Prenylcoumarins in One or Two Steps by a Microwave-Promoted Tandem Claisen Rearrangement/Wittig Olefination/Cyclization Sequence

Article abstract of DOI:10.1021/acs.joc.8b00667

The one-pot synthesis of 8-prenylcoumarins from 1,1-dimethylallylated salicylaldehydes and the stabilized ylide [(ethoxycarbonyl)methylene]triphenylphosphorane under microwave conditions was found to have a limited scope. The sequence suffers from a difficult and sometimes low-yielding synthesis of the precursors and from a competing deprenylation upon microwave irradiation. This side reaction occurs in particular with electron rich arenes with two or more alkoxy groups at adjacent positions, a prominent substitution pattern in naturally occurring 8-prenylcoumarins. Both limitations of this one-step sequence were overcome by a two-step synthesis consisting of a microwave-promoted tandem allyl ether Claisen rearrangement/Wittig olefination and a subsequent olefin cross metathesis with 2-methyl-2-butene. The cross metathesis step proceeds with a high selectivity and yields exclusively the desired prenyl, rather than the alternative crotyl substituent. Several naturally occurring 8-prenylcoumarins that were previously inaccessible have been synthesized in good overall yields along this route.

Full text of DOI:10.1021/acs.joc.8b00667

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To prenylcoumarins in one or two steps by microwave promoted
tandem Claisen rearrangement / Wittig olefination / cyclization sequence
Christiane Schultze, and Bernd Schmidt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00667 • Publication Date (Web): 11 Apr 2018
Downloaded from http://pubs.acs.org on April 11, 2018
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To prenylcoumarins in one or two steps by microwave promoted tandem Claisen
rearrangement / Wittig olefination / cyclization sequence
Christiane Schultze and Bernd Schmidt*
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Universitaet Potsdam, Institut fuer Chemie, KarlꢀLiebknechtꢀStraße 24ꢀ25, Dꢀ14476 Potsdamꢀ
Golm, Germany
eꢀmail: bernd.schmidt@uniꢀpotsdam.de
Table of contents graphic:
Abstract: The oneꢀpot synthesis of 8ꢀprenylcoumarins from 1,1ꢀdimethylallylated
salicylaldehydes and the stabilized ylide [(ethoxycarbonyl)methylene]triphenylphosphorane
under microwave conditions was found to have a limited scope. The sequence suffers from a
difficult and sometimes lowꢀyielding synthesis of the precursors and from a competing
deprenylation upon microwave irradiation. This side reaction occurs in particular with
electron rich arenes with two or more alkoxy groups at adjacent positions, a prominent
substitution pattern in naturally occurring 8ꢀprenylcoumarins. Both limitations of this oneꢀstep
sequence were overcome by a two step synthesis consisting of a microwave promoted tandem
allyl ether Claisenꢀrearrangement / Wittigꢀolefination and a subsequent olefin cross
metathesis with 2ꢀmethylꢀ2ꢀbutene. The cross metathesis step proceeds with high selectivity
and yields exclusively the desired prenylꢀ rather than the alternative crotyl substituent. Several
naturally occurring 8ꢀprenylcoumarins that were previously inaccessible have been
synthesized in good overall yields along this route.
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Introduction
Substituted coumarins are ubiquitious secondary metabolites that have been isolated from
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,2
more than 800 different species, mostly plants but also some microorganisms. From 2012 to
2015 the isolation of more than 400 coumarins, including new compounds and reꢀisolations of
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known compounds from new sources, have been reported. With these figures coumarins
remain among the most intensely investigated classes of secondary metabolites in
phytochemistry. Their pharmacological and physiological activities are too diverse to be
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comprehensively reviewed: they range from growth regulation and protection against UVꢀ
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light in the metabolite producing plants to antiꢀinflammatory, estrogenic, diuretic or
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acetylcholinesterase inhibiting
activities in mammals. Coumarins and other
phenylpropanoids often undergo a biosynthetic prenylation with dimethylallyldiphosphate in
9
ꢀ11
the presence of prenyltransferases.
In many cases the presence of one or more prenyl side
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chains at the aromatic core enhances the bioactivity of secondary metabolites dramatically.
This was for example observed for the cytotoxicities against glioma cells of the flavonoids
apigenin (not prenylated and inactive) and licoflavone C (structurally identical to apigenin,
13
but prenylated at position 8 and active at micromolar concentrations). One reason for the
beneficial effect of lipophilic prenyl groups on the bioactivity might be a faster permeation
1
4
through cell membranes. Prenylation is, however, not always the terminal step in the
biosynthesis of secondary plant metabolites: many naturally occurring coumarins bear alkyl
substituents at the aromatic core which are derived from the prenyl group by hydrogenation,
1
5
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epoxidation (e. g. meranzin) and subsequent epoxide opening (e. g. muralatin E),
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dihydroxylation followed by conjugation with other compounds (e. g. integerrimelin),
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dimerization to bicoumarins or allylic oxidation (which is occasionally followed by
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cyclization to γꢀbutyrolactones, e. g. micromunitin C, or furan substituents). Thus
prenylated coumarins are not only bioactive secondary metabolites themselves, they are also
important intermediates in the biosynthesis and synthesis of other natural products. Although
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the original prenyl group has been modified (mostly by oxidative transformations) in these
compounds, they are still considered as “simple prenylated coumarins” in the coumarin
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taxonomy (Figure 1).
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Figure 1. Representative simple prenylated coumarins.
The chemical synthesis of Cꢀprenylated coumarins and other phenylpropanoids is often
accomplished via thermally induced Claisen rearrangements of either prenylꢀ or 1,1ꢀ
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dimethylallyl ethers of phenols. While 1,1ꢀdimethylallyl ethers undergo a rearrangement to
orthoꢀprenylated phenols, prenyl ethers react to afford paraꢀprenylated phenols through
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successive Claisen and Copeꢀrearrangements. Many syntheses of C6ꢀ or C8ꢀprenylated
coumarins start from precursors with a preformed coumarin skeleton and an unprotected
hydroxy group, such as umbelliferone, which is first 1,1ꢀdimethylpropargylated, then partially
hydrogenated to the 1,1ꢀdimethylallylether and finally heated to induce a Claisen
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rearrangement to the prenylated coumarin. To access a wider scope of substitution patterns
it is often advantageous to start from other aromatic compounds and construct the coumarin
scaffold during the synthesis. One strategy, pioneered by the groups of Harwood and Mali,
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uses Oꢀprenylated cinnamates or salicylic aldehydes, respectively. The cinnamates undergo,
upon heating, a Claisen rearrangement, E/Zꢀisomerization and cyclization reaction to
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coumarins. With salicylic aldehydes as starting materials this tandem sequence is extended
by a Wittigꢀolefination step, which is achieved by addition of a stable ethoxycarbonylꢀylide to
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the reaction mixture.
In the course of a research program on microwave promoted tandem
reactions we also investigated this Wittigꢀolefination / Claisenꢀrearrangement / cyclization
sequence. We found, for example, that osthole (see figure 1) can be conveniently synthesized
from 4ꢀmethoxy salicyl aldehyde in just two steps by a Pdꢀcatalyzed 1,1ꢀdimethylallylation
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and the above mentioned microwave promoted tandem sequence. In continuation of this
project we planned to extend the synthesis to other prenylated coumarins, but met some
unforeseen difficulties. These problems and our solutions are discussed in this contribution.
Results and discussion
Scope and limitations of the one-step route. When we applied the conditions for the
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successful Pdꢀcatalyzed 1,1ꢀdimethylallylation of the osthole precursor 4ꢀmethoxy salicyl
aldehyde with allylcarbonate 2 to the double MOMꢀprotected salicyl aldehyde 1a, the desired
product 3a was obtained in only 26% yield (Table 1, entry 1). Raising the reaction
temperature from 0 °C to ambient temperature improved the yield only marginally to 30%
(entry 2), whereas heating to 40 °C (entry 3) or increasing the amount of catalyst to 5 mol %
led to a complete failure of the dimethylallylation (entry 4). A comparable yield of 28% was
obtained for the 2,4ꢀdimethoxysalicyl aldehyde 1n (entry 16). Interestingly, for the similarly
substituted benzophenone 1b the desired product could not even be detected in trace amounts
with this method (entry 5). Complete failure was also observed when we applied the Pdꢀ
catalyzed 1,1ꢀdimethylallylation to aldehyde 1c and benzophenone 1d, without any electron
donating substituents at the aromatic core (entries 6 and 7). Several other alkoxy salicyl
aldehydes, acetophenones and benzophenones 1e to 1l were converted to the expected 1,1ꢀ
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dimethylallyl ethers 3e to 3l in yields varying from 40% to 93% (entries 8 to 15), with the
exception of acetophenone 1h (entry 11) which reproducibly and unexplainably reacted only
in trace amounts to 3h (Table 1).
Table 1. Pdꢀcatalyzed 1,1ꢀdimethylallylation of phenols 1.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
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entry
1
R
R
R
R
3
Yield (%)
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a
1
1a
1a
1a
1a
1b
1c
1d
1e
1f
OMOM
OMOM
OMOM
OMOM
OMOM
H
H
H
OMOM
H
H
H
H
3a
3a
3a
3a
3b
3c
3d
3e
3f
2
OMOM
30
b
3
H
OMOM
< 5
< 5
< 5
< 5
< 5
93
c
4
H
OMOM
5
6
H
OMOM
C
6
H
5
5
H
H
H
H
7
H
H
C H
6
8
H
OMe
H
H
H
9
OMe
H
H
C H
52
6
5
5
10
1g
1h
1i
OMe
H
H
C H
3g
3h
3i
80
6
11
12
13
14
OMe
H
H
CH
CH
H
3
< 5
57
OMe
OMe
OMe
OMe
H
H
3
1j
OMe
OMOM
OMe
OMe
H
3j
63
1k
1l
H
H
3k
3l
66
15
OMe
OMe
H
40
16
1n
H
3n
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a
b
c
Reaction temperature 0 °C. Reaction temperature 40 °C. Catalyst loading 5 mol %.
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Compounds 3j,k,l were envisaged as precursors for three naturally occurring 8ꢀ
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31,32
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prenylcoumarins. The required salicyl aldehydes 1j, 1m,
1k and 1l were synthesized
from commercially available 2,4,5ꢀtrimethoxybenzaldehyde (4) and 3,4,5ꢀtrimethoxyphenol
(5) by following or adapting literature procedures (Scheme 1).
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Scheme 1. Synthesis of substituted salicyl aldehydes 1j,k,l.
With this set of precursors 3 in hand we next investigated the tandem Claisenꢀrearrangement /
Wittigꢀolefination / E/Zꢀisomerization / cyclization sequence by irradiating the precursors in
the presence of [(ethoxycarbonyl)methylene]triphenylphosphorane (6) in a microwave reactor
(Table 2). Good to excellent yields of 8ꢀprenylcoumarins 7 were obtained for the moderately
electron rich substrates 3e,f,g,i with one alkoxy group in metaꢀ or paraꢀposition to the
carbonyl group (entries 2 – 5). Compound 3a, with two MOMꢀprotected phenol groups in
orthoꢀ and paraꢀposition to the carbonyl group, underwent the tandem sequence to 7a in
considerably lower yield, but without formation of noticeable amounts of any byproducts
(entry 1). We were, however, particularly interested in the outcome of the tandem sequence
for aldehydes 3j,k,l, the precursors for the naturally occurring 8ꢀprenylcoumarins Oꢀmethyl
cedrelopsin (7j), cedrelopsin (7m) and muralatin C (7l) (see figure 1). OꢀMethylcedrelopsin
34
(
7j) shows strong cytotoxicity against KB cells in a low micromolar range. It was isolated
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from the stem bark of the tree Cedrelopsis grevei and very recently reisolated from the roots
of Toddalia asiatica, a medicinal plant widely distributed and used from east Africa to
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36
southeast Asia. Cedrelopsin (7m) was isolated from the leaves of Melicope borbonica and
37
more recently from avocado, the fruits of Persea americana, and from aerial parts of the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
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9
0
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0
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8
9
0
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plant Oldenlandia umbellata. It is cytotoxic against A549 cancer cell lines at low
3
8
micromolar concentrations. Muralatin C (7l) was isolated from the leaves of the Murraya
alata, a shrub native in China and Vietnam, and has so far not been tested for any
16
bioactivity.
Table 2. Microwave promoted tandem sequence for substrates 3.
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3
4
entry
3
R
R
R
R
t (min)
60
7
Yield (%)
1
2
3
4
5
3a
3e
3f
3g
3i
OMOM
H
H
OMOM
H
H
7a
7e
7f
7g
7i
50
72
91
72
84
22
33
20
31
54
OMe
H
H
H
60
OMe
H
C
C
6
6
H
5
5
60
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
60
H
H
CH3
H
60
a
6
3j
3j
OMe
OMe
H
60
7j
7j
7k
7k
7l
b
7
H
H
10
c
8
3k OMOM
3k OMOM
H
H
60
d
9
H
H
10
e
10
3l
OMe
OMe
H
60
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a
e
b
c
d
Byproduct: 8j (23%). Byproduct: 8j (31%). Byproduct: 8k (18%). Byproduct: 8k (27%).
Byproduct: 8l (16%).
Disappointingly, with all three precursors 3j,k,l the formation of the desired 8ꢀ
prenylcoumarins 7 is accompanied to a considerable extent by a deprenylation side reaction.
In the case of Oꢀmethyl cedrelopsin (7j) and cedrelopsinꢀMOMꢀether (7k) the 8ꢀprenylated
and deprenylated products were obtained in equal yields of ca. 20% (entries 6, 8). Reducing
the reaction time to 10 minutes improved the total yield of coumarin products, but did not
alter the ratio of prenylated and deprenylated products (entries 7, 9). The selectivity towards
muralatin C (7l) was better but with ca. 3 : 1 still not satisfactory (entry 10). The deprenylated
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products 8j, known as scoparone, and 8l are natural products themselves and were
identified as a potent vasodilator (8j) and tyrosinase inhibitor (8l), respectively. Compound
4
1
8
k
is the MOM ether of scopoletin, which is a phenolic coumarin with hypotensive
4
2
activity.
Although literature precedence for deprenylation as a competing side reaction to the Claisen
2
2,43ꢀ46
rearrangement exists,
we were surprised to observe deprenylated products in our case.
Normally, deprenylation occurs with prenylꢀ rather than 1,1ꢀdimethylallylꢀethers as starting
materials, because in these cases the initial Claisen rearrangement gives a sterically congested
2
ꢀ(1,1ꢀdimethylallyl)ꢀsubstituted cyclohexadienone, which rapidly undergoes a subsequent
Cope rearrangement. This sequence of sigmatropic rearrangements eventually results in a
paraꢀprenyl substituted phenol (these paraꢀproducts are occasionally referred to as
4
7
“anomalous” products). Only in those cases where the second step, the Cope rearrangement,
is hampered, rearomatization proceeds through elimination of isoprene. If, for example, the
48
position para to the prenyloxy group is blocked, quantitative deprenylation may occur.
A
mechanistic scenario that rationalizes the two different pathways leading to coumarins 7 and 8
is shown in Scheme 2. Based on observations very recently published by Konrádová et al. it
can be assumed that the Wittig olefination is the fastest step of the sequence, as it occurs
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already at 150 °C, whereas the E/Zꢀisomerization and cyclization requires temperatures higher
49
than 220 °C. Consequently, the Claisen rearrangement will occur from the cinnamates 9 and
lead to cyclohexadienones 10, which should rearomatize rapidly by tautomerism (dashed
arrow), giving eventually the 8ꢀprenylcoumarins 7. The alternative rearomatization pathway,
leading to deprenylated coumarins 8 (full arrows), would involve transfer of a proton from
one methyl group to the carbonyl oxygen and elimination of isoprene. Currently, we are
unable to present a convincing explanation for the deprenylation side reaction in this case.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
One might argue that deprenylation is observed only for coumarins with a substituent R at
position 7, which would lead to an increased steric hindrance in the transition state of the
Claisenꢀrearrangement. However, coumarins 7a and 7f (Table 2, entries 1, 3), which are also
substituted at this position, were obtained without formation of the respective deprenylated
coumarins. What all three examples, where deprenylation plays a role, have in common is the
presence of two electron donating substituents at positions 6 and 7. Considering that the final
step of the sequence, the E/Zꢀisomerizationꢀcyclization, apparently requires the highest
49
reaction temperature (beyond 220 °C, as outlined above ) opportunities to reduce the extent
of deprenylation appear to be very limited.
Scheme 2. Different scenarios leading to 8ꢀprenylcoumarins 7 and deprenylated coumarins 8.
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2
2
2
2
2
2
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3
3
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3
3
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3
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4
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4
4
4
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5
5
5
5
5
5
5
5
5
6
Alternative two-step route. Olefin cross metathesis of terminal alkenes with isobutene was
50
first investigated as an alternative access to prenylated products by Grubbs and coworkers.
By using isobutene as a solvent the equilibrium could be driven towards the prenylated
product, which is mainly due to the higher volatility of the coꢀproduct ethene. The same group
discovered that the use of 2ꢀmethylꢀ2ꢀbutene as a solvent and cross metathesis partner is more
convenient, because 2ꢀmethylꢀ2ꢀbutene is – in contrast to isobutene – a liquid at ambient
temperature. However, this alkene may in certain cases result in the formation of CM
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
50
products with only one methyl group at the double bond. This selectivity issue has more
recently been addressed by a comprehensive catalyst screening under conditions where the
5
1
CM partner is used in excess, but not as a solvent. As a result of this study it was discovered
that useful selectivities can only be obtained with the more active second generation catalysts,
whereas less active catalysts give larger amounts of homodimerization products. Since the
50
original report by Grubbs and coworkers cross metathesis reactions of allylsubstituted
precursors with isobutene or 2ꢀmethylꢀ2ꢀbutene have found a limited number of applications,
in particular for the synthesis of prenylated natural products. Examples are a truncated
5
2
53
54
garsubellin A derivative, garcinol and isogarcinol, nemorosone and leupyrrinsA and
1
55
56,57
58ꢀ60
B . A few prenylated flavonoids
and coumarins
have also been synthesized from the
1
corresponding Cꢀallylated precursors and 2ꢀmethylꢀ2ꢀbutene by cross metathesis.
Occasionally reported difficulties include the complete failure of the cross metathesis, which
5
8
could be overcome by conducting the reaction under microwave irradiation, the formation of
5
8
small amounts of crotyl rather than prenyl products, and the formation of major amounts of
5
9
homodimers, which was resolved by slow addition of the allylic substrate to the CM partner.
In light of these literature reports we expected that a two step synthesis of 8ꢀprenylcoumarins,
consisting of a tandem allylꢀClaisen rearrangement / Wittig olefination / cyclization sequence
and a subsequent cross metathesis, could be a useful alternative to the oneꢀstep tandem
sequence starting from 1,1ꢀdimethylallyl ethers 3 (table 2). In contrast to the starting materials
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8
9
3
, which are synthesized via the sometimes capricious Pdꢀcatalyzed dimethylallylation (table
1), the allylethers 11 required for the twoꢀstep sequence are much more conveniently
available. A second advantage of the twoꢀstep sequence is that the occasionally observed
deprenylation under microwave conditions (table 2 and scheme 2) can not occur with the
precursors 11, because elimination of a conjugated diene is not possible.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A set of allylethers 11, including precursors required for the synthesis of the 8ꢀ
prenylcoumarins 7j,k,l, which are inaccessible via the oneꢀstep sequence, were obtained by
Williamson allylation of phenols 1 under routine conditions (Table 3).
Table 3. Williamson allylation of phenols 1.
1
2
3
4
entry
1
R
R
R
R
11
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1h
1j
OMOM
OMOM
OMe
H
H
OMOM
H
11a
11b
11h
11j
Ref. 22
93
OMOM
6 5
C H
H
H
H
CH
3
84
OMe
OMe
OMe
OMe
H
H
80
1k
1l
OMOM
OMe
H
H
11k
11l
96
OMe
OMe
H
H
85
1n
1o
1p
1q
1r
OMe
H
11n
11o
11p
11q
11r
Ref. 26
89
OMOM
OMOM
OMOM
NHAc
H
H
H
H
C
6
H
5
98
1
1
0
1
H
H
CH
3
98
H
H
CH
3
92
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2
2
2
2
2
2
2
3
3
3
3
3
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3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The next step was the optimization of the microwave promoted tandem sequence with regard
to reaction temperature and ꢀtime for substrate 11o, which was chosen as a representative allyl
Claisen rearrangement precursor (Table 4). At a reaction temperature of 250 °C virtually
identical yields of ca. 60% were obtained for reaction times between 30 min and 60 min
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entries 1 – 3). With shorter reaction times between 10 min and 20 min (entries 4, 5) increased
yields of ca. 70% were observed. In all these cases TLC indicated quantitative conversion of
the starting material 11o, whereas unreacted starting material was observed after a reaction
time of 5 min (entry 6). Conversion also remained incomplete at a lower reaction temperature
of 220 °C, even after a reaction time of 20 or 30 min (entries 7,8). At 235 °C the isolated yield
exceeded those obtained at 220 °C already after a shorter reaction time of 10 min (entry 9),
but some unreacted starting material was still observed. In summary, microwave irradiation at
250 °C for 10 min ensures quantitative conversion and minimal loss of product through
competing decomposition and was therefore identified as the optimal reaction conditions.
Table 4. Optimization of reaction conditions for the tandem sequence.
entry
T (°C)
250
250
250
250
250
250
220
t (min)
60
Yield (%)
1
2
3
4
5
6
7
60
58
57
68
74
60
59
40
30
20
10
5
30
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220
235
20
10
44
63
These conditions were then applied to the other precursors 11 (Table 5). Quantitative
conversion of the starting material was observed in all cases and most products 12 could be
isolated in synthetically useful yields. A notable exception is the 6,7ꢀdimethoxy derivative
11j, which underwent reproducibly decomposition to a complex mixture of products, from
which the desired 8ꢀallyl comarin 12j could not be isolated (entry 4). The presence of an
electron donating group at C6 alone can not provide a plausible explanation for this failure,
because the similarly substituted 11k with an OMOMꢀgroup at C7 reacts to 12k in a moderate
yield of 47% (entry 5) and the 5,6,7ꢀtrimethoxy substituted derivative 11l undergoes the
tandem sequence to 12l in 71% yield (entry 6).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. Microwave promoted tandem sequence for substrates 11.
1
2
3
4
entry 11
R
R
R
R
12
Yield (%)
1
2
3
4
5
6
7
8
11a
11b
11h
11j
OMOM
OMOM
OMe
H
H
OMOM
OMOM
H
H
12a
12b
12h
12j
12k
12l
82
42
52
6 5
C H
H
CH
H
3
a
OMe
OMe
OMe
OMe
H
H
ꢀꢀ
11k
11l
OMOM
OMe
H
H
47
71
68
74
OMe
OMe
H
H
11n
11o
OMe
H
12n
12o
OMOM
H
H
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
9
11p
11q
11r
OMOM
OMOM
NHAc
H
H
H
H
H
H
C
6
H
5
12p
12q
12r
75
72
58
10
CH
CH
3
11
3
a
Quantitative decomposition.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Synthesis of CM precursor 12o’.
The set of 8ꢀallylcoumarins 12 listed in table 5 was supplemented by the phenol 12o’, which
was used to study the effect of a phenolic hydroxy group in the proximity of the allyl
substituent on the efficiency of the next step, the cross metathesis reaction. Compound 12o’
was synthesized from the corresponding MOMꢀether 12o by deprotection under acidic
conditions (Scheme 3).
Table 6. Cross metathesis of 8ꢀallylcoumarins 12 and 2ꢀmethylꢀ2ꢀbutene.
a
1
2
3
4
entry
12
Cond.
7
R
R
R
R
Yield (%)
1
2
3
4
5
12a
12h
12k
12l
1
1
1
1
1
7a OMOM
7h
OMe
H
H
OMOM
H
H
CH
H
82
87
3
7k OMOM OMe
H
97
7l
OMe
OMe
OMe
H
OMe
OMe
H
quant.
91
12n
7n
H
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7
8
9
6
7
8
9
12o
12r
12o’
12a
12b
12k
12o
12p
12q
1
1
1
2
2
2
2
2
2
7o OMOM
H
H
H
H
H
CH
H
92
47
< 5
74
74
91
80
94
95
7r
NHAc
OH
3
7o’
7a’
7b’
7k’
7o’
7p’
7q’
H
H
OH
H
OH
OH
H
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10
OH
H
C
6 5
H
11
OH
OMe
H
H
H
12
OH
H
1
1
3
4
OH
H
H
C
6 5
H
OH
H
H
CH
3
a
Conditions 1 (without MOMꢀdeprotection): CH
A (5 mol %), 20 °C, 16 h. Conditions 2 (with MOMꢀdeprotection): CH
ꢀbutene (110 equiv.), A (5 mol %), 20 °C, 16 h; evaporate, redissolve in methanol, add aq.
HCl (3 M), 80 °C, 1h.
2
Cl
2
(0.2 M), 2ꢀmethylꢀ2ꢀbutene (110 equiv.),
2
Cl (0.2 M), 2ꢀmethylꢀ
2
2
Two different protocols were investigated for the synthesis of 8ꢀprenylcoumarins 7 from their
ꢀallyl counterparts 12 by cross metathesis (Table 6). The first set of conditions proceeds with
8
conservation of the acid labile MOMꢀprotecting groups (entries 1 – 8). The second set of
conditions was adapted from a synthesis of prenylated isoflavones published by Blagg and
57
coworkers. With this protocol cross metathesis and cleavage of all MOM groups can be
achieved in a oneꢀpot fashion, resulting in the formation of 8ꢀprenylcoumarins with one or
two phenolic OHꢀgroups (entries 9 – 14). With two exceptions the expected cross metathesis
products were obtained in good to excellent yields. Substrate 12o’, with an unprotected
phenol adjacent to the allyl substituent, failed to react in the CM reaction and was
quantitatively recovered (entry 8). This is in contrast to an earlier report by Magolan and
5
9
Coster, who found that 12o’ reacts to mixtures of its self metathesis product and osthenol
7o’). The crucial difference between our conditions and the previously reported ones appears
to be the initial substrate concentration, which is an order of magnitude higher in our work
0.20 M vs. 0.015 M in Magolan’s and Coster’s study). That the initial substrate concentration
(
(
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
is pivotal for this substrate is underlined by the fact that Magolan and Coster were eventually
able to obtain 7o’ in high yield and selectivity by using a pseudoꢀhigh dilution protocol with
59
slow addition of a dilute solution of 12o’ to a solution of the CM partner and the catalyst.
We pursued an alternative approach to the synthesis of the natural product osthenol (7o’) by
submitting the MOMꢀprotected 8ꢀallyl coumarin 12o to the oneꢀpot cross metathesis /
deprotection sequence (entry 12). Osthenol (7o’) was isolated in 80% yield under these
conditions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The second less successful cross metathesis reaction was the conversion of the 7ꢀacetamide
substituted 8ꢀallylcoumarin 12r to its 7ꢀprenyl analogue 7r (entry 7). This reaction did not
proceed to completion under the standard conditions and gave the product only in a moderate
isolated yield of 47% with the standard catalyst loading of 5 mol %. A likely explanation for
the failure in the case of 12o’ and the incomplete conversion in the case of 12r is complete or
61
partial catalyst inhibition through chelation, either via formation of coordinative or covalent
bonds (Figure 2). For the acetamide substituted substrate 12r chelation may occur via the
nitrogen (structure C) or the oxygen (structure D), which would, however, require the
formation of a less likely eightꢀmembered chelate complex. Intramolecular coordination of
donor substituents, e. g. carbonyl groups, to Ruꢀalkylidenes has early on been proposed as a
6
2
rationale for catalyst inhibition. Related observations are the formation of inactive Ruꢀ
6
3
alkylidenes with orthoꢀmethoxy styrenes as metathesis substrates or the failure of RCM
64
reactions with 2ꢀallylquinoxalines, which has been attributed to the formation of stable six
membered quinoxalineꢀRuꢀalkylidene chelates.
Figure 2. Proposed formation of Ruꢀalkylidene chelates from substrates 12o’ and 12r.
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9
Among the 8ꢀprenylcoumarins successfully synthesized via cross metathesis or oneꢀpot cross
metathesis / deprotection are the natural products muralatin C (7l), coumurrayin (7n) and
cedrelopsin (7k’), which are inaccessible through the oneꢀstep microwave promoted tandem
sequence starting from 1,1ꢀdimethylallylethers as shown in table 2.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of muralatin H and attempted syntheses of toddalenone. Muralatin H (13) is a
16
new natural product from the shrub Murraya alata. It has recently been isolated together
with nine other new coumarins, including muralatin C (7l), and 22 natural products which had
previously been isolated from other sources. Two of these known compounds are
6
5
66
coumurrayin (7n) and toddalenone (15). Murraya alata and other plants of this family play
a role in traditional Chinese medicine for the treatment of many forms of pain, including pains
67
associated with inflammatory diseases. This prompted an investigation into the inhibitory
effects of both new and known coumarins from this plant on the production of NO in certain
macrophages, because NO is known to be a key signalling molecule in inflammatory
16
processes. Muralatin H (13), coumurrayin (7n) and toddalenone (15) were found to inhibit
16
NO production at IC50 values comparable to the control indomethacin. Although muralatin
H and toddalenone are not 8ꢀprenylcoumarins, we thought that these natural products should
also be synthetically accessible using the chemistry presented herein (Scheme 4). For both
target molecules the 8ꢀallylcoumarin 12n was chosen as the starting material. Muralatin H
68
(
13) was accessible through a LemieuxꢀJohnsonꢀoxidation in 87% yield. In contrast to the
original report, we used K OsO (OH) rather than OsO as a more convenient precatalyst. For
2
2
4
4
the synthesis of toddalenone (15) we envisaged a sequence of double bond isomerization
followed by cross metathesis with methylvinyl ketone. While the double bond isomerization
69,70
proceeds smoothly with the precatalyst RuClH(CO)(PPh
3
3
) ,
we were unable to accomplish
any cross metathesis reaction with the styrene 14. Among the parameters varied were the
solvent (dichloromethane or toluene), the temperature (ranging from ambient temperature to
71
1
10 °C), the precatalyst (second generation Grubbs’ catalyst A or the Umicore M catalyst
51
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
2
B, which is especially suited for cross metathesis reactions), the cross metathesis partner
(methyl vinyl ketone or methyl acrylate) and the use of phenol as a rate accelerating
7
3,74
additive.
Even the combination of the additive phenol, an increased catalyst loading of 10
mol % of second generation catalyst A, a larger amount of cross metathesis partner (20
equivalents) and microwave irradiation as a more efficient heating method did not lead to any
conversion. In all cases we could only recover unchanged starting material. To overcome the
limitations of the cross metathesis reaction for this particular application, we planned to
convert compound 14 to the corresponding 8ꢀformyl coumarin through oxidative cleavage of
the exocyclic double bond. The resulting coumarinꢀ8ꢀcarbaldehyde should then be subjected
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
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7
8
9
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1
2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to
a
Wittigꢀolefination
with
the
commercially
available
ylide
(
acetylmethylene)triphenylphosphorane. Unfortunately, the LemieuxꢀJohnson oxidation as
well as a twoꢀstep dihydroxylationꢀdiol cleavage failed for compound 14. We observed
complete conversion of the starting material, but obtained a highly polar and unsoluble
residue from which we could not isolate any defined products.
Scheme 4. Synthesis of muralatin H and attempted synthesis of toddalenone.
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Similar to the formation of stable and catalytically inactive or less active chelates proposed
above (see figure 2 and related discussion), we assume that the failure of any cross metathesis
reactions with 14 is also a result of catalyst inhibition through chelate formation. Coordinating
groups might either be the 7ꢀmethoxy substituent or the ring oxygen (position 1 of the
coumarin). Replacing the orthoꢀisopropoxy substituent in HoveydaꢀGrubbsꢀtype catalysts by
an orthoꢀmethoxy group results in a considerably less active catalyst, as already mentioned
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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0
1
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8
9
0
1
2
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8
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1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
63
above. Ligation through the carbonyl oxygen appears less likely due to geometrical
constraints in our case, but was found to impede metathesis activity efficiently for a Ruꢀ
75
alkylidene with an orthoꢀesterꢀsubstituted benzylidene ligand. Analogues of Hoveydaꢀ
Grubbsꢀtype catalysts in which the isopropoxystyrene moiety has been replaced by a
76
coumarin styrene ligand have been investigated by theoretical means. Catalysts bearing
chromenylꢀ and chromanyl substituted alkylidenes were synthesized and found to be
77,78
catalytically active.
Conclusions
In summary, we describe and discuss two alternative syntheses of 8ꢀprenyl coumarins, which
are ubiquitious natural products and potential lead structures for drugs. Both syntheses rely on
a microwave promoted tandem sequence of Claisen rearrangement, Wittig olefination,
isomerization and cyclization to form the coumarin scaffold and introduce the substituent in
the 8ꢀposition. The syntheses differ in the choice of the precursor: the straightforward, oneꢀ
step synthesis starts from 1,1ꢀdimethylallyl ethers and yields the 8ꢀprenyl coumarins directly.
Its main disadvantages are the sometimes capricious precursor synthesis through Pdꢀcatalyzed
dimethylallylation and the occasionally observed deprenylation under microwave conditions.
In those cases where 8ꢀprenyl coumarins are inaccessible selectively via this oneꢀstep
synthesis, a two step synthesis was found to be a useful alternative. This synthesis starts from
conveniently synthesized allyl ethers which react to 8ꢀallyl coumarins under microwave
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1
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2
2
2
2
2
2
2
2
2
3
3
3
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3
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3
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5
5
5
5
6
irradiation without any loss of the allyl group. The desired 8ꢀprenyl coumarins are then
available in a second step via cross metathesis with 2ꢀmethylꢀ2ꢀbutene. The synthetic value of
both routes was exemplified by the synthesis of the naturally occurring 8ꢀprenylcoumarins
muralatin C, cedrelopsin, coumurrayin and osthenol. In addition, the recently discovered
coumarin aldehyde muralatin H was synthesized in one step from an 8ꢀallyl coumarin by
oxidative CꢀCꢀdouble bond cleavage.
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8
9
0
Experimental Section
General methods. All experiments were conducted in dry reaction vessels under an
1
atmosphere of dry nitrogen. Solvents were purified by standard procedures. H NMR spectra
were obtained at 300 MHz in CDCl with CHCl (δ = 7.26 ppm) as an internal standard.
3
3
1
3
Coupling constants are given in Hz. C NMR spectra were recorded at 75 MHz in CDCl3
with CDCl (δ = 77.1 ppm) as an internal standard. Whenever the solubility or stability of the
sample or signal separation were insufficient in CDCl
following solvents: acetoneꢀd (acetoneꢀd
3
3
, it was replaced by one of the
1
6
5
as internal standard for H NMR spectroscopy, δ =
1
3
2
.05 ppm, CD COCD as internal standard for C NMR spectroscopy, δ = 29.8 ppm);
3
3
1
DMSOꢀd
6
(DMSOꢀd
5
as internal standard for H NMR spectroscopy,
δ
= 2.50 ppm, DMSOꢀ
1
3
d as internal standard for C NMR spectroscopy,
δ = 39.5 ppm). IR spectra were recorded as
6
−1
ATRꢀFTIR spectra. Wavenumbers (ν) are given in cm . The peak intensities are defined as
strong (s), medium (m) or weak (w). Lowꢀ and high resolution mass spectra were obtained by
EIꢀTOF or ESIꢀTOF. The following starting materials were purchased from chemical
suppliers: 1cꢀf, 1h, 1i. These starting materials were synthesized following literature
22
79
30
33
31
80
22
22
28
procedures: 1a, 1g, 1j, 1l, 1m, 1n, 1o, 11a, 11n.
(2-Hydroxy-4,6-bis(methoxymethoxy)phenyl)(phenyl)methanone (1b). A solution of
81
i
phenyl (2,4,6ꢀtrihydroxyphenyl)methanone (230 mg, 1.00 mmol) and NEtPr
2
(435 ꢀL, 2.50
mmol) in DMF (1.0 mL) was cooled to 0 °C. MOMꢀbromide (201 µL, 2.20 mmol) was added,
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the mixture was allowed to warm to ambient temperature and stirred for 12 h. A satd. aq.
solution of NH Cl (5 mL) and ethyl acetate (10 mL) was added. The organic layer was
4
separated and the aqueous layer was extracted twice with ethyl acetate (10 mL each). The
4
combined organic extracts were dried with MgSO , filtered and evaporated. The residue was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
purified by column chromatography on silica, using hexanes / ethyl acetate mixtures of
1
increasing polarity, to furnish 1b (191 mg, 0.60 mmol, 60%): yellowish oil; H NMR (300
MHz, CDCl ) δ 11.73 (s, 1H), 7.60 – 7.55 (m, 2H), 7.47 – 7.43 (m, 1H), 7.42 – 7.35 (m, 2H),
3
6.38 (d, J = 2.3 Hz, 1H), 6.27 (d, J = 2.3 Hz, 1H), 5.19 (s, 2H), 4.76 (s, 2H), 4.92 (s, 2H), 3.49
1
3
(s, 3H), 3.14 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 199.5, 165.0, 163.8, 159.8, 142.0, 131.1,
128.0, 127.8, 107.1, 97.5, 95.1, 95.0, 94.3, 56.6, 56.5; IR (ATR)
ν
2907 (w), 1742 (w), 1576
+
(
s), 1448 (m), 1274 (m), 1142 (s), 1051 (s); HRMS (EI) calcd for C H O [M ] 318.1103,
17
18
6
found 318.1105.
2-Hydroxy-5-methoxy-4-(methoxymethoxy)benzaldehyde (1k). A solution of 1m (168 mg,
i
1.00 mmol) and NEtPr
2
(261
ꢀL, 1.50 mmol) in CH
Cl
2 2
(5 mL) was cooled to 0 °C. MOMꢀ
bromide (119 µL, 1.30 mmol) was added, the mixture was allowed to warm to ambient
temperature and stirred for 12 h. A satd. aq. solution of NH Cl (5 mL) and ethyl acetate (10
4
mL) was added. The organic layer was separated and the aqueous layer was extracted twice
4
with ethyl acetate (10 mL each). The combined organic extracts were dried with MgSO ,
filtered and evaporated. The residue was purified by column chromatography on silica, using
hexanes / ethyl acetate mixtures of increasing polarity, to furnish 1k (182 mg, 0.86 mmol,
1
8
6%): offꢀwhite solid, mp 50ꢀ52°C; H NMR (300 MHz, CDCl
3
)
δ
11.19 (s, 1H), 9.70 (s,
13
1
H), 6.92 (s, 1H), 6.74 (s, 1H), 5.28 (s, 2H), 3.86 (s, 3H), 3.49 (s, 3H); C NMR (75 MHz,
194.3, 158.8, 154.8, 143.4, 114.0, 113.9, 103.8, 95.1, 56.7, 56.6; IR (ATR) 2959
CDCl
3
)
δ
ν
(w), 2834 (w), 1638 (s), 1501 (s), 1274 (s), 1140 (s), 1076 (m), 967 (m), 750 (s); HRMS (EI)
+
calcd for C H O [M ] 212.0685, found 212.0676.
10
12
5
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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8
2
(
2-Hydroxy-4-(methoxymethoxy)phenyl)(phenyl)methanone (1p).
Following the
procedure for 1k, (2,4ꢀdihydroxyphenyl)(phenyl)methanone (214 mg, 1.00 mmol) was
1
converted to 1p (212 mg, 0.82 mmol, 82%): yellow solid, mp 54ꢀ55°C; H NMR (300 MHz,
CDCl3)
.52 (dd, J = 8.9, 2.4 Hz, 1H), 5.23 (s, 2H), 3.49 (s, 3H); C NMR (75 MHz, CDCl
166.0, 163.8, 138.4, 135.5, 131.7, 129.0, 128.4, 114.1, 108.1, 104.1, 94.2, 56.5; IR (ATR)
958 (w), 2828 (w), 1623 (s), 1575 (m), 1499 (m), 1343 (m), 1252 (s), 1152 (s), 1076 (s), 994
δ 12.52 (s, 1H), 7.66 – 7.61 (m, 2H), 7.58 – 7.45 (m, 4H), 6.69 (d, J = 2.4 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
6
3
) δ 200.3,
ν
2
+
(s); HRMS (EI) calcd for C15
H
14
O
4
[M ] 258.0892, found 258.0897.
83
1
-(2-Hydroxy-4-(methoxymethoxy)phenyl)ethan-1-on (1q). Following the procedure for
1
k, 1ꢀ(2,4ꢀdihydroxyphenyl)ethanꢀ1ꢀone (152 mg, 1.00 mmol) was converted to 1q (194 mg,
1
0.99 mmol, 99%): yellowish oil; H NMR (300 MHz, CDCl
3
)
δ
12.59 (s, 1H), 7.63 (d, J = 8.8
Hz, 1H), 6.56 (d, J = 2.6 Hz, 1H), 6.54 (dd, J = 8.8, 2.6 Hz, 1H), 5.19 (s, 2H), 3.46 (s, 3H),
13
2
.55 (s, 3H); C NMR (75 MHz, CDCl
3
)
δ
202.8, 164.9, 163.7, 132.5, 114.9, 108.3, 103.9,
9
4.1, 56.5, 26.4; IR (ATR)
ν
2958 (w), 2829 (w), 1620 (s), 1502 (m), 1365 (s), 1247 (s), 1133
+
(s), 1061 (s), 988 (s); HRMS (EI) calcd for C10
H
12
O
4
[M ] 196.0736, found 196.0730.
84
N-(4-Acetyl-3-hydroxyphenyl)acetamide (1r). 3ꢀ(NꢀAcetylacetamido)phenylacetate (193
mg, 1.00 mmol) and AlCl (292 mg, 2.50 mmol) were mixed and heated to 70 °C for 0.5 h.
3
The mixture was cooled to ambient temperature, the resulting solid was pulverized and heated
to 180 °C for 5 h. After cooling to ambient temperature ice water (20 mL) was added
carefully and the mixture was stirred for 12 h. The solid was filtered and dried in vacuo to
1
furnish 1r (193 mg, 1.00 mmol, quant.): brownish solid, mp 109ꢀ110 °C; H NMR (300 MHz,
DMSOꢀd
6
)
δ
12.32 (s, 1H), 10.30 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H),
13
7
2
.05 (dd, J = 8.8, 2.0 Hz, 1H), 2.55 (s, 3H), 2.07 (s, 3H); C NMR (75 MHz, DMSOꢀd
6
)
δ
03.0, 169.3, 162.6, 146.3, 132.5, 115.3, 110.0, 105.7, 26.8, 24.3; IR (ATR)
ν 3306 (bw),
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109(w), 1678 (m), 1636 (s), 1602 (s), 1522 (s), 1410 (m), 1370 (s), 1249 (s); HRMS (EI)
+
calcd for C H O N [M ] 193.0739, found 193.0742.
10
11
3
General procedure for the Pd-catalyzed 1,1-dimethylallylation of phenols 1. The
appropriate phenol 1 (1.00 mmol) and carbonate 2 (372 mg, 2.00 mmol) were dissolved in
THF (10 mL). The solution was degassed by three freezeꢀpumpꢀthaw cycles before adding
Pd(PPh ) (11 mg, 1 mol %) under an atmosphere of dry nitrogen. The mixture was stirred for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
12 h at ambient temperature under inert gas atmosphere. All volatiles were evaporated and the
residue was purified by column chromatography on silica, using hexanes / MTBE mixtures of
increasing polarity as eluent.
2,4-Bis(methoxymethoxy)-6-((2-methylbut-3-en.2-yl)oxy)benzaldehyde (3a). Following
the general procedure, 1a (242 mg, 1.00 mmol) was converted to 3a (93 mg, 0.30 mmol,
1
30%): yellowish oil; H NMR (300 MHz, CDCl
3
)
δ
10.39 (s, 1H), 6.55 (d, J = 1.9 Hz, 1H),
6.46 (d, J = 1.9 Hz, 1H), 6.16 (dd, J = 17.6, 10.9 Hz, 1H), 5.31 – 5.16 (m, 4H), 5.13 (s, 2H),
13
3.51 (s, 3H), 3.47 (s, 3H), 1.54 (s, 6H); C NMR (75 MHz, CDCl
3
) δ 188.7, 162.5, 161.7,
160.2, 143.9, 114.2, 113.4, 100.9, 97.2, 95.0, 94.3, 81.8, 56.6, 56.4, 27.1; IR (ATR)
ν
2908
+
(w), 1683 (m), 1599 (s), 1433 (m), 1147 (s), 1054 (s); HRMS (EI) calcd for C16
H
22
O
6
[M ]
310.1416, found 310.1429.
85
5-Methoxy-2-((2-methylbut-3-en-2-yl)oxy)benzaldehyd (3e).
Following the general
procedure, 1e (152 mg, 1.00 mmol) was converted to 3e (205 mg, 0.93 mmol, 93%):
1
yellowish oil; H NMR (300 MHz, acetoneꢀd
6
)
δ
10.38 (s, 1H), 7.20 (d, J = 9.1 Hz, 2H), 7.11
(dd, J = 9.0, 2.5 Hz, 1H), 6.18 (dd, J = 17.6, 10.9 Hz, 1H), 5.26 (d, J = 17.6 Hz, 1H), 5.18 (d,
1
3
J = 10.9 Hz, 1H), 3.80 (s, 3H), 1.49 (s, 6H); C NMR (75 MHz, acetoneꢀd )
δ
190.3, 155.9,
6
154.0, 144.7, 130.6, 124.5, 122.7, 114.7, 110.3, 81.8, 55.9, 27.2; IR (ATR) ν 2980 (w), 2860
(w), 1677 (s), 1486 (s), 1388 (m), 1272 (s), 1211 (s), 1120 (s), 1035 (s); HRMS (EI) calcd for
+
C
13
H
16
O
3
[M ] 220.1099, found 220.1088.
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
6
(
4-Methoxy-2-((2-methylbut-3-en-2-yl)oxy)phenyl)(phenyl)methanon (3f). Following the
general procedure, 1f (228 mg, 1.00 mmol) was converted to 3f (153 mg, 0.52 mmol, 52%):
1
brownish oil; H NMR (300 MHz, CDCl
3
)
δ
7.75 – 7.72 (m, 2H), 7.52 – 7.48 (m, 1H), 7.45
(d, J = 8.5 Hz, 1H), 7.42 – 7.38 (m, 2H), 6.65 (d, J = 2.3 Hz, 1H), 6.60 (dd, J = 8.5, 2.3 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
2
H), 5.97 (dd, J = 17.6, 10.8 Hz, 1H), 5.09 (d, J = 17.0 Hz, 1H), 5.08 (d, J = 10.9 Hz, 1H),
1
3
.80 (s, 3H), 1.14 (s, 6H); C NMR (75 MHz, CDCl
3
)
δ
197.0, 162.5, 156.4, 144.1, 139.8,
2982 (w),
32.1, 131.8, 129.5, 128.0, 125.2, 113.8, 106.6, 105.8, 80.8, 55.5, 26.5; IR (ATR)
ν
838 (w), 1651(m), 1598 (s), 1445 (m), 1274 (s), 1203 (m), 1116 (s), 918(s), 748 (s); HRMS
+
(EI) calcd for C19
H
20
O
3
[M ] 296.1412, found 296.1409.
(5-Methoxy-2-((2-methylbut-3-en-2-yl)oxy)phenyl)(phenyl)methanon (3g). Following the
general procedure, 1g (228 mg, 1.00 mmol) was converted to 3g (237 mg, 0.80 mmol, 80%):
1
brownish oil; H NMR (300 MHz, CDCl )
δ 7.80 (dm, J = 8.4 Hz, 2H), 7.54 (tt, J = 8.4, 1.5
3
Hz, 1H), 7.44 (dd, J = 8.4, 8.4 Hz, 2H), 7.03 (d, J = 8.9 Hz, 1H), 6.95 (d, J = 3.1 Hz, 1H),
6
.91 (dd, J = 8.9, 3.1 Hz, 1H), 5.90 (dd, J = 17.5, 10.9 Hz, 1H), 5.01 (dm, J = 10.9 Hz, 1H),
1
3
4
3
.99 (dm, J = 17.5 Hz, 1H), 3.79 (s, 3H), 1.12 (s, 6H); C NMR (75 MHz, CDCl ) δ 197.5,
154.8, 147.6, 144.0, 138.4, 134.3, 132.8, 129.9, 128.2, 122.8, 117.4, 113.8, 113.7, 80.7, 55.8,
2
6.5; IR (ATR)
ν
2981 (w), 2835 (w), 1660(m), 1597 (m), 1483 (s), 1276 (m), 1214 (s), 1037
+
(s), 841(m), 749 (s); HRMS (EI) calcd for C H O [M ] 296.1412, found 296.1402.
19
20
3
1
-(5-Methoxy-2-((2-methylbut-3-en-2-yl)oxy)phenyl)ethan-1-one (3i). Following the
general procedure, 1i (166 mg, 1.00 mmol) was converted to 3i (134 mg, 0.57 mmol, 57%):
1
yellowish oil; H NMR (300 MHz, acetoneꢀd )
δ 7.13 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 3.3 Hz,
6
1
1
H), 6.94 (dd, J = 9.0, 3.3 Hz, 1H), 6.17 (dd, J = 17.6, 10.9 Hz, 1H), 5.23 (dm, J = 17.6 Hz,
13
H), 5.16 (dm, J = 10.9 Hz, 1H), 3.76 (s, 3H), 2.56 (s, 3H), 1.46 (s, 6H); C NMR (75 MHz,
200.4, 155.3, 149.6, 145.1, 134.9, 123.0, 118.7, 114.3, 113.8, 81.6, 55.9, 31.8,
27.2; IR (ATR) 2981 (w), 2936 (w), 1675 (m), 1484 (s), 1409 (m), 1279 (s), 1208 (s), 1124
6
acetoneꢀd ) δ
ν
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(
s), 1040 (s); MS(EI) m/z 234 (3), 166 (100), 151 (49), 69 (11); HRMS (EI) calcd for
+
C H O [M ] 234.1256, found 234.1252.
14
18
3
4
,5-Dimethoxy-2-((2-methylbut-3-en-2-yl)oxy)benzaldehyd (3j). Following the general
procedure, 1j (182 mg, 1.00 mmol) was converted to 3j (114 mg, 0.63 mmol, 63 %):
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yellowish oil; H NMR (300 MHz, CDCl
3
)
δ
10.29 (s, 1H), 7.29 (s, 1H), 6.72 (s, 1H), 6.20
(dd, J = 17.6, 10.8 Hz, 1H), 5.26 (d, J = 17.6 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 3.88 (s, 3H),
1
3
3.86 (s, 3H), 1.51 (s, 6H); C NMR (75 MHz, CDCl
21.9, 114.3, 108.1, 104.9, 81.5, 56.2, 29.9; IR (ATR)
3
)
δ
189.3, 155.6, 154.7, 145.0, 144.2,
1
ν 2980 (w), 2856 (w), 1669 (m), 1601
(m), 1504 (s), 1408 (m), 1273 (s), 1198 (s), 1116 (s), 1003 (s), 750 (s); HRMS (EI) calcd for
+
C H O [M ] 250.1205, found 250.1216.
14
18
4
5
-Methoxy-4-(methoxymethoxy)-2-((2-methylbut-3-en-2-yl)oxy)benzaldehyd
(3k).
Following the general procedure, 1k (212 mg, 1.00 mmol) was converted to 3k (184 mg, 0.66
1
mmol, 66%): yellowish oil; H NMR (300 MHz, acetoneꢀd
6
)
δ
10.27 (s, 1H), 7.24 (s, 1H),
7
.03 (s, 1H), 6.18 (dd, J = 17.6, 10.9 Hz, 1H), 5.28 (d, J = 17.7 Hz, 1H), 5.23 (s, 2H), 5.21 (d,
1
3
J = 10.9 Hz, 1H), 3.83 (s, 3H), 3.45 (s, 3H), 1.50 (s, 6H); C NMR (75 MHz, acetoneꢀd
6
) δ
188.8, 155.4, 153.0, 146.7, 144.6, 123.8, 114.8, 110.4, 109.4, 95.8, 82.0, 56.4, 56.3, 27.1; IR
(ATR)
ν
2983 (w), 2853 (w), 1672 (m), 1602 (m), 1500 (s), 1418 (m), 1267 (s), 1209 (s),
+
1
121 (s), 1073 (m), 750 (s); HRMS (EI) calcd for C H O [M ] 280.1311, found 280.1302.
15
20
5
2
,3,4-Trimethoxy-6-((2-methylbut-3-en-2-yl)oxy)benzaldehyd (3l). Following the general
procedure, 1l (212 mg, 1.00 mmol) was converted to 3l (112 mg, 0.40 mmol, 40%): yellowish
1
oil; H NMR (300 MHz, acetoneꢀd )
δ 10.26 (s, 1H), 6.65 (s, 1H), 6.24 (dd, J = 17.6, 10.8 Hz,
6
1
3
1
H), 5.31 (d, J = 17.6 Hz, 1H), 5.23 (dm, J = 10.9 Hz, 1H), 3.84 (s, 3H), 3.84 (s, 3H), 3.74 (s,
13
H), 1.51 (s, 6H); C NMR (75 MHz, acetoneꢀd
6
)
δ
188.1, 158.8, 157.0, 155.8, 145.3, 138.5,
2981 (w), 2937 (w), 1680 (m),
17.6, 114.4, 101.8, 82.3, 62.2, 61.1, 56.3, 27.0; IR (ATR)
ν
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
1
589 (s), 1487 (m), 1198 (s), 1098 (s), 997 (s); HRMS (EI) calcd for C H O [M ]
15 20 5
280.1311, found 280.1319.
2
,4-Dimethoxy-6-((2-methylbut-3-en-2-yl)oxy)benzaldehyd (3n). Following the general
procedure, 1n (182 mg, 1.00 mmol) was converted to 3n (70 mg, 0.28 mmol, 28%): yellowish
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
oil; H NMR (300 MHz, acetoneꢀd
6
)
δ
10.31 (s, 1H), 6.36 (s, 1H), 6.27 (s, 1H), 6.24 (dd, J =
1
7.7, 10.9 Hz, 1H), 5.30 (d, J = 17.7 Hz, 1H), 5.21 (d, J = 10.9 Hz, 1H), 3.83 (s, 3H), 3.81 (s,
13
3H), 1.52 (s, 6H); C NMR (75 MHz, acetoneꢀd
6
)
δ
188.8, 165.2, 162.9, 162.5, 144.3, 113.9,
1
1
08.0, 97.7, 92.1, 81.8, 56.0, 55.5, 27.1; IR (ATR) n 2977 (w), 2937 (w), 1772 (m), 1598 (s),
+
458 (m), 1214 (s), 1156 (s), 1113 (s), 749 (s); HRMS: no [M ] signal observed with different
ionization methods.
General procedure for the O-allylation of phenols 1. The appropriate phenol 1 (1.00 mmol)
was dissolved in acetone (5 mL) and K
2 3
CO (280 mg, 2.00 mmol) and allyl bromide (128 ꢀL,
1
.50 mmol) were added. The mixture was heated to 50 °C for 16 h and then cooled to ambient
temperature. Brine (20 mL) and ethyl acetate (30 mL) were added, the aqueous layer was
separated and extracted twice with ethyl acetate (30 mL each). The combined organic extracts
4
were dried with MgSO , filtered and evaporated. The residue was purified by column
chromatography on silica, using hexanes / MTBEꢀmixtures of increasing polarity as eluent.
(2-(Allyloxy)-4,6-bis(methoxymethoxy)phenyl)(phenyl)methanone (11b). Following the
general procedure, 1b (318 mg, 1.00 mmol) was converted to 11b (333 mg, 0.93 mmol, 93%):
1
yellowish oil; H NMR (300 MHz, CDCl
3
)
δ
7.90 – 7.83 (m, 2H), 7.55 – 7.48 (m, 1H), 7.45 –
7
.37 (m, 2H), 6.52 (d, J = 1.9 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 5.75 (ddt, J = 17.3, 10.5, 4.9
Hz, 1H), 5.18 (s, 2H), 5.07 (dm, J = 10.6 Hz, 1H), 5.10 (dm, J = 17.3 Hz, 1H), 5.02 (s, 2H),
1
3
4.43 (dt, J = 4.8, 1.5 Hz, 2H), 3.50 (s, 3H), 3.27 (s, 3H); C NMR (75 MHz, CDCl
3
)
δ
194.6,
59.9, 157.6, 156.1, 138.5, 133.0, 132.6, 129.5, 128.4, 117.2, 96.4, 95.5, 94.8, 94.7, 69.3,
6.3, 56.2; IR (ATR) 2905 (w), 2828 (w), 1668 (s), 1601 (s), 1447 (m), 1266 (s), 1312 (m),
1
5
ν
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+
1
149 (s), 1061 (s), 1020 (s), 912 (s); HRMS (EI) calcd for C H O [M ] 358.1416, found
20 22 6
358.1410.
8
6
1
-(2-(Allyloxy)-4-methoxyphenyl)ethan-1-one (11h). Following the general procedure, 1h
1
(
166 mg, 1.00 mmol) was converted to 11h (173 mg, 0.84 mmol, 84%): yellowish oil; H
NMR (300 MHz, CDCl 7.72 (d, J = 8.7 Hz, 1H), 6.41 (dd, J = 8.7, 2.2 Hz, 1H), 6.34 (d, J
2.1 Hz, 1H), 5.99 (ddt, J = 17.3, 10.6, 5.3 Hz, 1H), 5.35 (dm, J = 17.3 Hz, 1H), 5.23 (dm, J
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
) δ
=
1
3
= 10.5 Hz, 1H), 4.50 (d, J = 5.3 Hz, 2H), 3.72 (s, 3H), 2.50 (s, 3H); C NMR (75 MHz,
CDCl3)
δ
197.3, 164.3, 160.0, 132.5, 132.4, 121.3, 118.1, 105.5, 99.2, 69.4, 55.4, 31.9; IR
(
ATR) ν 2941 (w), 1660 (m), 1595 (s), 1498 (m), 1421 (m), 1358 (m), 1253 (s), 1200 (m),
1
169 (m), 1137 (m), 1015 (m), 907 (s); MS (EI) m/z 206 (3), 200 (50), 187 (38), 159 (34), 105
(100).
2-(Allyloxy)-4,5-dimethoxybenzaldehyde (11j). Following the general procedure, 1j (182
1
mg, 1.00 mmol) was converted to 11j (178 mg, 0.80 mmol, 80%): yellowish oil; H NMR
(300 MHz, CDCl
3
) δ 10.35 (s, 1H), 7.30 (s, 1H), 6.48 (s, 1H), 6.05 (ddt, J = 17.2, 10.5, 5.2
Hz, 1H), 5.43 (dm, J = 17.3 Hz, 1H), 5.32 (dm, J = 10.5 Hz, 1H), 4.62 (dt, J = 5.2, 1.4 Hz,
13
2H), 3.92 (s, 3H), 3.85 (s, 3H); C NMR (75 MHz, CDCl
3
)
δ
188.1, 157.8, 155.7, 143.9,
1
1
32.7, 118.2, 118.0, 108.9, 97.6, 70.4, 56.3, 56.2; IR (ATR) ν 3083 (w), 2993 (w), 2851 (w),
663 (s), 1603 (s), 1452 (s), 1343 (m), 1262 (s), 1197 (s), 1121 (s), 1016 (s); HRMS (EI)
+
calcd for C H O [M ] 222.0892, found 222.0885.
12
14
4
2
-(Allyloxy)-5-methoxy-4-(methoxymethoxy)benzaldehyde (11k). Following the general
procedure, 1k (212 mg, 1.00 mmol) was converted to 11k (242 mg, 0.96 mmol, 96%):
1
colourless solid, mp 58 – 60 °C; H NMR (300 MHz, CDCl
3
)
δ
10.37 (s, 1H), 7.33 (s, 1H),
6
.84 (s, 1H), 6.04 (ddt, J = 17.1, 10.5, 5.3 Hz, 1H), 5.43 (dm, J = 17.3 Hz, 1H), 5.31 (dm, J =
13
1
0.4 Hz, 1H), 5.28 (s, 2H), 4.60 (dm, J = 5.3 Hz, 2H), 3.86 (s, 3H), 3.51 (s, 3H); C NMR
188.3, 157.3, 153.3, 144.3, 132.6, 119.1, 118.4, 109.5, 101.7, 95.4, 70.2,
(75 MHz, CDCl3)
δ
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
56.6, 56.4; IR (ATR)
ν
2936 (w), 2856 (w), 1667 (s), 1605 (s), 1499 (s), 1419 (m), 1271 (s),
+
1210 (s), 1149 (s), 1122 (s); HRMS (EI) calcd for C13
H
16
O
5
[M ] 252.0998, found 252.0995.
6-(Allyloxy)-2,3,4-trimethoxybenzaldehyde (11l). Following the general procedure, 1l (212
1
mg, 1.00 mmol) was converted to 11l (214 mg, 0.85 mmol, 85%): orangeꢀcoloured oil; H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (300 MHz, CDCl
3
) δ 10.33 (s, 1H), 6.25 (s, 1H), 6.03 (ddt, J = 17.2, 10.4, 5.0 Hz, 1H),
5.47 (dm, J = 17.3 Hz, 1H), 5.30 (dm, J = 10.6 Hz, 1H), 4.59 (dt, J = 5.0, 1.5 Hz, 2H), 3.92 (s,
13
3H), 3.89 (s, 3H), 3.79 (s, 3H); C NMR (75 MHz, CDCl
3
)
δ
187.9, 159.0, 158.2, 156.4,
2937 (w), 2854 (w), 1674
136.4, 132.6, 118.1, 113.3, 93.5, 70.2, 62.1, 61.3, 56.2; IR (ATR)
ν
(s), 1590 (s), 1488 (m), 1452 (m), 1383 (m), 1330 (m), 1245 (s), 1197 (s), 1101 (s); HRMS
+
(
EI) calcd for C H O [M ] 252.0992, found 252.0988.
13 16
5
2-(Allyloxy)-4-(methoxymethoxy)benzaldehyde (11o). Following the general procedure, 1o
1
(182 mg, 1.00 mmol) was converted to 11o (197 mg, 0.89 mmol, 89%): colourless oil; H
NMR (300 MHz, CDCl
3
) δ 10.36 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.7 Hz, 1H),
6.60 (d, J = 1.7 Hz, 1H), 6.06 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.45 (d, J = 17.3 Hz, 1H), 5.33
1
3
(d, J = 10.6 Hz, 1H), 5.21 (s, 2H), 4.62 (d, J = 5.0 Hz, 2H), 3.48 (s, 3H); C NMR (75 MHz,
CDCl3) 188.4, 163.8, 162.7, 132.3, 130.4, 120.0, 118.3, 108.5, 100.7, 94.3, 69.3, 56.5; IR
δ
(
(
(
ATR)
ν
2901 (w), 2856 (w), 1676 (s), 1597 (s), 1498 (m), 1436 (m), 1255 (s), 1151 (s), 1076
+
s), 923 (m); HRMS (EI) calcd for C H O [M ] 222.0892, found 222.0897.
12
14
4
2-(Allyloxy)-4-(methoxymethoxy)phenyl)phenyl)methanone (11p). Following the general
procedure, 1p (258 mg, 1.00 mmol) was converted to 11p (292 mg, 0.98 mmol, 98%):
1
yellowish oil; H NMR (300 MHz, CDCl
3
)
δ
7.81 – 7.75 (m, 2H), 7.55 – 7.48 (m, 1H), 7.45 –
7
.36 (m, 3H), 6.72 (dd, J = 8.5, 2.2 Hz, 1H), 6.63 (d, J = 2.1 Hz, 1H), 5.69 (ddt, J = 17.2,
0.7, 4.8 Hz, 1H), 5.22 (s, 2H), 5.03 (dm, J = 10.7 Hz, 1H), 4.97 (dm, J = 17.2 Hz, 1H), 4.42
1
1
3
(dt, J = 4.8, 1.6 Hz, 2H), 3.50 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 195.9, 161.0, 158.5,
139.1, 132.4, 132.2, 132.1, 129.6, 128.1, 123.0, 117.1, 107.9, 101.5, 94.5, 69.1, 56.4; IR
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(ATR)
ν
3062 (w), 2902 (w), 1652 (m), 1600 (s), 1498 (m), 1447 (m), 1269 (s), 1149 (s),
+
1074 (s), 992 (s); HRMS (EI) calcd for C18
H
18
O
4
[M ] 298.1205, found 298.1205.
87
1-(2-(Allyloxy)-4-(methoxymethoxy)phenyl)ethan-1-one (11q). Following the general
procedure, 1q (196 mg, 1.00 mmol) was converted to 11q (231 mg, 0.98 mmol, 98%):
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yellowish oil; H NMR (300 MHz, CDCl
3
)
δ
7.79 (d, J = 8.7 Hz, 1H), 6.65 (dd, J = 8.7, 2.2
Hz, 1H), 6.59 (d, J = 2.1 Hz, 1H), 6.08 (ddt, J = 17.0, 10.6, 5.4 Hz, 1H), 5.44 (dm, J = 17.3
Hz, 1H), 5.32 (dm, J = 10.6 Hz, 1H), 5.19 (s, 2H), 4.61 (d, J = 5.4 Hz, 2H), 3.47 (s, 3H), 2.59
13
(s, 3H); C NMR (75 MHz, CDCl )
δ
197.8, 162.0, 159.9, 132.5, 132.4, 122.3, 118.4, 108.0,
3
100.9, 94.3, 69.5, 56.3, 32.1; IR (ATR)
ν
3083 (w), 2928 (w), 1663 (s), 1597 (s), 1496 (m),
+
1421 (m), 1358 (m), 1252 (s), 1152 (s), 993 (s); HRMS (EI) calcd for C H O [M ]
13 16
4
236.1049, found 236.1039.
8
8
N-(4-Acetyl-3-(allyloxy)phenyl)acetamide (11r). Following the general procedure, 1r (193
mg, 1.00 mmol) was converted to 11r (214 mg, 0.92 mmol, 92%): brownish solid, mp 109 ꢀ
1
111 °C; H NMR (300 MHz, DMSOꢀd
6
)
δ
10.20 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.52 (d, J =
1.4 Hz, 1H), 7.15 (dd, J = 8.6, 1.5 Hz, 1H), 6.10 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 5.45 (dm, J
= 17.3 Hz, 1H), 5.30 (dm, J = 10.5 Hz, 1H), 4.62 (d, J = 5.2 Hz, 2H), 2.49 (s, 3H), 2.06 (s,
1
3
3
1
1
H); C NMR (75 MHz, DMSOꢀd
6
) δ 196.5, 168.9, 158.6, 144.5, 133.0, 130.8, 122.1, 118.1,
10.7, 103.1, 68.9, 31.7, 24.2; IR (ATR)
ν
3321 (bw), 3189(w), 1667 (m), 1589 (s), 1529 (m),
+
417 (m), 1368 (m), 1255 (s), 1186 (m); HRMS (EI) calcd for C13
H
15
O
3
N [M ] 233.1052,
found 233.1041.
General procedure for the microwave-promoted tandem Claisen-rearrangement /
Wittig-olefination / cyclization sequence. A solution of allylethers 3 or 11 (1.00 mmol) and
ylide 6 (522 mg, 1.50 mmol) in N,Nꢀdiethylaniline (10 mL) was placed in a vessel suited for
microwave irradiation. The vessel was sealed and irradiated in a microwave reactor at 250 °C
for the time interval noted in the tables (10 min. or 60 min.). After cooling to ambient
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