylated products in 58% (14a) and 30%
(14b) yields, respectively, after only 1.5 h (entry 5).
4
5
4
18/47 (12)/—
1.5
—/58 (14a)/30
(14b)
The dimethoxy derivates were less reactive and required longer
reaction times. As previously observed, the unsaturated cinnamate
derivative 15 was less reactive than the saturated methyl ester 17
and gave the mono-prenylated products in 17% (16) and 64%
(18) yields, respectively (entries 6 and 7). Only the products
from prenylation at C2 were obtained, as determined by NOESY
correlations between the methylene protons indicated in ester 18
(Fig. 2).†
6
7
6
6
57/17 (16)/—
—/64 (18)/—
a Reactions were all performed on 2 mmol scale in 10 mL of anhydrous
toluene at 40 ◦C with 2 equiv. isoprene and 10 mol% Bi(OTf)3. b sm refers
to recovered starting material, mono product is either R = prenyl or R1 =
prenyl R2 = H, and bis refers to R1 = R2 = prenyl. c Entry 1, Table 2.
Fig. 2 Key NOESY correlation between highlighted protons.
The mono-methoxycinnamic esters were also investigated and
were the least reactive in this series (results not shown). Methyl
4-methoxycinnamate did not show any conversion after 6 h
and although methyl 4-methoxydihydrocinnamate appeared to
afford the mono-prenylated product by 1H NMR, it was a minor
component in an inseparable mixture by column chromatography
with unreacted starting material.
Application to phenols
Substituted phenols were subjected to the optimised reaction
conditions reported in Table 4 and the results are shown in Scheme
2 below.
These results demonstrate the possibility of selective and direct
prenylation of electron-rich aryl ethers present in various biolog-
ically active compounds, such as flavonoids and chalcones,1a,c–h
which could exhibit improved activities.
Treatment of the methyl ketone 19 with 10 mol% Bi(OTf)3 and
isoprene at 40 ◦C gave the cyclised product 20 directly in 26%
yield after 5 h, with the recovery of 55% of unreacted phenol
19 (Scheme 2). Leaving the reaction for 18 h, however, gave the
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phenol 30 to our reaction conditions gave the cyclised chroman 32
directly in 55% yield after 18 h (Scheme 4).
Scheme 2 Prenylation of phenol derivatives.
cyclised product 20 in 58% yield with 23% of recovered starting
material. The carboxylic acid 21 gave the corresponding chroman
22 in only 3% yield, with 92% unreacted starting material even after
24 h. The methyl ester 23, however, gave the chroman derivative
24 in 65% yield after 5 h, together with 11% of unreacted phenol
23.
Reaction of 2,4-dihydroxyacetophenone 25 with isoprene in the
presence of Bi(OTf)3 gave a mixture of compounds 26 (24%), 27
(10%) and 28 (13%) (Scheme 3). A different mixture of possible
products was observed when this reaction was catalysed with
H3PO4, as chromans 26 (14%), 28 (5%) and 29 (17%) were
obtained.12b
Scheme 4 Prenylation of phenol 30.
As previously described, the reaction presumably proceeds via
the ortho-prenylated phenol 31a, which undergoes cyclisation
under the reaction conditions to afford the chroman 32 (Scheme
4). The dienone 33, resulting from attack at the para-position with
respect to the phenol OH, was also isolated from the reaction
mixture in 26% yield. Only the chroman 32 was previously
reported in the reaction of phenol 30 and isoprene catalysed
by using zeolite HSZ-36017 or Sc(OTf)3 in ionic liquid.19
A
similar transformation was, however, observed in the reaction
between 3,4,5-trimethoxyphenol 30 and 3-chloro-3-methylbut-1-
yne with K2CO3, which gave the corresponding ether in addition
to the related dienone from para-attack.35 It is of great interest
that the dienone 33 is structurally similar to tarennane 34,
a natural product isolated from the whole plant of Tarenna
attenuata, that displays potent antioxidant activities against H2O2
damage.36
To prevent formation of the chroman and synthesise selectively
the ortho-prenylated phenol 31a, we investigated the protection
of the phenol group in situ. Phenol has been efficiently acetylated
by Ac2O in the presence of 1 mol% Bi(OTf)3 in 98% yield after
5 min at room temperature.37 Incorporation of Ac2O to our
optimised reaction conditions resulted in the initial protection
of the phenol 30 which, upon the addition of isoprene, gave the
desired prenylated product 35a as the acetate in 70% yield, together
with the bis-product 35b in 15% yield, in a one-pot transformation
(Scheme 5).
Scheme 3 Prenylation of resorcinol 25.
The chromans obtained in Schemes 2 and 3 could be generated
by the initial formation of the O-prenyl aryl ether and subsequent
rearrangement to the corresponding C-prenylated product,9,17,20,30
which has been previously reported with Bi(OTf)3.9b,31 However,
since the results obtained vide supra demonstrate that the presence
of a free phenolic OH is not necessary for prenylation, the reaction
presumably occurs through direct C-alkylation of the arene by a
Friedel–Crafts-type capture of the carbocation generated by the
protonation of isoprene by TfOH (cf. H3PO4).12a,12d Cyclisation of
the ortho-prenylated phenol under the reaction conditions would
then afford the observed 2,2-dimethylchroman product, which has
been previously achieved with HCl/AlCl3,32 BF3·OEt2.33 clay,30b
zeolites17 as well as Bi(OTf)3.9b,31
The prenylated phenol 31a has been isolated from the leaves and
stems of Piper clarkii and displays anti-invasive activity against
human MCF-7/6 breast carcinoma cells.34 Sartori previously
reported that the reaction of 3,4,5-trimethoxyphenol 30 with
isoprene in the presence of a zeolite catalyst gave the prenylated
phenol 31a in 40% yield at 80 ◦C or the corresponding chroman 32
at 120 ◦C.17 Youn also reported the synthesis of chroman 32 using
a Sc(OTf)3–ionic liquid catalyst system.19 Submission of the free
Removal of the acetal group was achieved under standard
conditions using K2CO3 in MeOH (Method A) to afford the
mono-prenylated phenol 31a in 49% yield and the bis-prenylated
derivative 31b in only 32% yield (Scheme 5). The cleavage of
aromatic acetates using K2CO3 in MeOH gave high yields of
related Plicatin B (89%)38 and the 8-prenyl isomer of derrubone
(90%),3b although variable results were also reported (15–67%)
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Experimental
General
NMR spectra were obtained on Varian Mercury VX (400 MHz)
or Bruker Avance III (400 MHz) spectrometers. The chemical
shifts are recorded in parts per million (ppm) with reference to
tetramethylsilane. The coupling constants J are quoted to the
nearest 0.5 Hz and are not corrected. Mass spectra were obtained
on a micrOTOFTM from Bruker Daltonics. Melting points were
obtained using a Reichert–Jung heated-stage microscope. Infrared
spectra were recorded on a Perkin–Elmer Spectrum RXI FT-IR
system and all values are recorded in cm-1. PE refers to petroleum
ether, bp 40–60 ◦C.
Methyl 3,4,5-trimethoxybenzoate 9, methyl E-3-(3,4,5-trimeth-
oxyphenyl)propenoate 11, methyl 3-(3,4,5-trimethoxyphenyl)-
propanoate 13, methyl E-3-(3,4-dimethoxyphenyl)propenoate 15
and methyl 4-hydroxybenzoate 23 were all synthesised from their
corresponding carboxylic acids following the procedure reported
by Parrain43 and gave samples that were consistent with the
spectroscopic data reported for 9,44 11,43 13,45 1546 and 23.47
Scheme 5 One- and two-step synthesis of 31a.
Methyl 3-(3,4-dimethoxyphenyl)propanoate (17). 10% palla-
dium on carbon (50 mg, 0.05 mmol) was added to a vigorously
stirred solution of methyl 3,4-dimethoxycinnamate (819 mg,
3.69 mmol) in EtOH (20 mL). After 3 cycles of purging the flask
with N2 then a vacuum, the flask was put under an atmosphere
with other similar substrates.39 Narender recently reported the use
of NaOAc in the deacetylation of structurally related aromatic
acetates in high yields.40 However, treatment of the acetate
35a with NaOAc in aqueous EtOH for 5 h (Method B), as
described by Narender,40 gave the desired phenol 31a in only 36%
yield, together with 40% recovered starting material. A one-pot
transformation from phenol 30 was also investigated and gave the
prenylated phenol 31a in 44% yield (Scheme 5). The acetophenone
derivative 36 was also isolated in 9% yield, which is obtained
from a Fries rearrangement of the aromatic acetate and has been
reported with BF3·OEt241 and in similar systems in the presence of
Bi(OTf)3.31,42
R
of H2. After 2 h, the mixture was filtered through Celiteꢀ, washed
thoroughly with EtOH, then the solvent removed under reduced
pressure to afford the methyl propionate 17 (821 mg, 99%) as a
colourless oil without need for further purification.
1H NMR dH (400 MHz, CDCl3) 6.84 (1H, d, J 8.5 Hz, C5–ArH),
6.77 (1H, dd, J 8.5 and 2.0 Hz, C6–ArH), 6.76 (1H, d, J 2.0 Hz,
C2–ArH), 3.90 (3H, s, ArOMe), 3.88 (3H, s, ArOMe), 3.70 (3H, s,
CO2Me), 2.93 (2H, t, J 7.5 Hz, ArCH2) and 2.64 (2H, t, J 7.5 Hz,
CH2CO2Me); 13C NMR dC (100 MHz, CDCl3) 173.4, 149.0, 147.6,
133.2, 120.1, 111.8, 111.4, 56.0, 55.9, 51.6, 36.0 and 30.6.
Consistent with the spectroscopic data previously reported.48
Conclusions
General procedure: formation of prenylated and chroman
compounds
The procedure described here represents a novel and practical
Friedel–Crafts-type prenylation of electron-rich aryl ethers and
phenols under mild reaction conditions using readily available
and atom-efficient isoprene. The reaction of the acetate-protected
phenol demonstrates that this substituent is also an effective
substrate in the reaction and can be used to afford selectively the
ortho-prenylated phenol without the formation of the chroman.
The application of this methodology to the efficient synthesis of a
natural product (31a) and non-natural analogues (33 and 31b) is
also reported.
Many biologically active compounds possess an electron-rich
aromatic core. Since prenylation can lead to enhanced activi-
ties, the transformation described herein could find applications
in medicinal chemistry programmes, increasing the number of
compounds available for screening. The mild reaction conditions,
predictable selectivity and functionality generated makes this
reaction a very useful medicinal chemistry tool. The formation of
C–C and C–O bonds in the presence of an inexpensive and easy-
to-handle catalyst under mild reaction conditions is also worthy
of note.
Bi(OTf)3 (136 mg, 0.2 mmol) was added to a vigorously stirred
solution of the arene (2 mmol) and isoprene (400 ml, 4 mmol)
in anhydrous toluene (10 mL) in a thick-walled pressure tube
at room temperature under Ar. The tube was sealed and the
reaction heated at 40 ◦C for between 75 min and 24 h and the
crude reaction mixture (often dark purple/black in colour) was
applied directly to a silica gel chromatography column to afford
the purified product(s). Representative reactions have also been
performed in a conventional round-bottomed flask with a tightly
fitted stopper to afford similar results.
1,2,3-Trimethoxy-4-(3-methylbut-2-en-1-yl)benzene (6a) and
2,3,4-trimethoxy-1,5-bis(3-methylbut-2-en-1-yl)benzene
(6b).
Following the general procedure, 1,2,3-trimethoxybenzene 5
(336 mg, 2 mmol) gave, after 75 min and subsequent column
chromatography [silica, PE–Et2O gradient from 100 : 0 to 90 : 10],
the mono-product 6a (292 mg, 62%) and the bis-product 6b
(122 mg, 20%) as colourless oils.
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Mono-product (6a). IR nmax (thin film) 2936, 1599, 1495, 1464,
1416, 1294, 1256, 1096 and 1017; 1H NMR dH (400 MHz, CDCl3)
6.86 (1H, d, J 8.5 Hz, ArH), 6.64 (1H, d, J 8.5 Hz, ArH), 5.28
(1H, triplet of septets, J 7.5 and 1.5 Hz, CH CMe2), 3.91 (3H,
s, OMe), 3.90 (3H, s, OMe), 3.87 (3H, s, OMe), 3.31 (2H, d, J
7.5 Hz, ArCH2), 1.77 (3H, br s, CH CMeAMeB) and 1.77 (3H,
br s, CH CMeAMeB); 13C NMR dC (100 MHz, CDCl3) 152.0,
151.8, 142.4, 132.0, 127.9, 123.5, 123.3, 107.4, 60.7, 60.7, 56.0,
28.2, 25.7 and 17.7.
the mono-product 12 (302 mg, 47%) as a colourless oil in addition
to ester 11 (90 mg, 18%).
IR nmax (thin film) 2937, 1719 (C O), 1631, 1592, 1566, 1487,
1409, 1347, 1289, 1254, 1168, 1124; 1H NMR dH (400 MHz,
CDCl3) 7.92 (1H, d, J 15.5 Hz, CH CHCO2Me), 6.87 (1H, s,
ArH), 6.26 (1H, d, J 15.5 Hz, CH CHCO2Me), 5.02 (1H, t, J
6.5 Hz, CH CMe2), 3.89 (3H, s, OMe), 3.86 (3H, s, OMe), 3.83
(3H, s, OMe), 3.79 (3H, s, OMe), 3.42 (2H, d, J 6.5 Hz, ArCH2),
1.81 (3H, s, CH CMeAMeB) and 1.67 (3H, s, CH CMeAMeB);
13C NMR dC (100 MHz, CDCl3) 167.4, 151.9, 151.7, 144.2, 142.6,
131.6, 129.0, 128.6, 123.1, 118.0, 105.3, 61.0, 60.8, 55.9, 51.6, 25.7,
25.0 and 17.9; MS (+ESI) m/z 343 (MNa+, 11%); HRMS (+ESI)
Found MNa+, 343.1508; C18H24NaO5 requires MNa+ 343.1521.
Consistent with the spectroscopic data previously reported.26
Bis-product (6b). IR nmax (thin film) 2965, 2931, 1479, 1460,
1
1411, 1325, 1235, 1092, 1065 and 1015; H NMR dH (400 MHz,
CDCl3) 6.67 (1H, s, ArH), 5.25 (2H, triplet of septets, J 7.0 and
1.5 Hz, CH CMe2), 3.91 (3H, s, OMe), 3.83 (6H, s, OMe), 3.27
(4H, d, J 7.0 Hz, ArCH2) and 1.74 (12H, d, J 1.5 Hz, CH CMe2);
13C NMR dC (100 MHz, CDCl3) 149.8, 146.3, 132.0, 130.3, 124.2,
123.3, 60.8, 60.6, 28.4, 25.7 and 17.8; MS (+ESI) m/z 305 (MH+,
9%); HRMS (+ESI) Found MH+, 305.2103; C19H29O3 requires
MH+ 305.2117.
Methyl 3-(3,4,5-trimethoxy-2-(3-methylbut-2-en-1-yl)phenyl)-
propanoate (14a) and methyl 3-(3,4,5-trimethoxy-2,6-bis(3-
methylbut-2-en-1-yl)phenyl)propanoate (14b). Following the gen-
eral procedure, ester 13 (508 mg, 2 mmol) gave, after 90 min
and subsequent column chromatography [silica, PE–Et2O gradient
from 100 : 0 to 80 : 20], the mono-product 14a (376 mg, 58%) and
the bis-product 14b (233 mg, 30%) as colourless oils.
1-Bromo-3,4,5-trimethoxy-2-(3-methylbut-2-en-1-yl)benzene
(8). Following the general procedure, the aryl bromide 7 (494 mg,
2 mmol) gave, after 7 h and subsequent column chromatography
[silica, PE–Et2O gradient from 100 : 0 to 95 : 5], the product 8
(275 mg, 44%) as a colourless oil in addition to recovered starting
material 7 (246 mg, 50%).
Mono-product (14a). Rf [PE–Et2O 80 : 20] 0.27; IR nmax (thin
film) 2935, 1739 (C O), 1599, 1578, 1494, 1453, 1406, 1338, 1283,
1239, 1196, 1121, 1073 and 1042; 1H NMR dH (400 MHz, CDCl3)
6.53 (1H, s, ArH), 5.08–5.04 (1H, m, CH CMe2), 3.87 (3H, s,
OMe), 3.86 (3H, s, OMe), 3.84 (3H, s, OMe), 3.71 (3H, s, OMe),
3.33 (2H, d, J 6.5 Hz, ArCH2CH CMe2), 2.93–2.89 (2H, m,
ArCH2CH2CO2Me) 2.60–2.56 (2H, m, CH2CO2Me), 1.79 (3H, br
s, CH CMeAMeB) and 1.71 (3H, d, J 1.0 Hz, CH CMeAMeB);
13C NMR dC (100 MHz, CDCl3) 173.4, 152.1, 151.5, 140.9, 134.2,
131.1, 126.2, 123.8, 108.4, 60.9, 60.7, 56.0, 51.6, 35.5, 28.3, 25.6,
25.2 and 17.8; MS (+ESI) m/z 345 (MNa+, 24%); HRMS (+ESI)
Found MNa+, 345.1661; C18H26NaO5 requires MNa+ 345.1678.
Rf [PE–Et2O 70 : 30] 0.63; IR nmax (thin film) 2935, 1590, 1482,
1452, 1430, 1396, 1313, 1270, 1237, 1195, 1156, 1113, 1045 and
1
1019; H NMR dH (400 MHz, CDCl3) 6.87 (1H, s, ArH), 5.12
(1H, triplet of septets, J 7.0 and 1.5 Hz, CH CMe2), 3.84, (6H,
s, OMe), 3.82 (3H, s, OMe), 3.42, (2H, d, J 7.0 Hz, ArCH2),
1.79 (3H, br s, CH CMeAMeB) and 1.68 (3H, d, J 1.0 Hz,
CH CMeAMeB); 13C NMR dC (100 MHz, CDCl3) 152.6, 152.1,
142.0, 131.8, 128.1, 122.1, 117.9, 112.0, 61.1, 60.7, 56.2, 29.3, 25.7
and 18.1; MS (+ESI) m/z 315 (MH+, 97%), 317 (MH+, 100)
and 337 (MNa+, 23); HRMS (+ESI) Found MNa+, 337.0400;
C14H1979BrNaO3 requires MNa+ 337.0415.
Bis-product (14b). Rf [PE–Et2O 80 : 20] 0.51; IR nmax(thin film)
2948, 2933, 1740 (C O), 1463, 1416, 1334, 1195, 1170, 1096,
1048 and 982; 1H NMR dH (400 MHz, CDCl3) 5.10–5.06 (2H, m,
CH CMeAMeB), 3.91 (3H, s, OMe), 3.85 (6H, s, OMe), 3.72 (3H,
s, OMe), 3.36 (4H, d, J 6.5 Hz, ArCH2CH CMe2), 2.93–2.89
(2H, m, ArCH2CH2CO2Me), 2.50–2.46 (2H, m, CH2CO2Me),
1.79 (6H, d, J 1.0 Hz, CH CMeAMeB) and 1.71 (6H, d, J 1.0 Hz,
CH CMeAMeB); 13C NMR dC (100 MHz, CDCl3) 173.4, 150.3,
144.8, 133.0, 131.1, 129.5, 124.0, 60.8, 60.4, 51.5, 34.9, 25.7, 25.6,
24.8 and 17.8; MS (+ESI) m/z 391 (MH+, 20%); HRMS (+ESI)
Found MH+, 391.2652; C23H35O5 requires MH+ 391.2485.
Methyl 3,4,5-trimethoxy-2-(3-methylbut-2-en-1-yl)benzoate
(10). Following the general procedure, ester 9 (452 mg, 2 mmol)
gave, after 5 h and subsequent column chromatography [silica,
PE–Et2O gradient from 100 : 0 to 95 : 5], the product 10 (87 mg,
15%) as a colourless oil in addition to ester 9 (384 mg, 85%).
IR nmax (thin film) 2939, 1723 (C O), 1594, 1491, 1455, 1431,
1
1401, 1337, 1222, 1154, 1115 and 1055; H NMR dH (400 MHz,
Methyl E-3-(4,5-dimethoxy-2-(3-methylbut-2-en-1-yl)phenyl)-
propenoate (16). Following the general procedure, ester 15
(446 mg, 2 mmol) gave, after 6 h and subsequent column
chromatography [silica, PE–Et2O gradient from 100 : 0 to 90 : 10],
the mono-product 16 (100 mg, 17%) as a colourless oil.
CDCl3) 7.17 (1H, s, ArH), 5.12 (1H, triplet of septets, J 6.5 and
1.5 Hz, CH CMe2), 3.91 (3H, s, OMe), 3.86 (3H, s, OMe), 3.86
(3H, s, OMe), 3.82 (3H, s, OMe), 3.62 (2H, d, J 6.5 Hz, ArCH2),
1.75 (3H, d, J 0.5 Hz, CH CMeAMeB) and 1.66 (3H, d, J 1.0 Hz,
CH CMeAMeB); 13C NMR dC (100 MHz, CDCl3) 168.0, 152.3,
151.0, 145.7, 131.1, 130.7, 125.2, 123.8, 109.7, 61.0, 60.7, 56.1,
52.0, 25.9, 25.7 and 17.9; MS (+ESI) m/z 295 (MH+, 29%) and
317 (MNa+, 12); HRMS (+ESI) Found MH+, 295.1551; C16H23O5
requires MH+ 295.1546.
IR nmax (thin film) 2934, 1715 (C O), 1602, 1514, 1458, 1268,
1
1167 and 1102; H NMR dH (400 MHz, CDCl3) 7.95 (1H, d,
J 16.0 Hz, CH CHCO2Me), 7.05 (1H, s, ArH), 6.68 (1H, s,
ArH), 6.24 (1H, d, J 16.0 Hz, CH CHCO2Me), 5.16 (1H, triplet
of septets, J 7.0 and 1.5 Hz, CH CMe2), 3.87 (3H, s, OMe),
3.87 (3H, s, OMe), 3.78 (3H, s, OMe), 3.40 (2H, d, J 7.0 Hz,
ArCH2), 1.76 (3H, br s, CH CMeAMeB) and 1.71 (3H, d, J
1.0 Hz, CH CMeAMeB); 13C NMR dC (100 MHz, CDCl3) 167.7,
151.0, 147.6, 142.1, 135.5, 132.6, 125.0, 122.9, 116.3, 112.6, 109.0,
Methyl E -3-(3,4,5-trimethoxy-2-(3-methylbut-2-en-1-yl)-
phenyl)propenoate (12). Following the general procedure, ester
11 (504 mg, 2 mmol) gave, after 4 h and subsequent column
chromatography [silica, PE–Et2O gradient from 100 : 0 to 90 : 10],
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56.0, 55.9, 51.5, 31.8, 25.7 and 17.9; MS (+ESI) m/z 313 (MNa+,
9%); HRMS (+ESI) Found MNa+, 313.1424; C17H22NaO4 requires
MNa+ 313.1416.
NMR dH (400 MHz, CDCl3) 7.78 (1H, d, J 2.0 Hz, C5–ArH),
7.76 (1H, dd, J 8.5 and 2.0 Hz, C7–ArH), 6.77 (1H, d, J 8.5 Hz,
C8–ArH), 3.86 (3H, s, OMe), 2.80 (2H, t, J 7.0 Hz, C4–CH2), 1.82
(2H, t, J 7.0 Hz, C3–CH2) and 1.34 (6H, s, CMe2); 13C NMR dC
(100 MHz, CDCl3) 167.1, 158.3, 131.6, 129.1, 121.5, 120.6, 117.2,
75.3, 51.7, 32.6, 26.9 and 22.3.
Methyl 3-(4,5-dimethoxy-2-(3-methylbut-2-en-1-yl)phenyl)-
propanoate (18). Following the general procedure, ester 17
(448 mg, 2 mmol) gave, after 6 h and subsequent column
chromatography [silica, PE–Et2O gradient from 100 : 0 to 90 : 10],
the mono-product 18 (376 mg, 64%) as a colourless oil.
Consistent with the spectroscopic data previously reported.12c
1-(7-Hydroxy-2,2-dimethylchroman-6-yl)ethanone (26), 1-(5-
hydroxy-2,2-dimethylchroman-8-yl)ethanone (27) and 1-(2,2,8,8-
tetramethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f ]chromen-6-yl)eth-
anone (28). Following the general procedure, phenol 25 (304 mg,
2 mmol) gave, after 8 h and subsequent column chromatography
[silica, PE–EtOAc gradient from 100 : 0 to 70 : 30], the chroman
products 26 (105 mg, 24%) as a white solid, 27 (46 mg, 10%) as a
white solid and 28 (77 mg, 13%) as a colourless oil.
Rf [PE–Et2O 50 : 50] 0.32; IR nmax (thin film) 2934, 2851, 1737
1
(C O), 1516, 1458, 1361, 1271, 1209 and 1093; H NMR dH
(400 MHz, CDCl3) 6.69 (1H, s, ArH), 6.69 (1H, s, ArH), 5.21
(1H, triplet of septets, J 7.0 and 1.5 Hz, CH CMe2), 3.85 (3H, s,
OMe), 3.85 (3H, s, OMe), 3.69 (3H, s, OMe), 3.29 (2H, d, J 7.0 Hz,
ArCH2CH CMe2), 2.92–2.88 (2H, m, ArCH2CH2CO2Me),
2.59–2.55 (2H, m, CH2CO2Me), 1.75 (3H, br s, CH CMeAMeB)
and 1.74 (3H, br s, CH CMeAMeB); 13C NMR dC (100 MHz,
CDCl3) 173.4, 147.5, 147.2, 132.1, 131.7, 130.4, 123.4, 113.0, 112.7,
56.0, 55.9, 51.5, 35.5, 31.3, 27.8, 25.7 and 17.9; MS (+ESI) m/z 293
(MH+, 15%) and 315 (MNa+, 27); HRMS (+ESI) Found MH+,
293.1723; C17H25O4 requires MH+ 293.1753.
◦
Chroman (26). Mp 115–118 C (from EtOAc); lit.12b 118–
◦
119 C; IR nmax (thin film) 2937, 2957, 1867, 1647 (C O), 1612,
1495, 1369, 1288, 1280, 1161, 1118, 1058 1020 and 885; 1H NMR
dH (400 MHz, CDCl3) 12.30 (1H, s, OH), 7.41 (1H, s, C5–ArH),
6.28 (1H, s, C8–ArH), 2.71 (2H, t, J 7.0 Hz, C4–CH2), 2.70 (3H,
s, COMe), 1.80 (2H, t, J 7.0 Hz, C3–CH2) and 1.33 (6H, s, CMe2);
13C NMR dC (100 MHz, CDCl3) 202.3, 162.8, 161.4, 132.2, 113.9,
112.7, 104.6, 75.9, 32.7, 26.4, 26.1 and 21.7.
1-(2,2-Dimethylchroman-6-yl)ethanone (20). Following the
general procedure, phenol 19 (272 mg, 2 mmol) gave, after 18 h
and subsequent column chromatography [silica, PE–Et2O–EtOAc
gradient from 100 : 0 : 0 to 85 : 15 : 0 then 50 : 0 : 50], the chroman
20 (235 mg, 58%) as a white solid in addition to phenol 19 (62 mg,
23%).
Consistent with the spectroscopic data previously reported.12b,50
Chroman (27). Mp 165–170 ◦C (from EtOAc); IR nmax (thin
Rf [PE-Et2O 70 : 30] 0.63; Mp 89–93 ◦C (from CH2Cl2); IR nmax
(thin film) 2976, 1670 (C O), 1537, 1498, 1419, 1358, 1289, 1265,
film) 3172, 2974, 2931, 1638 (C O), 1583, 1433, 1362, 1277, 1217,
1
1157, 1119 and 1051; H NMR dH (400 MHz, CDCl3) 7.68 (1H,
1
1156 and 1117; H NMR dH (400 MHz, CDCl3) 7.75 (1H, d, J
d, J 8.5 Hz, C7–ArH), 7.20 (1H, broad s, OH), 6.47 (1H, d, J
8.5 Hz, C6–ArH), 2.74 (2H, t, J 7.0 Hz, C4–CH2), 2.64 (3H, s,
COMe), 1.87 (2H, t, J 7.0 Hz, C3–CH2) and 1.43 (6H, s, CMe2);
13C NMR dC (100 MHz, CDCl3) 199.7, 159.2, 156.4, 129.9, 120.3,
108.5, 107.0, 75.3, 32.2, 31.6, 26.9 and 17.0.
2.5 Hz, C5–ArH), 7.73 (1H, dd, J 8.5 and 2.5 Hz, C7–ArH), 6.81
(1H, d, J 8.5 Hz, C8–ArH), 2.83 (2H, t, J 6.5 Hz, C4–CH2), 2.54
(3H, s, COMe), 1.84 (2H, t, J 6.5 Hz, C3–CH2) and 1.37 (6H, s,
CMe2); 13C NMR dC (100 MHz, CDCl3) 196.9, 158.6, 130.5, 129.4,
128.3, 120.7, 117.2, 75.5, 32.5, 26.9, 26.2 and 22.4.
Chroman (28). IR nmax (thin film) 2974, 2933, 1662 (C O),
1603, 1579, 1457, 1357, 1298, 1258, 1178, 1154, 1120 and 1096;
1H NMR dH (400 MHz, CDCl3) 7.48 (1H, s, C5–ArH), 2.70 (2H,
t, J 7.0 Hz, C4–CH2), 2.60 (2H, t, J 7.0 Hz, C10–CH2), 2.56 (3H,
s, COMe), 1.76 (2H, t, J 7.0 Hz, C9–CH2), 1.76 (2H, t, J 7.0 Hz,
C3–CH2), 1.35 (6H, s, C(8)–CMe2) and 1.32 (6H, s, C2–CMe2);
13C NMR dC (100 MHz, CDCl3) 198.6, 156.2, 153.8, 129.2, 120.0,
111.9, 109.4, 75.3, 74.7, 32.8, 32.3, 31.8, 27.1, 26.8, 21.7 and 17.2.
Consistent with the spectroscopic data previously reported.12b
Consistent with the spectroscopic data previously reported.16b
2,2-Dimethylchroman-6-carboxylic acid (22). Following the
general procedure, phenol 21 (276 mg, 2 mmol) gave, after 24 h and
subsequent column chromatography [silica, PE–EtOAc gradient
from 100 : 0 to 40 : 60], the chroman 22 (14 mg, 3%) as a white
solid in addition to phenol 21 (254 mg, 92%).
IR nmax (thin film) 2975, 1681 (C O), 1608, 1578, 1443, 1411,
1324, 1296, 1265, 1156 and 1120; 1H NMR dH (400 MHz, CDCl3)
7.86 (1H, d, J 2.0 Hz, C5–ArH), 7.84 (1H, dd, J 8.5 and 2.0 Hz,
C7–ArH), 6.82 (1H, d, J 8.5 Hz, C8–ArH), 2.84 (2H, t, J 7.0 Hz,
C4–CH2), 1.84 (2H, t, J 7.0 Hz, C3–CH2) and 1.36 (6H, s, CMe2);
13C NMR dC (100 MHz, CDCl3) 172.1, 159.1, 132.4, 129.9, 120.8,
120.7, 117.4, 75.6, 32.5, 26.9 and 22.3; MS (+ESI) m/z 207 (MH+,
100%) and 229 (MNa+, 45); HRMS (+ESI) Found MH+, 207.1033;
C12H15O3 requires MH+ 207.1021.
5,6,7-Trimethoxy-2,2-dimethylchroman (32) and 3,4,5-tri-
methoxy-4-(3-methylbut-2-en-1-yl)-cyclohexa-2,5-dienone
(33).
Following the general procedure, phenol 30 (368 mg, 2 mmol)
gave, after 18 h and subsequent column chromatography [silica,
PE–Et2O gradient from 100 : 0 to 85 : 15 then PE–EtOAc gradient
from 50 : 50 to 30 : 70], the chroman product 32 (279 mg, 55%) as
a colourless oil and the dienone 33 (132 mg, 26%) as a white solid.
Consistent with the spectroscopic data previously reported.49
Methyl 2,2-dimethylchroman-6-carboxylate (24). Following
the general procedure, phenol 23 (304 mg, 2 mmol) gave, after 5 h
and subsequent column chromatography [silica, PE–Et2O gradient
from 100 : 0 to 85 : 15] the chroman 24 (285 mg, 65%) as a white
solid in addition to phenol 23 (32 mg, 11%).
Chroman (32). Rf [PE-Et2O 80 : 20] 0.52; IR nmax (thin film)
2973, 2937, 1611, 1489, 1460, 1413, 1324, 1203, 1158, 1131, 1098,
1045 and 1013; 1H NMR dH (400 MHz, CDCl3) 6.15 (1H, s, C8–
ArH), 3.87 (3H, s, C6–OMe), 3.79 (3H, s, C5–OMe), 3.78 (3H,
s, C7–OMe), 2.63 (2H, t, J 7.0 Hz, C4–CH2), 1.73 (2H, t, J
7.0 Hz, C3–CH2), 1.30 (3H, s, C2–CMeAMeB) and 1.28 (3H, s,
C2–CMeAMeB); 13C NMR dC (100 MHz, CDCl3) 152.4, 151.4,
Rf [PE-Et2O 70 : 30] 0.61; IR nmax (thin film) 2975, 2948, 1716
1
(C O), 1613, 1581, 1493, 1437, 1290, 1263, 1155 and 1118; H
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150.0, 135.4, 106.7, 96.6, 74.0, 61.0, 60.5, 55.8, 32.4, 26.7, 26.7 and
17.0.
were washed with saturated brine (15 mL), dried over anhydrous
Na2SO4, filtered and the solvent removed under reduced pressure.
Column chromatography [silica, PE–EtOAc gradient from 100 : 1
to 75 : 25] afforded the phenol product.
Consistent with the spectroscopic data previously reported.19
Dienone (33). Rf [PE–EtOAc 40 : 60] 0.50; Mp 106–109 ◦C
(from CH2Cl2); IR nmax (thin film) 2934, 2852, 1659 (C O),
1625, 1597, 1459, 1374, 1240, 1215, 1163, 1078 and 888; 1H
NMR dH (400 MHz, CDCl3) 5.56 (2H, s, C2/C6–CH), 4.66 (1H,
triplet of septets, J 7.5 and 1.5 Hz, CH CMe2), 3.73 (6H, s,
C3/C5–OMe), 3.08 (3H, s, C4–OMe), 2.67 (2H, d, J 7.5 Hz,
CH2CH CMe2), 1.56 (3H, br s, CH CMeAMeB) and 1.52 (3H,
br s, CH CMeAMeB); 13C NMR dC (100 MHz, CDCl3) 187.3,
169.4, 136.3, 115.7, 104.3, 79.4, 56.0, 52.5, 35.6, 25.7 and 17.6; MS
(+ESI) m/z 253 (MH+); HRMS (+ESI) Found MH+, 253.1427;
C14H21O4 requires MH+ 253.1440.
Method B: Following a procedure reported by Narender et al.,40
NaOAc (10 equiv.) was added to a solution of the acetate (1
equiv.) in EtOH/H2O (10 : 1, 5.5 mL mmol-1) and the reaction
heated at reflux for 5 h. After cooling, the reaction was diluted
with H2O (15 mL) and extracted with EtOAc (3 ¥ 15 mL). The
organic fractions were combined, washed with saturated brine
(15 mL), dried over anhydrous Na2SO4, filtered and the solvent
removed under reduced pressure. Column chromatography [silica,
PE–EtOAc gradient from 100 : 1 to 75 : 25] afforded the phenol
product.
3,4,5-Trimethoxy-2-(3-methylbut-2-en-1-yl)phenol (31a). Fol-
lowing Method A, acetate 35a (411 mg, 1.4 mmol) gave the
phenol 31a (173 mg, 49%) as a yellow amorphous solid. Following
Method B, acetate 35a (132 mg, 0.45 mmol) gave the phenol 31a
(41 mg, 36%) as a yellow amorphous solid, in addition to acetate
35a (53 mg, 40%).
3,4,5-Trimethoxy-2-(3-methylbut-2-en-1-yl)-phenyl acetate
(35a) and 3,4,5-trimethoxy-2,6-bis(3-methylbut-2-en-1-yl)phenyl
acetate (35b). Incorporating the procedure reported by
Mohammadpoor–Baltork,37 Ac2O (283 ml, 3 mmol) was added
to a rapidly stirred suspension of Bi(OTf)3 (136 mg, 0.2 mmol)
and phenol 30 (368 mg, 2 mmol) in anhydrous toluene (10 mL)
in a thick-walled pressure tube at room temperature under Ar.
After 5 min, isoprene (400 ml, 4 mmol) was added to the solution
and the tube was sealed and the reaction heated at 40 ◦C for 1 h.
Column chromatography [silica, PE–Et2O gradient from 100 : 0 to
90 : 10] gave the mono-prenylated product 35a (414 mg, 70%) and
the bis-prenylated product 35b (108 mg, 15%) as colourless oils.
Rf [PE–EtOAc 75 : 25] 0.25; IR nmax (thin film) 3392, 2963, 1935,
1607, 1505, 1463, 1415, 1357, 1237, 1197, 1164, 1126, 1082, 1040
and 993; 1H NMR dH (400 MHz, CDCl3) 6.20 (1H, s, C6–ArH),
5.70 (1H, s, OH), 5.19 (1H, triplet of septets, J 7.0 and 1.5 Hz,
CH CMe2), 3.83 (3H, s, OMe), 3.79 (3H, s, OMe), 3.72 (3H,
s, OMe), 3.31 (2H, d, J 7.0 Hz, ArCH2), 1.78 (3H, d, J 1.0 Hz,
CH CMeAMeB) and 1.70 (3H, d, J 1.0 Hz, CH CMeAMeB);
13C NMR dC (100 MHz, CDCl3) 151.9, 151.9, 150.9, 136.1, 133.6,
122.6, 113.0, 96.6, 61.2, 61.0, 55.9, 25.7, 22.8 and 17.8; MS (+ESI)
m/z 253 (MH+ 100%) and 275 (MNa+, 92); HRMS (+ESI) Found
MNa+, 275.1272 C14H20NaO4 requires MNa+ 275.1259.
Mono-product (35a). Rf [PE–Et2O 80 : 20] 0.37; IR nmax (thin
film) 2937, 1767 (C O), 1608, 1490, 1456, 1408, 1368, 1339,
1206, 1122, 1075 and 1042; 1H NMR dH (400 MHz, CDCl3) 6.38
(1H, s, C6–ArH), 5.06 (1H, triplet of septets, J 7.0 and 1.5 Hz,
CH CMe2), 3.85 (3H, s, OMe), 3.84 (3H, s, OMe), 3.80 (3H, s,
OMe), 3.17 (2H, d, J 7.0 Hz, ArCH2), 2.27 (3H, s, Ac), 1.73 (3H, br
s, CH CMeAMeB) and 1.66 (3H, d, J 1.0 Hz, CH CMeAMeB);
13C NMR dC (100 MHz, CDCl3) 169.5, 152.3, 151.7, 144.5, 140.5,
131.3, 122.7, 120.1, 102.4, 61.0, 60.8, 56.0, 25.6, 23.5, 20.8 and
17.7; MS (+ESI) m/z 295 (MH+, 24%), 317 (MNa+, 20); HRMS
(+ESI) Found MH+, 295.1533; C16H23O5 requires MH+ 295.1546.
Consistent with the spectroscopic data previously reported.34b
3,4,5-Trimethoxy-2,6-bis(3-methylbut-2-en-1-yl)phenol (31b).
Following Method A, acetate 35b (100 mg, 0.27 mmol) gave the
phenol 31b (28 mg, 32%) as a colourless oil.
IR nmax (thin film) 3461, 2964, 2933, 1605, 1462, 1418, 1357,
1256, 1171, 1097, 1051 and 987; 1H NMR dH (400 MHz, CDCl3)
5.59 (1H, s, OH), 5.21 (2H, triplet of septets, J 7.0 and 1.5 Hz,
CH CMe2), 3.85(3H, s, C4–OMe), 3.84(6H, s, C3/5–OMe), 3.34
(4H, d, J 7.0 Hz, ArCH2), 1.80 (6H, d, J 1.0 Hz, CH CMeAMeB)
and 1.72 (6H, d, J 1.0 Hz, CH CMeAMeB); 13C NMR dC
(100 MHz, CDCl3) 150.1, 149.2, 140.3, 133.4, 122.6, 116.8, 61.1,
60.9, 25.8, 23.1 and 17.8; MS (+ESI) m/z 321 (MH+, 50%); HRMS
(+ESI) Found MH+, 321.2066; C19H29O4 requires MH+ 321.2066.
Bis-product (35b). Rf [PE–Et2O 80 : 20] 0.61; IR nmax (thin film)
2935, 1765 (C O), 1600, 1463, 1416, 1367, 1346, 1204, 1097,.
1
1048 and 982; H NMR dH (400 MHz, CDCl3) 5.08 (2H, triplet
of septets, J 7.0 and 1.5 Hz, CH CMe2), 3.87 (3H, s, C4–OMe),
3.82 (6H, s, C3/5–OMe), 3.16 (4H, broad s, ArCH2), 2.52 (3H,
s, Ac), 1.73 (6H, d, J 1.0 Hz, CH CMeAMeB) and 1.73 (6H,
d, J 1.0 Hz, CH CMeAMeB); 13C NMR dC (100 MHz, CDCl3)
169.3, 150.3, 144.8, 143.2, 131.3, 123.7, 122.7, 61.0, 60.6, 25.6,
24.1, 20.6 and 17.8; MS (+ESI) m/z 363 (MH+, 5%) and 385
(MNa+, 14); HRMS (+ESI) Found MNa+, 385.1975 C21H30NaO5
requires MNa+ 385.1991.
3,4,5-Trimethoxy-2-(3-methylbut-2-en-1-yl)phenol (31a) and
1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethanone (36). Incorporat-
ing the procedure reported by Mohammadpoor–Baltork,37 Ac2O
(283 ml, 3 mmol) was added to a rapidly stirred suspension of
Bi(OTf)3 (136 mg, 0.2 mmol) and phenol 30 (368 mg, 2 mmol) in
anhydrous toluene (10 mL) in a thick-walled pressure tube at room
temperature under Ar. After 5 min, isoprene (400 ml, 4 mmol) was
added to the◦solution and the tube was sealed and the reaction
heated at 40 C for 4 h. The solvent was removed and following
the procedure reported by Bates et al.,38 the residue was dissolved
in MeOH (10 mL) and K2CO3 (552 mg, 4 mmol) was added. The
reaction was stirred for 50 min at room temperature and then
quenched with saturated aqueous NH4Cl (30 mL) and extracted
General procedure: deacetylation of aromatic acetates
Method A: Following a procedure reported by Bates et al. but
at a different concentration,38 K2CO3 (2 equiv.) was added to a
solution of the acetate (1 equiv.) in MeOH (5 mL mmol-1) at room
temperature and the reaction was stirred for 2 h. The suspension
was quenched with saturated aqueous NH4Cl (30 mL) and
extracted with EtOAc (3 ¥ 15 mL). The combined organic fractions
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with CH2Cl2 (3 ¥ 30 mL). The combined organic fractions were
washed with saturated brine (30 mL), dried over anhydrous
Na2SO4, filtered and the solvent removed under reduced pressure.
Column chromatography [silica, PE–EtOAc gradient from 100 : 0
to 70 : 30] gave the mono-prenylated product 31a (223 mg, 44%),
consistent with the spectroscopic data reported, in addition to the
acetophenone product 36 (39 mg, 9%) as colourless oils.
C. L. Miranda, J. F. Stevens, M. L. Deinzer and D. R. Buhler, Food
Chem. Toxicol., 2001, 39, 437; (d) Y. Nishiyama, K. Iwasa, S. Okada,
S. Takeuchi, M. Moriyasu, M. Kamigauchi, J. Koyama, A. Takeuchi,
H. Tokuda, H.-S. Kim, Y. Wataya, K. Takeda, Y.-N. Liu, P.-C. Wu, K.
F. Bastow, T. Akiyama and K.-H. Lee, Heterocycles, 2010, 81, 1193.
9 For a review of various methods see (a) C. Hoarau and T. R. R. Pettus,
Synlett, 2003, 127 and references cited therein; (b) T. Ollevier and T. M.
Mwene-Mbeja, Synthesis, 2006, 3963.
10 T. Kumano, S. B. Richard, J. P. Noel, M. Nishiyama and T. Kuzuyama,
Bioorg. Med. Chem., 2008, 16, 8117.
11 (a) L. Bolzoni, G. Casiraghi, G. Casnati and G. Sartori, Angew. Chem.,
Int. Ed. Engl., 1978, 17, 684; (b) M. Matsui and H. Yamamoto, Bull.
Chem. Soc. Jpn., 1995, 68, 2663.
12 (a) A. R. Bader and W. C. Bean, J. Am. Chem. Soc., 1958, 80, 3073;
(b) V. K. Ahluwalia and K. K. Arora, Tetrahedron, 1981, 37, 1437;
(c) V. K. Ahluwalia, R. S. Jolly and A. K. Tehim, Tetrahedron, 1982,
38, 3673; (d) V. K. Ahluwalia, K. K. Arora and R. S. Jolly, J. Chem.
Soc., Perkin Trans. 1, 1982, 335; (e) V. K. Ahluwalia, I. Mukherjee and
K. Mukherjee, Indian J. Chem. B, 1984, 23, 1124; (f) M. Tsukayama, T.
Horie, Y. Iguchi and M. Nakayama, Chem. Pharm. Bull., 1988, 36, 592;
(g) K. Omura, J. Org. Chem., 1989, 54, 1987; (h) S. Koul, J. L. Koul,
S. C. Taneja, K. L. Dhar, D. S. Jamwal, K. Singh, R. K. Reen and J.
Singh, Bioorg. Med. Chem., 2000, 8, 251.
13 G. P. Kalena, A. Jain and A. Banerji, Molecules, 1997, 2, 100.
14 Y. Yamamoto and K. Itonaga, Org. Lett., 2009, 11, 717.
15 R. Ramage, J. Green and A. J. Blake, Tetrahedron, 1991, 47, 6353.
16 (a) M. Matsui and H. Yamamoto, Bull. Chem. Soc. Jpn., 1995, 68, 2657;
(b) T. Narender, K. P. Reddy and Shweta, Synth. Commun., 2009, 39,
384.
Acetophenone product (36). 1H NMR dH (400 MHz, CDCl3)
13.39 (1H, s, OH), 6.22 (1H, s, C5–ArH), 3.97 (3H, s, OMe), 3.87
(3H, s, OMe), 3.76 (3H, s, OMe) and 2.63 (3H, s, COMe); 13C
NMR dC (100 MHz, CDCl3) 203.3, 161.9, 160.1, 155.2, 134.8,
108.5, 96.1, 61.0, 60.9, 56.0 and 31.8.
Consistent with the spectroscopic data previously reported.41
Acknowledgements
We wish to thank Dr Timothy J. Woodman (University of Bath)
for his assistance with the NMR spectra, Dr Anneke Lubben
(University of Bath) for the mass spectra and Dr Daniel P. Furkert
for the initial gift and suggestion of Bi(OTf)3. We are grateful to the
University of Bath for the studentship to KEJ and to the RCUK
for the Fellowship awarded to LC, together with the University of
Bath. LC is also a member of Cancer Research at Bath (CR@B).
17 F. Bigi, S. Carloni, R. Maggi, C. Muchetti, M. Rastelli and G. Sartori,
Synthesis, 1998, 301.
18 S. W. Youn and J. I. Eom, J. Org. Chem., 2006, 71, 6705.
19 S. W. Youn, Synlett, 2007, 3050.
20 L. A. Adrio and K. K. Hii, Chem. Commun., 2008, 2325.
21 (a) D. N. Sarma, P. Baruah, U. C. Pandey and R. P. Sharma, Tetrahedron
Lett., 1984, 25, 5581; (b) A. J. Walkington and D. A. Whiting,
Tetrahedron Lett., 1989, 30, 4731.
Notes and references
1 (a) D. Barron and R. K. Ibrahim, Phytochemistry, 1996, 43, 921; (b) K.
C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S. Barluenga
and H. J. Mitchell, J. Am. Chem. Soc., 2000, 122, 9939; (c) A. Di Pietro,
G. Conseil, J. M. Pe´rez-Victoria, G. Dayan, H. Baubichon-Cortay, D.
Trompier, E. Steinfels, J.-M. Jault, H. de Wet, M. Maitrejean, G. Comte,
A. Boumendjel, A.-M. Mariotte, C. Dumontet, D. B. McIntosh, A.
Goffeau, S. Castanys, F. Gamarro and D. Barron, Cell. Mol. Life Sci.,
2002, 59, 307; (d) V. S. Parmar, N. K. Sharma, M. Husain, A. C.
Watterson, J. Kumar, L. A. Samuelson, A. L. Cholli, A. K. Prasad, A.
Kumar, S. Malhotra, N. Kumar, A. Jha, A. Singh, I. Singh Himanshu,
A. Vats, N. A. Shakil, S. Trikha, S. Mukherjee, S. K. Sharma, S. K.
Singh, A. Kumar, H. N. Jha, C. E. Olsen, C. P. Stove, M. E. Bracke and
M. M. Mareel, Bioorg. Med. Chem., 2003, 11, 913; (e) B. Botta, A. Vitali,
P. Menendez, D. Misiti and G. Delle Monache, Curr. Med. Chem., 2005,
12, 713; (f) T. Akihisa, H. Tokuda, D. Hasegawa, M. Ukiya, Y. Kimura,
F. Enjo, T. Suzuki and H. Nishino, J. Nat. Prod., 2006, 69, 38; (g) K.
Yazaki, K. Sasaki and Y. Tsurumaru, Phytochemistry, 2009, 70, 1739;
(h) D. I. Batovska and I. T. Todorova, Curr. Clin. Pharmacol., 2010, 5,
1.
2 (a) M. G. Marcu, T. W. Schulte and L. Neckers, J. Natl. Cancer Inst.,
2000, 92, 242; (b) M. G. Marcu, A. Chadli, I. Bouhouche, M. Catelli
and L. M. Neckers, J. Biol. Chem., 2000, 275, 37181.
3 (a) M. K. Hadden, L. Galam, J. E. Gestwicki, R. L. Matts and B.
S. J. Blagg, J. Nat. Prod., 2007, 70, 2014; (b) J. M. Hastings, M. K.
Hadden and B. S. J. Blagg, J. Org. Chem., 2008, 73, 369; (c) B. Botta, P.
Menendez, G. Zappia, R. A. de Lima, R. Torge and G. Delle Monache,
Curr. Med. Chem., 2009, 16, 3414.
22 With buta-1,3-diene: O. A. Sadygov and Kh. M. Alimardanov, Russ. J.
Org. Chem., 2007, 43, 1661.
23 (a) S. Araki, S. Manabe and Y. Butsugan, Chem. Lett., 1982, 797;
(b) Y. Butsugan, K. Nagai, F. Nagaya, H. Tabuchi, K. Yamada and
S. Araki, Bull. Chem. Soc. Jpn., 1988, 61, 1707; (c) A. V. Malkov, P.
Spoor, V. Vinader and P. Kocˇovsky´, J. Org. Chem., 1999, 64, 5308;
(d) S. Mukherjee, V. Kumar, A. K. Prasad, H. G. Raj, M. E. Bracke, C.
E. Olsen, S. C. Jain and V. S. Parmar, Bioorg. Med. Chem., 2001, 9, 337;
(e) J.-H. Min, J.-S. Lee, J.-D. Yang and S. Koo, J. Org. Chem., 2003, 68,
7925; (f) S. Brajeul, B. Delpech and C. Marazano, Tetrahedron Lett.,
2007, 48, 5597; (g) J. Ricci, S. Poulain-Martini and E. Dun˜ach, C. R.
Chim., 2009, 12, 916.
24 (a) T. Ollevier, E. Nadeau and V. Desyroy, “Bismuth(III) Trifluo-
romethanesulfonate” in e-EROS Electronic Encyclopedia of Reagents
for Organic Synthesis, ed. P. L. Fuchs, John Wiley & Sons: Chichester,
2009; (b) N. M. Leonard, L. C. Wieland and R. S. Mohan, Tetrahedron,
2002, 58, 8373; (c) S. Antoniotti, Synlett, 2003, 1566; (d) H. Gaspard-
Iloughmane and C. Le Roux, Eur. J. Org. Chem., 2004, 2517; (e) R.
Mohan, Nat. Chem., 2010, 2, 336; (f) M. Rueping, B. J. Nachtsheim
and T. Scheidt, Org. Lett., 2006, 8, 3717.
25 C. Le Roux and J. Dubac, Synlett, 2002, 181.
26 M. A. Tarselli, A. Liu and M. R. Gagne´, Tetrahedron, 2009, 65, 1785.
27 (a) F. H. A. Kwie, C. Baudoin-Dehoux, C. Blonski and C. Lherbet,
Synth. Commun., 2010, 40, 1082; (b) B. Bouguerne, P. Hoffmann and
C. Lherbet, Synth. Commun., 2010, 40, 915.
4 (a) R. Monteiro, H. Becker, I. Azevedo and C. Calhau, J. Agric. Food
Chem., 2006, 54, 2938; (b) E. Lupinacci, J. Meijerink, J.-P. Vincken, B.
Gabriele, H. Gruppen and R. F. Witkamp, J. Agric. Food Chem., 2009,
57, 7274.
5 G. W. Burton and K. U. Ingold, Acc. Chem. Res., 1986, 19, 194.
6 F. Zelefack, D. Guilet, N. Fabre, C. Bayet, S. Chevalley, S. Ngouela,
B. N. Lenta, A. Valentin, E. Tsamo and M.-G. Dijoux-Franca, J. Nat.
Prod., 2009, 72, 954.
28 R. Dumeunier and I. E. Marko´, Tetrahedron Lett., 2004, 45, 825.
29 T. Ollevier and E. Nadeau, Org. Biomol. Chem., 2007, 5, 3126.
30 (a) A. M. Bernard, M. T. Cocco, V. Onnis and P. P. Piras, Synthesis,
1998, 256; (b) W. G. Dauben, J. M. Cogen and V. Behar, Tetrahedron
Lett., 1990, 31, 3241.
31 B. Sreedhar, V. Swapna and Ch. Sridhar, Synth. Commun., 2004, 34,
1433.
32 Y. Wang, J. Wu and P. Xia, Synth. Commun., 2006, 36, 2685.
33 T. Narender and K. P. Reddy, Tetrahedron Lett., 2007, 48, 7628.
34 (a) S. Jensen, C. E. Olsen, O. D. Tyagi, P. M. Boll, F. A. Hussaini, S.
Gupta, K. S. Bisht and V. S. Parmar, Phytochemistry, 1994, 36, 789;
(b) V. S. Parmar, S. Gupta, K. S. Bisht, S. Mukherjee, P. M. Boll and
W. Errington, Acta Chem. Scand., 1996, 50, 558; (c) V. S. Parmar, M.
7 S. Prado, H. Ledeit, S. Michel, M. Koch, J. C. Darbord, S. T. Cole, F.
Tillequin and P. Brodin, Bioorg. Med. Chem., 2006, 14, 5423.
8 (a) M. Maitrejean, G. Comte, D. Barron, K. El Kirat, G. Conseil and A.
Di Pietro, Bioorg. Med. Chem. Lett., 2000, 10, 157; (b) C. L. Miranda,
J. F. Stevens, V. Ivanov, M. McCall, B. Frei, M. L. Deinzer and D.
R. Buhler, J. Agric. Food Chem., 2000, 48, 3876; (c) R. J. Rodriguez,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5201–5210 | 5209
©

View Article Online
E. Bracke, J. Philippe, J. Wengel, S. C. Jain, C. E. Olsen, K. S. Bisht, N.
K. Sharma, A. Courtens, S. K. Sharma, K. Vennekens, V. Van Marck,
S. K. Singh, N. Kumar, A. Kumar, S. Malhotra, R. Kumar, V. K.
Rajwanshi, R. Jain and M. M. Mareel, Bioorg. Med. Chem., 1997, 5,
1609.
41 S. Combes, J.-P. Finet and D. Siri, J. Chem. Soc., Perkin Trans. 1, 2002,
38.
42 T. Ollevier, V. Desyroy, M. Asim and M.-C. Brochu, Synlett, 2004, 2794.
43 J. Bourdron, L. Commeiras, P. Barbier, V. Bourgarel-Rey, E. Pasquier,
N. Vanthuyne, J.-C. Hubaud, V. Peyrot and J.-L. Parrain, Bioorg. Med.
Chem., 2006, 14, 5540.
35 P. E. Brown, R. A. Lewis and M. A. Waring, J. Chem. Soc., Perkin
Trans. 1, 1990, 2979.
44 P. W. Elsinghorst, C. M. Gonza´lez Tanarro and M. Gu¨tschow, J. Med.
Chem., 2006, 49, 7540.
36 X. W. Yang, J. S. Wang, Y. H. Wang, H. T. Xiao, X. J. Hu, S. Z. Mu, Y.
L. Ma, H. Lin, H. P. He, L. Li and X. J. Hao, Planta Med., 2007, 73,
496.
45 V. Kumar, A. Sharma and A. K. Sinha, Helv. Chim. Acta, 2006, 89,
483.
37 I. Mohammadpoor-Baltork, H. Aliyan and A. Reza Khosropour,
Tetrahedron, 2001, 57, 5851.
46 A. El-Batta, C. Jiang, W. Zhao, R. Anness, A. L. Cooksy and M.
Bergdahl, J. Org. Chem., 2007, 72, 5244.
47 R. Gopinath and B. K. Patel, Org. Lett., 2000, 2, 577.
48 D. d. L. Moreira, E. F. Guimara˜es and M. A. C. Kaplan, Phytochem-
istry, 2000, 55, 783.
49 M. O. Fatope and D. J. Abraham, J. Med. Chem., 1987, 30, 1973.
50 Q. Wang, X. She, X. Ren, J. Ma and X. Pan, Tetrahedron: Asymmetry,
2004, 15, 29.
38 R. W. Bates, C. J. Gabel, J. Ji and T. Rama-Devi, Tetrahedron, 1995, 51,
8199.
39 J. R. Mays, S. A. Hill, J. T. Moyers and B. S. J. Blagg, Bioorg. Med.
Chem., 2010, 18, 249.
40 T. Narender, K. P. Reddy and G. Madhur, Synth. Commun., 2009, 39,
1949.
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This journal is
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