Synthesis of Allyl- and Prenylcoumarins via Microwave-Promoted Tandem Claisen Rearrangement/Wittig Olefination

Article abstract of DOI:10.1055/s-0035-1560501

Allyl, dimethylallyl, crotyl, and prenyl ethers of various aromatic ortho-hydroxy carbonyl compounds undergo a tandem sequence of Claisen rearrangement, carbonyl olefination, and cyclization upon microwave irradiation in the presence of a stabilized ylide. The products are multiply substituted 6- or 8-allylated or prenylated coumarins (2H-chromen-2-ones).

Full text of DOI:10.1055/s-0035-1560501

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 141–149
paper
141
B. Schmidt, M. Riemer
Paper
Synthesis
Synthesis of Allyl- and Prenylcoumarins via Microwave-Promoted
Tandem Claisen Rearrangement/Wittig Olefination
Bernd Schmidt*
Martin Riemer
O
Ph3P
Universitaet Potsdam, Institut fuer Chemie,
Karl-Liebknecht-Strasse 24-25, 14476 Potsdam-Golm,
Germany
OEt
MeO
O
O
MeO
O
O
bernd.schmidt@uni-potsdam.de
MW, 250 °C, 1 h
Received: 18.08.2015
Accepted after revision: 22.09.2015
Published online: 20.10.2015
bond9 of the coumarate, and cyclization to the final prod-
ucts.3,4 Mali et al. and others extended this sequence by
starting from O-allylated or O-prenylated salicylaldehydes,
which were heated in the presence of a stabilized ylide to
200 °C for 4–12 hours in N,N-dimethylaniline or without
solvent.5–8,10 Under these conditions, the (E)-coumarates
are formed initially in a Wittig olefination and react then
via Claisen rearrangement, E/Z-isomerization, and cycliza-
tion to the prenyl- or allylcoumarins.
DOI: 10.1055/s-0035-1560501; Art ID: ss-2015-z0490-op
Abstract Allyl, dimethylallyl, crotyl, and prenyl ethers of various aro-
matic ortho-hydroxy carbonyl compounds undergo a tandem sequence
of Claisen rearrangement, carbonyl olefination, and cyclization upon
microwave irradiation in the presence of a stabilized ylide. The products
are multiply substituted 6- or 8-allylated or prenylated coumarins (2H-
chromen-2-ones).
Key words aldehydes, coumarins, ketones, microwave irradiation,
olefination, tandem reaction, ylides
a) previous work:
first a protecting ...then an essential
group...
substituent
We have very recently developed a synthesis of 6- and
8-allyl-substituted 4H-chromen-4-one derivatives 2 from
alkenyl or alkynyl ketones 1.1,2 This approach, which relies
on a microwave-promoted tandem Claisen rearrange-
ment/6-endo-cyclization sequence, makes dual use of the
allyl ether moiety in the starting material. During the syn-
thesis of the tandem precursors, the allyl ether serves as a
protecting group for the acidic and oxidation sensitive phe-
nol. Upon its cleavage by Claisen rearrangement, the nucle-
ophilic phenol required for the 6-endo-cyclization is liber-
ated, and the allyl (or prenyl) substituent is transferred to
the 6- or 8-position as an essential part of the target struc-
ture (Scheme 1). With a view to translating this scheme to
the use of allyl ethers in a microwave-promoted synthesis
of isomeric 6- or 8-allyl-substituted 2H-chromen-2-ones
(coumarins), we reinvestigated an approach that was pio-
neered by Harwood et al.3,4 and Mali et al.5–8 Harwood and
co-workers reported that O-prenylated or allylated (E)-cou-
marates [(E)-3-phenylprop-2-enoates] react upon heating
in refluxing N,N-diethylaniline to give 6- or 8-allyl- or
-prenylcoumarins. This sequence involves one or two sig-
matropic rearrangements, E/Z-isomerization of the double
R1
O
O
O
O
R1
MW
Rn
Rn
1
2
b) this work:
O
X
O
O
O
+
MW
O
Ph3P
Rn
Rn
R1
R1
3
4
5
Scheme 1 Microwave-promoted tandem Claisen rearrangement/
cyclization and tandem Claisen rearrangement/olefination/cyclization
approaches to 4H-chromen-4-ones and 2H-chromen-2-ones
Typically, yields of ca. 50% of prenylated or allylated
coumarins are obtained under these conditions. Later, oth-
ers investigated Mali’s tandem sequence in refluxing diphe-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

142
B. Schmidt, M. Riemer
Paper
Synthesis
nyl ether (bp 258 °C), but no substantial improvement was
reported with regard to selectivity, yield, and reaction
time.11,12
At the outset we investigated the steps of the tandem
sequence, olefination, and Claisen rearrangement with sub-
sequent isomerization/cyclization, separately. To this end,
coumarate 8a was synthesized from o-(allyloxy)benzalde-
hyde (3a) via Horner–Wadsworth–Emmons olefination and
then subjected to the conditions previously established by
us for the Claisen rearrangement/6-endo-cyclization, i.e.
microwave irradiation at 250 °C for one hour in N,N-dieth-
ylaniline.1,2 This resulted in a full conversion of the starting
material into 8-allylcoumarin 5a, which was isolated in 83%
yield. This result shows that the standard microwave condi-
tions can efficiently promote the Claisen rearrangement
and the E/Z-isomerization of the coumarate. Next, we in-
vestigated the first step of the sequence, the Wittig olefina-
tion, by subjecting a mixture of 3a and [(ethoxycarbon-
yl)methylene]triphenylphosphorane (4a) to microwave ir-
radiation in N,N-diethylaniline. By choosing a temperature
of 100 °C, we ensured that the olefination reaction proceed-
ed cleanly and quantitatively, without any Claisen rear-
rangement or E/Z-isomerization, to furnish coumarate 8a in
84% yield. Eventually, 3a and 4a were irradiated at 250 °C
for one hour, resulting in the formation of 8-allylcoumarin
5a in 74% yield, which corresponds well with the theoreti-
cal yield of 70% for the two-step synthesis (Scheme 2).
In particular for reactions with very high activation bar-
riers, microwave irradiation has been found to be a useful
alternative form of energy supply. Reaction times can nor-
mally be substantially reduced, leading to smaller amounts
of decomposition products and hence improved yields. In
addition, dedicated microwave reactors have power, tem-
perature, and pressure control mechanisms that ensure re-
producibility and a high degree of safety even if the reac-
tion mixture is heated beyond its boiling point in a closed
vessel.13–16 These considerations, and the indisputable bio-
medicinal relevance of naturally occurring coumarins,17–23
prompted us to investigate the tandem sequence leading di-
rectly from O-allylated aldehydes or ketones 3 and stabi-
lized ylides 4 to substituted coumarins 5 under microwave
conditions (Scheme 1). We were particularly interested to
investigate whether microwave conditions would allow an
expansion of the substrate scope to benzo- or acetophe-
nones (R1 = aryl or methyl in structure 3), which would re-
act to 4-aryl- or 4-alkylcoumarins bearing an allyl or prenyl
substituent at C6 or C8. There has been an increased inter-
est in these special substitution patterns over the past two
decades, because they have been discovered in numerous
natural products isolated from plants of the family Clusia-
ceae.24–27 A representative example is mammea A/AA (6),
which was isolated from the seeds of the tree Mammea
americana, and found to be cytotoxic against a range of hu-
man colon cancer cell lines and display high anti-oxidant
activity.26 On the other hand, non-natural 4-alkyl- or 4-
arylcoumarins have been synthesized and tested in various
biological assays to gain insight into structure-activity rela-
tionships.20,28–34 In this regard, coumarins with a bulky and
hydrophobic aryl substituent at C4 were found to be better
inhibitors of P-glycoprotein, a transmembrane drug trans-
porter responsible for pumping cytotoxic drugs out of can-
cer cells, which has been identified as a major mechanism
for multidrug resistance in chemotherapy.29 An example of
a coumarin that has been used to study and identify the in-
hibitor binding site of hepatitis C virus non-structural pro-
tein 5B (a potential antiviral target) is compound 7 (Figure
1).33
O
P
CO2Et
EtO
EtO
NaH, THF, 65 °C (88%)
O
O
O
CO2Et
Ph3P
CO2Et
(4a)
3a
8a
N,N-diethylaniline (0.15 M)
MW, 100 °C, 1 h (84%)
Ph3P
CO2Et
N,N-diethylaniline
(0.15 M), MW
O
O
(4a)
250 °C, 1 h (83%)
N,N-diethylaniline
(0.15 M), MW
250 °C, 1 h (74%)
5a
Scheme 2 Tandem olefination/Claisen rearrangement/isomeriza-
tion/cyclization sequence vs. two-step procedure
A variety of allyl aryl ethers 3a–k were then subjected
to the optimized conditions (Table 1). In almost all cases the
expected 8-allylcoumarins 5a–k were isolated in syntheti-
cally useful yields (≥70%), with the exception of 7-methoxy-
substituted coumarin 5c, which was reproducibly obtained
in a yield of 40% (entry 3).
HO
O
O
HO
O
O
O
OH
OH
Mammea A/AA (6)
7
Figure 1 Representative examples for a natural 6 and synthetic 7 al-
lylated or prenylated 4-arylcoumarins
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

143
B. Schmidt, M. Riemer
Paper
Synthesis
Table 1 Scope of the Tandem Sequence for Allyl Ethers
ly high to result in the formation of atropisomers. The pre-
cursor 3l was synthesized from commercial benzophenone
9 in quantitative yield and irradiated under standard condi-
tions, resulting in the formation of 5l, which was isolated in
a fair yield of 54% (Scheme 4).
Ph3P
(4a)
CO2Et
R4
R3
O
R4
R3
O
O
N,N-diethylaniline (0.15 M)
O
O
MW, 250 °C, 1 h
P
CO2Et
R2
R1
R2
R1
MeO
O
O
MeO
O
EtO
EtO
3
5
CO2Et
NaH, THF, 65 °C
Entry
3
R1
R2
R3
R4
Product Yield (%)
3c
8c (94%)
1
2
3a
H
H
H
H
5a
5b
5c
5d
5e
5f
74
3b
3c
3d
3e
3f
H
OMe
H
H
OMe
OMe
H
62
N,N-diethylaniline
3
H
H
40
(0.15 M)
MeO
O
O
4
H
H
Br
77
MW, 250 °C, 1 h
5
H
H
2-MeOC6H4
H
76
6
Me
Me
Me
Me
Ph
Ph
H
H
H
80
5c (66%)
7
3g
3h
3i
H
OMe
Cl
H
5g
5h
5i
78
Scheme 3 Microwave irradiation of coumarate 8c
8
H
H
74
9
H
Br
H
H
quant.
73
10
11
3j
H
H
5j
Br
MeO
OH
MeO
O
3k
H
H
OMe
5k
67
(3.0 equiv)
K2CO3 (4.0 equiv)
O
O
OH
O
acetone, 50 °C
Interestingly, the yields were substantially higher for
the 5,7-dimethoxycoumarin 5b (entry 2) and the 7-meth-
oxy-4-phenyl derivative 5k (entry 11). The corresponding
precursors 3b,c,k have in common that an electron-donat-
ing substituent is located ortho or para to the carbonyl
group, which might affect the olefination as well as the E/Z
isomerization. We investigated the Claisen rearrange-
ment/cyclization steps for the outlier 5c separately by syn-
thesizing 8c independently via Horner–Wadsworth–
Emmons olefination of 3c. Coumarate 8c was then subject-
ed to microwave irradiation under the standard conditions,
resulting in the formation of 5c in 66% yield. Although this
yield is significantly lower than that observed for the un-
substituted derivative 5a (83%, see Scheme 2), we can not
conclude that the Claisen rearrangement/isomerization
part of the tandem sequence is solely responsible for the
comparatively low yield under tandem conditions (Scheme
3). We concluded this part of the investigation into the tan-
dem sequence with the bis(allyloxy)benzophenone 3l. This
substrate was expected to be comparatively challenging,
because in order to obtain a useful yield for the tandem se-
quence, two Claisen rearrangements had to proceed simul-
taneously and selectively in high yield, and the Wittig olefi-
nation step might be impeded by the bulky 2,4-disubstitut-
ed aryl substituents. We thought, however, that this
substrate should be interesting because its reaction in the
tandem sequence would reduce the molecular symmetry
from C2v in the precursor to Cs in the product, or even to C1
if the rotation barrier around the C4-aryl bond is sufficient-
9
3l (quant.)
OMe
OMe
MeO
O
O
N,N-diethylaniline
(0.15 M)
MW, 250 °C, 1 h
OH
5l (54%)
OMe
Scheme 4 Symmetry-reducing dual Claisen rearrangement/Wittig
olefination/cyclization sequence
In biaryl compounds, a di-ortho-substitution pattern
will normally only induce atropisomerism if both substitu-
ents are sterically demanding, but other substituents in the
meta- and para-positions will also affect the rotational bar-
rier through steric or electronic effects.35 Axial chirality and
atropisomerization in 4-arylcoumarins have previously
been investigated using NMR, HPLC, and DFT methods, with
the result that 6-isopropyl-4-(o-tolyl)coumarin is configu-
rationally stable at ambient temperature, and that the bar-
rier for atropisomerization is further increased by an addi-
tional substituent in the meta-position of the 4-aryl sub-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

144
B. Schmidt, M. Riemer
Paper
Synthesis
stituent.36 For compound 5l, all attempts to separate
atropisomers via HPLC on chiral stationary phases (Chiral-
cel ODH and ADH) failed, even if the temperature was re-
duced to 12 °C. It is currently unclear whether this failure
must be attributed to an insufficient resolution on the chi-
ral stationary phases or to fast atropisomerization due to a
very low rotational barrier.
In addition to the allyl ethers 3a–l studied so far, we in-
vestigated a crotyl ether 3m2 and two 1,1-dimethylallyl
ethers 3n and 3o in the tandem sequence. The crotyl ether
3m reacted under standard conditions to the coumarin 5m,
with a but-3-en-2-yl side chain at C8, the substitution pat-
tern expected for a single Claisen rearrangement. Gratify-
ingly, no positional isomers resulting from a subsequent
Cope rearrangement (which have been observed for some
thermal Claisen rearrangements of crotyl ethers)37–39 were
detected in this case (Scheme 5).
sulting from other sigmatropic rearrangements, e.g. a sub-
sequent Cope rearrangement, were detected (Scheme 6).
The prenylated coumarin 5o is a natural product known
as osthole. It was first isolated from the roots of Angelica
archangelica42 and later from numerous other plants.43–45 It
has been reported to show numerous interesting bioactivi-
ties,46 inter alia anti-inflammatory activity44 and activity as
a Ca2+-channel antagonist.47
In the next step we investigated whether the tandem
conditions would be compatible with a substitution pattern
predestined for a para-Claisen rearrangement. Migration of
the allyl moiety to the para-position occurs regularly when
both ortho-positions of the allyl ether are blocked, as for ex-
ample in 3p. The para-Claisen rearrangement is a cascade
of Claisen rearrangement, Cope rearrangement, and even-
tually enolization, which would accordingly give 13 via 12a
or 12b.48 In our particular case, one ortho-substituent has
to be a formyl group, which might result in a highly unde-
sirable decarbonylation to 14 if the initial Claisen rear-
rangement proceeds via 12b. This decarbonylation has in-
deed been reported to occur upon heating 3p to 200 °C, giv-
ing 14 in synthetically useful yields (Scheme 7).49
Ph3P
(4a)
CO2Et
O
O
O
N,N-diethylaniline (0.15 M)
O
MW, 250 °C, 1 h
3m
5m (73%)
Scheme 5 Tandem Claisen rearrangement/Wittig olefination se-
quence for a crotyl ether 3m
MeO
MeO
O
OH
O
The 1,1-dimethylallyl ethers 3n2 and 3o were synthe-
sized from o-hydroxybenzaldehydes 10a and 10b, respec-
tively, via palladium-catalyzed allylation with 1,1-dimeth-
ylallyl carbonate 11.40,41 Under standard conditions, 3n and
3o were converted into the 8-prenylcoumarins 5n and 5o in
81% and 68% yield, respectively. As for 3m, no products re-
O
12a
13
MeO
and/or
MeO
O
MeO
O
OH
O
O
3p
CO
12b
14
H
Scheme 7 Possible pathways for 2-allyloxy-3-substituted benzalde-
hydes under Claisen rearrangement conditions
OBoc
(11)
R2
R1
OH
R2
R1
O
[Pd(PPh3)4]
(1.0 mol%)
THF, 0 °C
O
O
To test whether the danger of decarbonylation can be
averted under tandem conditions, we synthesized the
known allyl, crotyl, and prenyl ethers 3p–r50 via Williamson
etherification. These starting materials were then subjected
to the standard conditions. Gratifyingly, for all three exam-
ples the 6-substituted coumarins 5p–r, the products ex-
pected for a para-Claisen rearrangement pathway, were
isolated (Scheme 8).
We could not detect any decarbonylation products,
most likely because olefination of the aldehyde is too fast
for any sigmatropic rearrangement to compete (compare
conditions for the microwave-promoted two-step reaction
shown in Scheme 2).
10a (R1 = OMOM, R2 = H)
10b (R1 = H, R2 = OMe)
3n (98%)
3o (87%)
Ph3P
(4a)
CO2Et
R2
R1
O
O
N,N-diethylaniline (0.15 M)
MW, 250 °C, 1 h
5n (R1 = OMOM, R2 = H; 81%)
5o (R1 = H, R2 = OMe; 68%)
Scheme 6 Synthesis of 8-prenylcoumarins 5n and osthole (5o)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

145
B. Schmidt, M. Riemer
Paper
Synthesis
if a cyclization involving the allenyl substituent as outlined
above is faster than the E/Z-isomerization step required for
coumarin formation. The experimental results clearly show
that the latter scenario is preferred, because we could not
detect any coumarin product in the reaction mixture, but
isolated benzofuran 23 and benzopyran 24 in a combined
yield of ca. 60%. In light of the literature precedence on
propargyl Claisen rearrangements discussed above, the
rather high proportion of endo-cyclization product is quite
intriguing. Presumably, the ylide 4a (which is used in ex-
cess) reacts as a base and catalyzes the formation of a phe-
nolate analogous to 17 (see Scheme 9), which would pave
the way for the endo-cyclization product 23.
R1
R2
O
MeO
O
O
Ph3P
(4a)
CO2Et
MeO
N,N-diethylaniline (0.15 M)
MW, 250 °C, 1 h
R2
O
R1
3p (R1 = R2 = H)
3q (R1 = Me, R2 = H)
3r (R1 = R2 = Me)
5p (55%)
5q (65%)
5r (42%)
Scheme 8 6-Substituted coumarins via para-Claisen rearrange-
ment/Wittig olefination
Finally, we investigated the compatibility of the tandem
sequence with a propargyl Claisen rearrangement.51–53 This
transformation was originally discovered for aryl propargyl
ethers, which react at high temperatures to give benzopy-
ran derivatives.54 Compared to the allyl Claisen rearrange-
ment, its propargyl variant has found few applications.55–57
The mechanism proposed for this reaction proceeds via sig-
matropic rearrangement of an aryl propargyl ether such as
15 to an allenyl ketone 16. A sequence of enolization to 19
and 1,5-H-shift to 20 sets the stage for a final electrocyclic
ring closure, leading to the isolated product 21.56,58,59 Sub-
stantial amounts of endo-cyclization products, such as ben-
zofuran 18, have only been reported when the propargyl
Claisen rearrangement was conducted in the presence of a
base, because this leads to a deprotonation of 16 to pheno-
late 17, which undergoes cyclization and reprotonation to
the 2-methylbenzofuran (18) (Scheme 9).58,60
O
CO2Et
23 (36%)
Ph3P
(4a)
CO2Et
+
O
N,N-diethylaniline (0.15 M)
O
MW, 250 °C, 1 h
O
22
CO2Et
24 (25%)
Scheme 10 Tandem propargyl Claisen/cyclization/Wittig olefination
sequence
In summary, we describe conditions for a microwave-
promoted tandem sequence leading from ortho-allyloxy-
substituted aromatic aldehydes or ketones to allyl-, crotyl-,
or prenyl-substituted coumarins. The sequence involves
Wittig olefination, Claisen rearrangement, and thermally
induced E/Z-isomerization, and is terminated by lactoniza-
tion. The advantages of our conditions over conventional
heating conditions used previously are: reduced reaction
times, improved yields, and a broader substrate scope. This
makes the method potentially highly useful for the synthe-
sis of numerous naturally occurring coumarins, inter alia
those with an alkyl or aryl substituent at the 4-position.
•
•
H
H
O
O
O
O
Δ
H
15
16
17
18
•
O
OH
O
19
20
21
All experiments were conducted in dry reaction vessels under an at-
mosphere of dry N2. Solvents were purified by standard procedures.
1H NMR spectra were obtained at 300 MHz with a Bruker ARX-300
spectrometer in CDCl3 with CHCl3 (δ = 7.26) as an internal standard,
or in C6D6 with C6D5H (δ = 7.18) as an internal standard. 13C NMR
spectra were recorded at 75 MHz with a Bruker ARX-300 in CDCl3
with CDCl3 (δ = 77.0) as an internal standard or in C6D6 with C6D6
(δ = 128.0) as an internal standard. IR spectra were recorded as ATR-
FTIR spectra on a Perkin-Elmer UART-two spectrophotometer. LRMS
and HRMS were obtained by EI-TOF (Micromass Manchester Waters
Inc.) or ESI-TOF (Micromass Manchester Waters Inc.). Microanalyses
were obtained with an Elementar-Vario EL-III apparatus. Microwave
Scheme 9 Mechanistic rationale for the formation of benzofurans and
benzopyrans from aryl propargyl ethers
We investigated the reaction of propargyl ether 22 and
phosphorane 4a in the tandem Claisen rearrangement/
Wittig olefination/cyclization sequence (Scheme 10). This
starting material could react to give an 8-allenylcoumarin,
in analogy to the allyl aryl ethers investigated so far. Alter-
natively, a benzopyran or benzofuran product might result,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

146
B. Schmidt, M. Riemer
Paper
Synthesis
reactions were carried out in an Anton-Paar-monowave-300 reactor
at 250 °C (monowave, maximum power 850 W, temperature control
via IR-sensor, vial volume 20 mL).
1H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 9.6 Hz, 1 H), 7.48 (s, 2 H),
6.44 (d, J = 9.6 Hz, 1 H), 5.96 (ddt, J = 17.3, 10.3, 6.7 Hz, 1 H), 5.20–5.11
(m, 2 H), 3.57 (d, J = 6.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 160.1, 150.9, 142.6, 134.9, 134.5, 130.8,
128.4, 120.3, 117.8, 117.7, 116.9, 33.1.
8-Allyl-2H-chromen-2-ones 5 by Microwave-Promoted Tandem
Wittig Reaction/Isomerization/Cyclization; General Procedure
HRMS (EI): m/z [M]+ calcd for C12H9O279Br: 263.9786; found:
A solution of the appropriate aldehyde or ketone 3 (0.50 mmol) and
[(ethoxycarbonyl)methylene]triphenylphosphorane (4a, 261 mg, 0.75
mmol) in N,N-diethylaniline (5 mL) was placed in a vessel suited for
irradiation in a dedicated microwave reactor. The vessel was sealed
and irradiated at 250 °C for 1 h. It was then cooled to r.t., the mixture
was diluted with EtOAc (50 mL) and washed 1 M HCl (3 × 30 mL). The
organic extract was dried (MgSO4), filtered, and evaporated. The resi-
due was chromatographed (silica gel, hexane–MTBE), to furnish the
coumarins 5.
273.9769.
8-Allyl-6-(2-methoxyphenyl)-2H-chromen-2-one (5e)
Following the general procedure, 3e (118 mg, 0.44 mmol) was con-
verted into 5e (98 mg, 0.34 mmol, 76%); colorless oil.
IR (ATR): 1721 (s), 1579 (m), 1465 (m), 1240 (s), 1165 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 9.5 Hz, 1 H), 7.58 (d, J = 1.9
Hz, 1 H), 7.52 (d, J = 2.0 Hz, 1 H), 7.40–7.28 (m, 2 H), 7.05 (dd, J = 7.4,
7.4, 1.7 Hz, 1 H), 7.01 (d, J = 8.3 Hz, 1 H), 6.43 (d, J = 9.5 Hz, 1 H), 6.06
(ddt, J = 16.8, 10.0, 6.7 Hz, 1 H), 5.19 (dm, J = 17.0 Hz, 1 H), 5.12 (dm,
J = 10.4 Hz, 1 H), 3.83 (s, 3 H), 3.67 (d, J = 6.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 161.0, 156.4, 150.9, 144.2, 135.4, 134.8,
133.9, 130.7, 129.3, 129.0, 127.9, 126.9, 121.1, 118.5, 116.9, 116.4,
111.4, 55.7, 33.3.
8-Allyl-2H-chromen-2-one (5a)9
Following the general procedure, 3a (121 mg, 0.75 mmol) was con-
verted into 5a (103 mg, 0.55 mmol, 74%); colorless oil.
IR (ATR): 1717 (s), 1601 (m), 1176 (m), 1116 (m), 829 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 9.5 Hz, 1 H), 7.36 (dd,
J = 7.5, 1.3 Hz, 1 H), 7.32 (dd, J = 7.8, 1.5 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1
H), 6.37 (d, J = 9.5 Hz, 1 H), 5.97 (ddt, J = 16.8, 10.1, 6.7 Hz, 1 H), 5.11
(dm, J = 17.0 Hz, 1 H), 5.08 (dm, J = 10.1 Hz, 1 H), 3.57 (d, J = 6.6 Hz, 2
H).
HRMS (EI): m/z [M]+ calcd for C19H16O3: 292.1074; found: 292.1099.
8-Allyl-4-methyl-2H-chromen-2-one (5f)
Following the general procedure, 3f (88 mg, 0.50 mmol) was convert-
ed into 5f (80 mg, 0.40 mmol, 80%); colorless oil.
13C NMR (75 MHz, CDCl3): δ = 160.7, 151.8, 143.8, 135.3, 132.4, 128.3,
IR (ATR): 1716 (s), 1383 (m), 1449 (w), 1173 (m), 855 cm–1 (m).
126.1, 124.2, 118.7, 116.8, 116.3, 33.2.
HRMS (EI): m/z [M]+ calcd for C12H10O2: 186.0681; found: 186.0686.
1H NMR (300 MHz, CDCl3): δ = 7.45 (d, J = 7.8 Hz, 1 H), 7.36 (d, J = 7.3
Hz, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 6.24 (s, 1 H), 5.98 (ddt, J = 16.8, 10.1,
6.7 Hz, 1 H), 5.09 (d, J = 17.2 Hz, 1 H), 5.07 (d, J = 10.1 Hz, 1 H), 3.57 (d,
J = 6.6 Hz, 2 H), 2.40 (d, J = 0.9 Hz, 3 H).
8-Allyl-5,7-dimethoxy-2H-chromen-2-one (5b)6
Following the general procedure, 3b (111 mg, 0.50 mmol) was con-
verted into 5b (76 mg, 0.31 mmol, 62%); colorless oil.
13C NMR (75 MHz, CDCl3): δ = 160.7, 152.7, 151.3, 135.5, 132.3, 128.4,
IR (ATR): 1711 (m), 1602 (s), 1433 (m), 1329 (m), 1116 cm–1 (s).
123.9, 122.8, 119.8, 116.7, 114.9, 33.4, 18.9.
HRMS (EI): m/z [M]+ calcd for C13H12O2: 200.0837; found: 200.0840.
1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 9.6 Hz, 1 H), 6.28 (s, 1 H),
6.06 (d, J = 9.6 Hz, 1 H), 5.89 (ddt, J = 16.3, 10.0, 6.2 Hz, 1 H), 4.98 (dm,
J = 17.1 Hz, 1 H), 4.91 (dm, J = 10.0 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H),
3.44 (d, J = 6.2 Hz, 2 H).
8-Allyl-6-methoxy-4-methyl-2H-chromen-2-one (5g)
Following the general procedure, 3g (60 mg, 0.29 mmol) was convert-
ed into 5g (52 mg, 0.23 mmol, 78%); colorless solid; mp 70–71 °C.
13C NMR (75 MHz, CDCl3): δ = 161.7, 161.1, 155.6, 153.6, 138.9, 135.7,
IR (ATR): 1707 (s), 1583 (s), 1462 (m), 1160 (s), 1052 cm–1 (m).
114.8, 110.5, 108.0, 103.6, 90.3, 56.1, 55.9, 26.3.
HRMS (EI): m/z [M]+ calcd for C14H14O4: 246.0892; found: 246.0880.
1H NMR (300 MHz, CDCl3): δ = 6.96 (d, J = 2.7 Hz, 1 H), 6.86 (d, J = 2.8
Hz, 1 H), 6.25 (s, 1 H), 5.97 (ddt, J = 16.8, 10.1, 6.7 Hz, 1 H), 5.11 (dm,
J = 16.5 Hz, 1 H), 5.08 (dm, J = 10.1 Hz, 1 H), 3.82 (s, 3 H), 3.56 (d,
J = 6.6 Hz, 2 H), 2.39 (s, 3 H).
8-Allyl-7-methoxy-2H-chromen-2-one (5c)61
Following the general procedure, 3c (96 mg, 0.50 mmol) was convert-
ed into 5c (43 mg, 0.20 mmol, 40%); colorless solid; mp 137–138 °C.
13C NMR (75 MHz, CDCl3): δ = 160.9, 155.6, 152.4, 145.9, 135.3, 129.8,
IR (ATR): 1715 (m), 1602 (s), 1249 (s), 1117 (s), 836 cm–1 (m).
120.4, 119.4, 117.0, 115.4, 105.6, 55.8, 33.6, 19.0.
HRMS (EI): m/z [M]+ calcd for C14H14O3: 230.0943; found: 230.0945.
1H NMR (300 MHz, CDCl3): δ = 7.59 (d, J = 9.5 Hz, 1 H), 7.30 (d, J = 8.6
Hz, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.18 (d, J = 9.4 Hz, 1 H), 5.92 (ddt,
J = 16.4, 10.0, 6.3 Hz, 1 H), 5.03 (dm, J = 17.1 Hz, 1 H), 4.94 (dm,
J = 10.0 Hz, 1 H), 3.88 (s, 3 H), 3.55 (d, J = 6.3 Hz, 2 H).
8-Allyl-6-chloro-4-methyl-2H-chromen-2-one (5h)
Following the general procedure, 3h (75 mg, 0.36 mmol) was convert-
ed into 5h (62 mg, 0.26 mmol, 74%); colorless solid; mp 65–67 °C.
13C NMR (75 MHz, CDCl3): δ = 161.3, 160.3, 152.9, 143.8, 135.1, 126.7,
IR (ATR): 1715 (s), 1574 (m), 1421 (m), 1361 (m), 866 cm–1 (s).
116.0, 115.3, 112.9, 112.9, 107.4, 56.1, 26.8.
HRMS (EI): m/z [M]+ calcd for C13H12O3: 216.0786; found: 216.0779.
1H NMR (300 MHz, CDCl3): δ = 7.41 (d, J = 2.1 Hz, 1 H), 7.33 (d, J = 2.1
Hz, 1 H), 6.30 (s, 1 H), 5.95 (ddt, J = 17.2, 10.0, 6.7 Hz, 1 H), 5.22–5.00
(m, 2 H), 3.56 (d, J = 6.6 Hz, 2 H), 2.40 (s, 3 H).
8-Allyl-6-bromo-2H-chromen-2-one (5d)
13C NMR (75 MHz, CDCl3): δ = 160.0, 151.7, 149.8, 134.6, 131.9, 130.5,
129.3, 122.3, 121.0, 117.6, 116.0, 33.3, 18.9.
Following the general procedure, 3d (121 mg, 0.50 mmol) was con-
verted into 5d (102 mg, 0.38 mmol, 77%); colorless oil.
IR (ATR): 1722 (s), 1565 (m), 1168 (m), 1119 (m), 856 cm–1 (m).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

147
B. Schmidt, M. Riemer
Paper
Synthesis
HRMS (EI): m/z [M]+ calcd for C13H11O235Cl: 234.0448; found:
8-(But-3-en-2-yl)-2H-chromen-2-one (5m)
234.0439.
Following the general procedure, 3m (132 mg, 0.75 mmol) was con-
verted into 5m (109 mg, 0.55 mmol, 73%); colorless oil.
8-Allyl-6-bromo-4-methyl-2H-chromen-2-one (5i)
IR (ATR): 1720 (s), 1598 (m), 1116 (m), 833 (m), 751 cm–1 (m).
Following the general procedure, 3i (128 mg, 0.50 mmol) was con-
verted into 5i (139 mg, 0.50 mmol, quant.); colorless oil.
IR (ATR): 1729 (s), 1359 (m), 1137 (m), 920 (m), 852 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.51 (d, J = 1.7 Hz, 1 H), 7.42 (d, J = 1.8
Hz, 1 H), 6.24 (s, 1 H), 5.91 (ddt, J = 17.1, 10.1, 6.7 Hz, 1 H), 5.16–5.06
(m, 2 H), 3.51 (d, J = 6.6 Hz, 2 H), 2.35 (d, J = 1.1 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 9.5 Hz, 1 H), 7.37 (dd,
J = 7.5, 1.4 Hz, 1 H), 7.30 (dd, J = 7.7, 1.5 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 1
H), 6.36 (d, J = 9.5 Hz, 1 H), 6.01 (ddd, J = 17.3, 10.3, 6.2 Hz, 1 H), 5.09
(dm, J = 17.2 Hz, 1 H), 5.06 (dm, J = 10.0 Hz, 1 H), 4.15 (pent., J = 7.0
Hz, 1 H), 1.35 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.7, 151.2, 144.0, 141.2, 133.6, 130.2,
13C NMR (75 MHz, CDCl3): δ = 159.7, 151.5, 150.2, 134.6, 134.5, 130.7,
126.0, 124.3, 118.8, 116.2, 114.2, 35.1, 19.6.
HRMS (EI): m/z [M]+ calcd for C13H12O2: 200.0837; found: 200.0858.
125.2, 121.4, 117.6, 116.7, 115.8, 33.2, 18.8.
HRMS (EI): m/z [M]+ calcd for C13H11O279Br: 277.9942; found:
277.9921.
6-(Methoxymethoxy)-8-(3-methylbut-2-enyl)-2H-chromen-2-one
(5n)
8-Allyl-4-phenyl-2H-chromen-2-one (5j)
Following the general procedure, 3n (125 mg, 0.50 mmol) was con-
verted into 5n (111 mg, 0.41 mmol, 81%); colorless solid; mp 72–
74 °C.
IR (ATR): 1720 (s), 1580 (m), 1448 (m), 1150 (s), 1016 cm–1 (s).
Following the general procedure, 3j (119 mg, 0.50 mmol) was con-
verted into 5j (95 mg, 0.36 mmol, 73%); yellow solid; mp 110–113 °C.
IR (ATR): 1710 (s), 1595 (m), 1367 (m), 1248 (m), 1165 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.59 (d, J = 9.5 Hz, 1 H), 7.01 (d, J = 2.5
Hz, 1 H), 6.93 (d, J = 2.5 Hz, 1 H), 6.33 (d, J = 9.5 Hz, 1 H), 5.26 (tm,
J = 6.0 Hz, 1 H), 5.12 (s, 2 H), 3.48–3.41 (m, 5 H), 1.69 (s, 6 H).
1H NMR (300 MHz, CDCl3): δ = 7.56–7.50 (m, 3 H), 7.47–7.42 (m, 3 H),
7.36 (dd, J = 8.1, 1.2 Hz, 1 H), 7.17 (t, J = 7.7 Hz, 1 H), 6.37 (s, 1 H), 6.07
(ddt, J = 16.8, 10.0, 6.7 Hz, 1 H), 5.18 (dm, J = 16.8 Hz, 1 H), 5.15 (dm,
J = 10.1 Hz, 1 H), 3.68 (d, J = 6.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 160.9, 153.3, 147.1, 143.7, 134.3, 131.2,
13C NMR (75 MHz, CDCl3): δ = 160.6, 156.0, 152.0, 135.5, 135.5, 132.5,
129.6, 128.8, 128.7, 128.5, 125.3, 123.9, 118.9, 116.8, 115.0, 33.6.
121.4, 120.5, 119.0, 116.6, 110.7, 94.8, 56.0, 27.6, 25.7, 17.8.
HRMS (EI): m/z [M]+ calcd for C16H18O4: 274.1205; found: 274.1234.
HRMS (EI): m/z [M]+ calcd for C18H14O2: 262.0994; found: 262.1010.
7-Methoxy-8-(3-methylbut-2-enyl)-2H-chromen-2-one (Osthole,
5o)62
8-Allyl-7-methoxy-4-phenyl-2H-chromen-2-one (5k)
Following the general procedure, 3o (110 mg, 0.50 mmol) was con-
verted into 5o (83 mg, 0.34 mmol, 68%); colorless solid; mp 65–67 °C.
IR (ATR): 1717 (s), 1603 (s), 1278 (m), 1249 (s), 1116 cm–1 (s).
Following the general procedure, 3k (134 mg, 0.50 mmol) was con-
verted into 5k (98 mg, 0.34 mmol, 67%); colorless oil.
IR (ATR): 1716 (s), 1596 (s), 1371 (s), 1277 (s), 1077 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.57 (d, J = 9.4 Hz, 1 H), 7.25 (d, J = 8.5
Hz, 1 H), 6.79 (d, J = 8.6 Hz, 1 H), 6.17 (d, J = 9.4 Hz, 1 H), 5.19 (t, J = 7.1
Hz, 1 H), 3.88 (s, 3 H), 3.49 (d, J = 7.2 Hz, 2 H), 1.80 (s, 3 H), 1.63 (s, 3
H).
13C NMR (75 MHz, CDCl3): δ = 161.4, 160.2, 152.8, 143.8, 132.6, 126.3,
121.2, 117.8, 113.0, 112.9, 107.4, 56.1, 25.8, 21.9, 17.9.
1H NMR (300 MHz, CDCl3): δ = 7.52–7.44 (m, 3 H), 7.44–7.36 (m, 2 H),
7.31 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 6.17 (s, 1 H), 5.98 (ddt,
J = 17.1, 10.0, 6.3 Hz, 1 H), 5.09 (dm, J = 17.1 Hz, 1 H), 4.99 (dm,
J = 10.0 Hz, 1 H), 3.89 (s, 3 H), 3.63 (d, J = 6.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 161.3, 160.3, 156.1, 153.0, 135.8, 135.2,
129.5, 128.8, 128.4, 126.0, 116.2, 115.4, 112.9, 111.9, 107.1, 56.1, 27.0.
HRMS (EI): m/z [M]+ calcd for C15H16O3: 244.1099; found: 244.1085.
HRMS (EI): m/z [M]+ calcd for C19H16O3: 292.1099; found: 292.1078.
6-Allyl-8-methoxy-2H-chromen-2-one (5p)
8-Allyl-4-(3-allyl-2-hydroxy-4-methoxyphenyl)-7-methoxy-2H-
chromen-2-one (5l)
Following the general procedure, 3p (150 mg, 0.78 mmol) was con-
verted into 5p (92 mg, 0.43 mmol, 55%); colorless solid; mp 87–89 °C.
IR (ATR): 1724 (s), 1580 (m), 1395 (w), 1257 (w), 1155 cm–1 (w).
Following the general procedure, 3l (172 mg, 0.50 mmol) was con-
verted into 5l (103 mg, 0.27 mmol, 54%); colorless solid; mp 183 °C.
IR (ATR): 3284 (br w), 1699 (m), 1598 (s), 1375 (m), 1270 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 9.5 Hz, 1 H), 6.87 (d, J = 1.5
Hz, 1 H), 6.83 (d, J = 1.3 Hz, 1 H), 6.36 (d, J = 9.5 Hz, 1 H), 5.92 (ddt,
J = 16.1, 10.8, 6.7 Hz, 1 H), 5.16–4.98 (m, 2 H), 3.90 (s, 3 H), 3.37 (d,
J = 6.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 160.3, 147.1, 143.7, 142.3, 136.5, 136.5,
119.2, 118.7, 116.8, 116.7, 114.5, 56.2, 39.8.
1H NMR (300 MHz, CDCl3): δ = 7.18 (d, J = 8.8 Hz, 1 H), 7.06 (d, J = 8.5
Hz, 1 H), 6.78 (d, J = 8.9 Hz, 1 H), 6.62 (d, J = 8.5 Hz, 1 H), 6.21 (s, 1 H),
6.07–5.89 (m, 2 H), 5.42 (s, 1 H), 5.15 (dm, J = 17.3 Hz, 1 H), 5.09 (dm,
J = 10.1 Hz, 1 H), 5.03 (dm, J = 17.3 Hz, 1 H), 4.98 (dm, J = 10.1 Hz, 1
H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.61 (d, J = 6.3 Hz, 2 H), 3.54 (d, J = 6.2
Hz, 2 H)
13C NMR (75 MHz, CDCl3): δ = 161.6, 160.5, 159.3, 153.4, 152.9, 152.1,
136.0, 135.3, 128.3, 126.3, 116.3, 116.0, 115.9, 115.5, 114.8, 113.3,
113.2, 107.3, 103.6, 56.2, 56.0, 27.7, 27.1.
HRMS (EI): m/z [M]+ calcd for C13H12O3: 216.0786; found: 216.0777.
(E)-6-(But-2-enyl)-8-methoxy-2H-chromen-2-one (5q)
Following the general procedure, 3q (145 mg, 0.70 mmol) was con-
verted into 5q (104 mg, 0.45 mmol, 65%); colorless solid; mp 78–
79 °C.
HRMS (EI): m/z [M]+ calcd for C23H22O5: 378.1467; found: 378.1434.
IR (ATR): 1717 (s), 1578 (s), 1394 (m), 1154 (m), 1085 cm–1 (s).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

148
B. Schmidt, M. Riemer
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 9.5 Hz, 1 H), 6.86 (d, J = 1.0
Hz, 1 H), 6.81 (d, J = 1.2 Hz, 1 H), 6.35 (d, J = 9.5 Hz, 1 H), 5.61–5.48 (m,
2 H), 3.90 (s, 3 H), 3.30 (d, J = 3.8 Hz, 2 H), 1.67 (d, J = 3.7 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560501.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C NMR (75 MHz, CDCl3): δ = 160.4, 147.0, 143.7, 142.1, 137.6, 129.2,
127.3, 119.2, 118.5, 116.7, 114.4, 56.2, 38.6, 17.9.
HRMS (EI): m/z [M]+ calcd for C14H14O3: 230.0943; found: 230.0965.
References
(1) Schmidt, B.; Riemer, M.; Schilde, U. Synlett 2014, 25, 2943.
(2) Schmidt, B.; Riemer, M.; Schilde, U. Eur. J. Org. Chem. 2015, in
press.
(3) Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Chem.
Commun. 1986, 1264.
8-Methoxy-6-(3-methylbut-2-enyl)-2H-chromen-2-one (5r)
Following the general procedure, 3r (85 mg, 0.39 mmol) was convert-
ed into 5r (40 mg, 0.16 mmol, 42%); colorless oil.
IR (ATR): 2920 (w), 1718 (s), 1578 (m), 1463 (m), 1086 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.63 (d, J = 9.5 Hz, 1 H), 6.89 (d, J = 1.5
Hz, 1 H), 6.83 (d, J = 1.5 Hz, 1 H), 6.39 (d, J = 9.5 Hz, 1 H), 5.30 (t, J = 7.3
Hz, 1 H), 3.94 (s, 3 H), 3.36 (d, J = 7.2 Hz, 2 H), 1.77 (s, 3 H), 1.72 (s, 3
H).
(4) Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Perkin
Trans. 1 1994, 3101.
(5) Mali, R. S.; Sandhu, P. K.; Manekar-Tilve, A. J. Chem. Soc., Chem.
Commun. 1994, 251.
(6) Mali, R. S.; Sandhu, P. K. Synth. Commun. 1994, 24, 2883.
(7) Mali, R. S.; Joshi, P. P. Synth. Commun. 2001, 31, 2753.
(8) Mali, R. S.; Joshi, P. P.; Sandhu, P. K.; Manekar-Tilve, A. J. Chem.
Soc., Perkin Trans. 1 2002, 371.
13C NMR (75 MHz, CDCl3): δ = 160.4, 147.1, 143.6, 138.3, 133.7, 122.2,
119.2, 118.2, 116.8, 116.4, 114.4, 56.3, 34.0, 25.7, 17.9.
HRMS (EI): m/z [M]+ calcd for C15H16O3: 244.1094; found: 244.1095.
(9) Boeck, F.; Blazejak, M.; Anneser, M. R.; Hintermann, L. Beilstein J.
Org. Chem. 2012, 8, 1630.
(10) Guz, N. R.; Lorenz, P.; Stermitz, F. R. Tetrahedron Lett. 2001, 42,
6491.
(11) Patre, R. E.; Shet, J. B.; Parameswaran, P. S.; Tilve, S. G. Tetrahe-
dron Lett. 2009, 50, 6488.
Ethyl (E)-3-(2-Methylbenzofuran-7-yl)acrylate (23) and Ethyl (E)-
3-(2H-Chromen-8-yl)acrylate (24)
Following the general procedure, 22 (120 mg, 0.75 mmol) was con-
verted into a separable mixture of 23 (63 mg, 0.27 mmol, 36%) and 24
(42 mg, 0.18 mmol, 25%).
(12) Patre, R. E.; Parameswaran, P. S.; Tilve, S. G. ARKIVOC 2011, (ix),
68; http://www.arkat-usa.org/home.
(13) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(14) Kappe, C. O. Chimia 2006, 60, 308.
Ethyl (E)-3-(2-Methylbenzofuran-7-yl)acrylate (23)
Colorless oil; yield: 63 mg (0.27 mmol, 36%).
IR (ATR): 1706 (s), 1632 (m), 1426 (m), 1267 (m), 1161 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 16.1 Hz, 1 H), 7.50 (d, J = 7.6
Hz, 1 H), 7.32 (d, J = 7.3 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 6.99 (d,
J = 16.1 Hz, 1 H), 6.42 (s, 1 H), 4.33 (q, J = 7.1 Hz, 2 H), 2.52 (s, 3 H),
1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 167.5, 156.1, 152.9, 140.0, 130.0, 125.1,
122.9, 122.2, 121.0, 118.8, 102.8, 60.6, 14.5, 14.2.
(15) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127.
(16) Microwaves in Organic Synthesis; de la Hoz, A.; Loupy, A., Eds.;
Wiley-VCH: Weinheim, 2012.
(17) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477.
(18) Murray, R. D. H. Fortschr. Chem. Org. Naturst. 2002, 83, 1.
(19) McGlacken, G. P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22, 369.
(20) Riveiro, M. E.; De Kimpe, N.; Moglioni, A.; Vazquez, R.; Monczor,
F.; Shayo, C.; Davio, C. Curr. Med. Chem. 2010, 17, 1325.
(21) Musa, M. A.; Cooperwood, J. S.; Khan, M. O. F. Curr. Med. Chem.
2008, 15, 2664.
HRMS (EI): m/z [M]+ calcd for C14H14O3: 230.0943; found: 230.0961.
Ethyl (E)-3-(2H-Chromen-8-yl)acrylate (24)
(22) Bansal, Y.; Sethi, P.; Bansal, G. Med. Chem. Res. 2013, 22, 3049.
(23) Medina, F. G.; Marrero, J. G.; Macias-Alonso, M.; Gonzalez, M. C.;
Cordova-Guerrero, I.; Teissier Garcia, A. G.; Osegueda-Robles, S.
Nat. Prod. Rep. 2015, 32, DOI: 10.1039/C1034NP00162A.
(24) Guilet, D.; Séraphin, D.; Rondeau, D.; Richomme, P.; Bruneton, J.
Phytochemistry 2001, 58, 571.
(25) Guilet, D.; Hélesbeux, J.-J.; Séraphin, D.; Sévenet, T.; Richomme,
P.; Bruneton, J. J. Nat. Prod. 2001, 64, 563.
(26) Yang, H.; Protiva, P.; Gil, R. R.; Jiang, B.; Baggett, S.; Basile, M. J.;
Reynertson, K. A.; Weinstein, I. B.; Kennelly, E. J. Planta Med.
2005, 71, 852.
(27) López-Pérez, J. L.; Olmedo, D. A.; del Olmo, E.; Vásquez, Y.; Solís,
P. N.; Gupta, M. P.; San Feliciano, A. J. Nat. Prod. 2005, 68, 369.
(28) Bedoya, L. M.; Beltrán, M.; Sancho, R.; Olmedo, D. A.; Sánchez-
Palomino, S.; del Olmo, E.; López-Pérez, J. L.; Muñoz, E.;
Feliciano, A. S.; Alcamí, J. Bioorg. Med. Chem. Lett. 2005, 15,
4447.
Colorless oil; yield: 42 mg (0.18 mmol, 25%).
IR (ATR): 1704 (m), 1630 (m), 1446 (m), 1161 (s), 802 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.92 (d, J = 16.2 Hz, 1 H), 7.33 (dd,
J = 7.8, 1.1 Hz, 1 H), 6.97 (dd, J = 7.5, 1.5 Hz, 1 H), 6.86 (t, J = 7.5 Hz, 1
H), 6.51 (d, J = 16.2 Hz, 1 H), 6.42 (dt, J = 9.9, 1.8 Hz, 1 H), 5.82 (dt,
J = 9.9, 3.5 Hz, 1 H), 4.92 (dd, J = 3.5, 1.8 Hz, 2 H), 4.27 (q, J = 7.1 Hz, 2
H), 1.35 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 167.5, 153.2, 139.4, 128.5, 128.3, 124.4,
122.9, 122.3, 122.2, 121.2, 119.0, 65.9, 60.4, 14.5.
HRMS (EI): m/z [M]+ calcd for C14H14O3: 230.0943; found: 230.0933.
Acknowledgment
We thank Evonik for generous donations of solvents. Support from
the equal opportunities fund of the Faculty of Science is gratefully ac-
knowledged. We thank Prof. Pablo Wessig, University of Potsdam, for
dynamic enantioselective HPLC measurements.
(29) Raad, I.; Terreux, R.; Richomme, P.; Matera, E.-L.; Dumontet, C.;
Raynaud, J.; Guilet, D. Bioorg. Med. Chem. 2006, 14, 6979.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149

149
B. Schmidt, M. Riemer
Paper
Synthesis
(30) Grimm, E. L.; Brideau, C.; Chauret, N.; Chan, C.-C.; Delorme, D.;
Ducharme, Y.; Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Guay,
J.; Hamel, P.; Riendeau, D.; Soucy-Breau, C.; Tagari, P.; Girard, Y.
Bioorg. Med. Chem. Lett. 2006, 16, 2528.
(31) Ducharme, Y.; Blouin, M.; Brideau, C.; Châteauneuf, A.; Gareau,
Y.; Grimm, E. L.; Juteau, H.; Laliberté, S.; MacKay, B.; Massé, F.;
Ouellet, M.; Salem, M.; Styhler, A.; Friesen, R. W. ACS Med. Chem.
Lett. 2010, 1, 170.
(45) Lv, H.-N.; Wang, S.; Zeng, K.-W.; Li, J.; Guo, X.-Y.; Ferreira, D.;
Zjawiony, J. K.; Tu, P.-F.; Jiang, Y. J. Nat. Prod. 2015, 78, 279.
(46) Zhang, Z.-R.; Leung, W. N.; Cheung, H. Y.; Chan, C. W.
Evidence-Based Complementary and Alternative Medicine; 2015
Article ID 919616, doi: 919610.911155/912015/919616;
http://www.hindawi.com/journals/ecam/.
(47) Fusi, F.; Sgaragli, G.; Ha, L. M.; Cuong, N. M.; Saponara, S. Eur. J.
Pharmacol. 2012, 680, 22.
(32) Timonen, J. M.; Nieminen, R. M.; Sareila, O.; Goulas, A.;
Moilanen, L. J.; Haukka, M.; Vainiotalo, P.; Moilanen, E.;
Aulaskari, P. H. Eur. J. Med. Chem. 2011, 46, 3845.
(33) Nichols, D. B.; Leão, R. A. C.; Basu, A.; Chudayeu, M.; de Moraes,
P. d F.; Talele, T. T.; Costa, P. R. R.; Kaushik-Basu, N. Chem. Biol.
Drug Des. 2013, 81, 607.
(34) Gomez-Verjan, J. C.; Estrella-Parra, E. A.; González-Sánchez, I.;
Vázquez-Martínez, E. R.; Vergara-Castañeda, E.; Cerbón, M. A.;
Reyes-Chilpa, R. J. Pharm. Pharmacol. 2014, 66, 1189.
(35) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384.
(36) Lunazzi, L.; Mancinelli, M.; Mazzanti, A.; Pierini, M. J. Org. Chem.
2010, 75, 5927.
(37) Quartieri, F.; Mesiano, L. E.; Borghi, D.; Desperati, V.; Gennari,
C.; Papeo, G. Eur. J. Org. Chem. 2011, 6794.
(38) Huang, K.-S.; Wang, E.-C.; Chen, H.-M. J. Chin. Chem. Soc. 2004,
51, 585.
(39) Mehta, G.; Maity, P. Tetrahedron Lett. 2007, 48, 8865.
(40) Kawamura, T.; Hayashi, M.; Mukai, R.; Terao, J.; Nemoto, H. Syn-
thesis 2012, 44, 1308.
(48) Wunderli, A.; Winkler, T.; Hansen, H.-J. Helv. Chim. Acta 1977,
60, 2436.
(49) Dallacker, F.; Sluysmans, R. Monatsh. Chem. 1969, 100, 560.
(50) Molina, P.; Alajarin, M.; Vidal, A.; Fenau-Dupont, J.; Declerq, J. P.
J. Org. Chem. 1991, 56, 4008.
(51) Viola, A.; Collins, J. J.; Filipp, N. Tetrahedron 1981, 37, 3765.
(52) Martín Castro, A. M. Chem. Rev. 2004, 104, 2939.
(53) Tejedor, D.; Mendez-Abt, G.; Cotos, L.; Garcia-Tellado, F. Chem.
Soc. Rev. 2013, 42, 458.
(54) Iwai, I.; Ide, J. Chem. Pharm. Bull. 1962, 10, 926.
(55) Subramanian, R. S.; Balasubramanian, K. K. Tetrahedron Lett.
1988, 29, 6797.
(56) Majumdar, K. C.; Bhattacharyya, T. Tetrahedron Lett. 2001, 42,
4231.
(57) Yang, Z.-Y.; Xia, Y.; Xia, P.; Brossi, A.; Lee, K.-H. Tetrahedron Lett.
1999, 40, 4505.
(58) Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.; Suzuki, M. Chem.
Pharm. Bull. 1992, 40, 1148.
(59) Macor, J. E.; Langer, O. D.; Gougoutas, J. Z.; Malley, M. F.;
Cornelius, L. A. M. Tetrahedron Lett. 2000, 41, 3541.
(60) Ishikawa, T.; Mizutani, A.; Miwa, C.; Oku, Y.; Komano, N.;
Takami, A.; Watanabe, T. Heterocycles 1997, 45, 2261.
(61) Liu, G.-L.; Hao, B.; Liu, S.-P.; Wang, G.-X. Eur. J. Med. Chem. 2012,
54, 582.
(41) Riemer, M. Synlett 2014, 25, 1041.
(42) Böcker, E.; Hahn, A. J. Prakt. Chem. 1911, 83, 243.
(43) Thongthoom, T.; Songsiang, U.; Phaosiri, C.; Yenjai, C. Arch.
Pharm. Res. 2010, 33, 675.
(44) Liao, P.-C.; Chien, S.-C.; Ho, C.-L.; Wang, E. I. C.; Lee, S.-C.; Kuo,
Y.-H.; Jeyashoke, N.; Chen, J.; Dong, W.-C.; Chao, L. K.; Hua, K.-F.
J. Agric. Food Chem. 2010, 58, 10445.
(62) Dien, P. H.; Nhan, N. T.; Le Thuy, H. T.; Quang, D. N. Nat. Prod.
Res. 2011, 26, 2107.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 141–149