Palladium(II)-Catalyzed Intramolecular C-H Alkenylation for the Synthesis of Chromanes

Article abstract of DOI:10.1021/acs.joc.8b03051

The intramolecular Pd(II)-catalyzed alkenylation of aryl homoallyl ethers constitutes a mild, versatile, and efficient procedure for the synthesis of highly and diversely substituted chromanes and 2H-chromenes. The use of p-TsOH as an additive allows more efficient reactions that could be carried out a room temperature in most cases. The procedure has a wide scope, allowing the synthesis of alkylidenechromanes and 2H-chromenes substituted at C-2 or C-3 of the chromene moiety, thus accessing relevant flavenes and isoflavenes, and even coumarins, in high yields (59 to 91%, 32 examples).

Full text of DOI:10.1021/acs.joc.8b03051

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Article
Palladium(II)-catalyzed Intramolecular C-
H Alkenylation for the Synthesis of Chromanes
Asier Carral-Menoyo, Alexander Misol, Marcos Gomez-Redondo, Nuria Sotomayor, and Esther Lete
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 14 Jan 2019
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The Journal of Organic Chemistry
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Palladium(II)-catalyzed Intramolecular C-H
Alkenylation for the Synthesis of Chromanes
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Asier Carral-Menoyo, Alexander Misol, Marcos Gómez-Redondo, Nuria Sotomayor* and Esther Lete*
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco /
Euskal Herriko Unibertsitatea UPV/EHU. Apdo. 644. 48080 Bilbao (Spain)
R4
CO R
2
CH3
R3
O
PdCl2(CH3CN)2
(5 mol %)
R3
R2
R2
BQ (1 equiv.)
p-TsOH (1 equiv.)
Dioxane, rt
R2
R1
R1
O
O
R1
mild conditions
wide scope
8 examples, 59-77%
24 examples, 60-91%
Abstract. The intramolecular Pd(II)-catalyzed alkenylation of aryl homoallyl ethers constitutes a mild,
versatile, and efficient procedure for the synthesis of highly and diversely substituted chromanes, and
2H-chromenes. The use of p-TsOH as additive allows more efficient reactions that could be carried out
a room temperature in most cases. The procedure has a wide scope, allowing the synthesis of
alkylidenechromanes and 2H-chromenes substituted at C-2 or C-3 of the chromene moiety, thus
accessing relevant flavenes and isoflavenes, and even coumarins, in high yields (59 to 91%, 32
examples)
Introduction
Carbon-carbon bond formation through transition metal-catalyzed cross-coupling reactions constitutes
1
one of the most powerful tools both in industry and academic organic synthesis. Oxidative-coupling
2
reactions, particularly palladium (II)-catalyzed intramolecular C-H alkenylation reaction of arenes and
3
heteroarenes, provide a direct route to carbocyclic and heterocyclic frameworks. In contrast to the
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Mizoroki-Heck reaction, this atom-economical approach eliminates the need for preactivated coupling
partners (halides or triflates), although a stoichiometric oxidant is required to regenerate the Pd(II)
active species. The intramolecular variant is mainly limited to C-H alkenylation of electron-rich
heteroarenes (e.g. indole and pyrrole) and/or to the construction of five-membered rings. Representative
examples include aerobic oxidative annulations of indoles and pyrroles for the construction of five-, six-
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and even seven-membered rings and cyclization of allyl aryl ethers for the synthesis of benzofuran
5
derivatives. The potential of these Pd(II)-catalyzed alkenylations has also been shown in the synthesis
6
7
of pyrrole-containing natural products, such as (+)-rhazinal or dragmacidins.
Depending on the structural features of the substrate and the experimental conditions, different
mechanistic pathways can operate (i.e. arene metalation-alkene insertion or alkene activation-arene
insertion), which in turn may lead to different regioisomeric products. For example, Pd(II)-catalyzed
intramolecular reactions of N-phenylacrylamides in the presence of Pd(II) catalysts and oxidants has
8
been reported to afford oxindoles, and even when β-hydride elimination is not allowed, the Ar-Pd(II)-
9
intermediate undergoes a 5-exo-trig cyclization followed by nucleophile capture or subsequent C-H
alkylation.10 However, the reaction can be directed to the position, achieving the selective
intramolecular C–H alkenylation of related N-alkyl substituted N-phenylacrylamides to give 4-
substituted quinolin-2[1H]-ones.11
HO
OCH3
OCH3
OCH3
OCH3
O
H3CO
O
OH
OCH3
Candenatenin E
anticancer
Anti-inflamatory
O
O
O
N
H
O
N
O
H3CO
O
Analgesic and
Osteogenic
muscle relaxant
Figure 1. Biologically active 2H-chromene and chromane derivatives
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To expand the synthetic utility of this procedure, we decided to investigate C–H alkenylation
1
2
reactions for the synthesis of oxygen heterocycles, such as chromanes. The chromane and 2H-chromene
moieties are important structural motifs present in a wide variety of bioactive natural products,12
pharmaceuticals13 and photochromic materials for different applications (laser dyes, fluorescence
probes, etc.).14 For example, 4-alkylidenechromanes have shown their potential as antagonists of
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transient receptor type 1 (TRPV1) for pain relief and as muscle relaxants. Besides, they are used as
1
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building blocks in the synthesis of 6-oxastereoid derivatives. On the other hand, flav-2-enes, (2-aryl-
1
9
2
H-chromenes), have shown anticancer, anti-inflammatory or antiviral activity, while isoflavenes (3-
ary-2H-chromenes) have been recently identified as novel potential osteogenic agents20 (Figure 1).
Therefore, rapid access to chromenes bearing substituents at specific positions is of great interest to both
synthetic and medicinal chemistry. Chromenes have been prepared via intramolecular cyclization of
advanced intermediates using metal-free Bronsted and Lewis acid/base catalysis and transition-metal
2
1
catalyzed reactions, although only a few examples of oxidative C-H alkenylation reactions have been
described for the synthesis of chromenes. Youn reported the Pd(II)-catalyzed oxidative cyclization of
ally aryl ethers to obtain benzofurans, through a Claisen rearrangement followed by an oxidative 5-exo-
trig cyclization. The procedure could also be extended to homoallyl ethers, obtaining 2H-chromenes
after isomerization of the initially formed exocyclic double bond.22 Besides, the carbonylative
cyclization of aryl homoallyl ethers has also been reported for the synthesis of 4-substituted
chromanes.23 We have recently described the use of Pd(II)-catalyzed intramolecular alkenylation
reaction of N-protected homoallyl anilines to access quinolines and dihydroquinolines, through 6-exo
cyclization processes. Thus, starting from the same precursor, conditions could be selected to favor the
one pot formation of 4-substituted quinolines. Under milder reaction conditions, 1,2-dihydroquinolines
2
4
were obtained after isomerization of the double bond. This procedure would be complementary to the
related Mizoroki-Heck reaction that led to the formation of 4-methylidenetetrahydroquinolines.25
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Results and Discussion
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6
In connection with our interest in palladium catalyzed cyclization reactions,11,24,25,26 our goal was to
expand the synthetic utility of this type of 6-exo intramolecular alkenylation reaction into the synthesis
of chromanes and 2H-chromenes. We reasoned that a Pd(II)-oxidative cyclization could be applied for
the synthesis of 4-akylidenechromanes, avoiding the isomerization of the double bond. Thus, if a 5-
0
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aryloxypent-2-enoate such as I (R = CO R) (Scheme 1) is selected as a substrate, the presence of the
2
conjugated alkoxycarbonyl group would prevent the exocyclic/endocyclic isomerization of the double
4
bond, leading to the formation of II. Without the presence of the ester group (R = H), the initially
formed exocyclic double bond would be expected to isomerize to the more stable endocyclic double
bond, leading to the formation of 2H-chromenes. We decided to study the applicability of this reaction
2
to the synthesis of diversely substituted chromanes I and 2H-chromenes II, including flavenes (R = Ar)
3
and isoflavenes (R = Ar)
CO R
2
R4 = CO R
2
R4
R2
R1
O
Pd(II)
-exo
R3
II
6
R2
[O]
CH3
R1
O
R3
R4 = H
I
R2
R1
O
III
4
Scheme 1. Pd(II)-catalyzed cyclization of 5-aryloxypent-2-enoates (R = CO R) and homoallyl ethers
2
4
(
R = H)
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Table 1. Cyclization of 1a.
1
2
3
4
5
6
7
8
9
CO CH3
CO CH3
2
2
OCH3
OCH3
PdCl (CH CN)
2
2
3
(5 mol %)
rt, oxidant,
solvent
H CO
O
H CO
3
O
3
1a
2a
[O]a
additive a solvent
t (h) 2a(%)b
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
c
d
1
2
3
4
5
6
7
8
9
1
PhCO tBu p-TsOH
AcOH
24
3
F+c
p-TsOH
p-TsOH
AcOH
24
d
F+c
mesitylene
dioxane
dioxane
dioxaneh
dioxane
dioxane
dioxane
dioxane
24
d
e
p-BQ
p-BQf
p-BQg
p-BQ
Ag(OAc)
p-BQ
Na CO
96
2
3
3
3
e
Na CO
48
2
e
Na CO
24
2
-
-
48
74
e
120
24
Ag CO
56
73
2
3
0
p-BQ
p-TsOH
24
a1 equiv. Yield of isolated pure compound. Cu(OAc) (5
mol %) was used as co-oxidant. Decomposition.
Unreacted 1a (95-100%) was recovered. Pd(OAc) (5
mol %) was used. Pd(OAc) (10 mol %) was used. The
b
c
2
d
e
f
2
g
h
2
reaction was performed at 70 ºC
First, 5-aryloxypent-2-enoate 1a was selected as a substrate to test the reaction (Table 1). For that
1
1
purpose we started from the conditions previously optimized for the obtention of quinolones (Table 1,
24
entry 1) or quinolines (Table 1, entry 2) using PdCl (CH CN) (5 mol %) as catalyst, in the presence
2
3
2
+
of p-TsOH and using t-butyl perbenzoate or N-fluoro-2,4,6-trimethylpyridinium triflate (F ) as oxidant.
However, only decomposition was observed in acetic acid or in mesitylene (entry 3) at room
temperature. Next, we tested the conditions previously reported for the cyclization of homoallyl ethers,22
in the presence of a base and using p-benzoquinone as the oxidant (entry 4), but no evolution of the
substrate was achieved. No reactivity was observed when Pd(OAc) was used as catalyst (entry 5), not
2
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even with higher catalyst loading and at 70ºC (entry 6). In fact, the base had a detrimental effect as 2a
was obtained in a good yield with complete regio- and diastereoselectivity with no base over 48 h (entry
7). The use of silver (I) as an oxidant was not efficient (entry 8), while in combination with p-
benzoquinone gave a moderate yield of 2a after 24 h (entry 9). Finally, the addition of p-TsOH
1
2
3
4
5
6
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
2
7
enhanced the reactivity, probably generating a more electrophilic Pd(II) species, and the reaction time
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
could be shortened to 24 h, with no loss of yield (entry 10 vs. 7).
Table 2. Synthesis of chromanes 2b-h
CO R3
PdCl (CH CN)
CO R3
2
2
OCH3
OCH3
2
3
2
R1
H CO
R1
H CO
(5 mol %)
BQ (1 equiv.)
p-TsOH (1 equiv.)
O
R2
O
R2
3
3
Dioxane, rt, 24 h
1b-h
2b-h
R1
R2
R3
1
2
Yield
a
(%)
1
2
3
4
5
6
7
8
9
1
1b
1c
H
H
H
H
H
H
H
H
H
CH3 CH3 2b
80
59
49
77
44
70
35
59
69
60
Ph
H
H
H
H
H
H
CH3 2c
1d
1db
1e
Et
Et
2d
2d
n-Bu 2e
n-Bu 2e
t-Bu 2f
t-Bu 2f
1eb
1f
1f b
1gb
1hb
CH3 t-Bu 2g
0
OCH3
CH3 CH3 2h
a
b
Yield of isolated pure compound. PdCl (CH CN) (10 mol %) was used.
2
3
2
Once the reaction conditions had been selected, we extended the reaction into the synthesis of different
chromanes 2b-h (Table 2). Substitution at C-2 is tolerated (Table 2, entries 1, 9, 10) and, thus, flavan 2c
could also be accessed (Table 2, entry 2). Different substitution at the ester moiety is also allowed;
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however, the reactions did not proceed to full conversion in 24 h (Table 2, entries 3, 5, 7), so an increase
of the catalyst loading (10 mol %) was required to obtain good yields within the same reaction time
(Table 2, entries 4, 6, 8). Besides, the reaction could also extended to a 6,7,8-trimethoxy substituted
chromane, such as 2h (entry 10). All chromanes 2a-h were obtained with complete stereoselectivity, as
E diastereomers, and as single regioisomers.
1
2
3
4
5
6
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
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4
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4
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4
4
4
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5
5
5
5
5
5
5
6
0
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3
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9
0
1
2
3
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7
8
9
0
1
2
3
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0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Two related reaction mechanisms could be proposed for this cyclization (Scheme 2). On one hand, C-H
electrophilic palladation of the aromatic ring with a cationic palladium species (favored by the addition
of p-TSOH) could occur to obtain an aryl palladium (II) intermediate I, which would undergo a syn
olefin insertion to afford II. Subsequent syn -hydride elimination is possible to give the observed E
stereochemistry for the alkene in 2. This mechanism has been proposed for related alkenylations of
electron rich aromatic systems,5,11 so this reaction would be considered as an intramolecular Fujiwara-
2
8
Moritani reaction or dehydrogenative Heck reaction. On the other hand, a Pd(II) alkene activation
followed by anti nucleophilic attack of the arene to the Pd(II)  complex,22,29 would lead to a
3
3
diastereomeric intermediate such as IV. In this case, alignment of the C(sp )-Pd(II) and C(sp )-H bonds
required for the direct syn -hydride elimination on IV would give the Z-configured 2 (Z-2), which is
not detected in any case. An anti elimination would thus be required for the obtention of 2, with the
observed E-configuration, from IV. However, IV could undergo epimerization at the  carbon through
the formation of an oxo--allylpalladium(II) intermediate29b to form II, allowing the syn - elimination
to obtain 2 with the observed E-configuration. To check if this was possible, we carried out the
cyclization of (Z)-1a and, under the same reaction conditions, 2a was obtained in comparable yield with
complete diastereoselectivity (Scheme 3). Thus, the reaction is not stereospecific. This does not rule out
either mechanism, but shows that palladium enolate intermediate could epimerize, to give the more
stable E diastereomer after syn-elimination.
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CO R1
2
1
2
3
4
5
6
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
R
O
1
PdX2
arene palladation
alkene activation
CO R1
2
1
CO R
2
II
II
Pd X
2
Pd X
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
R
R
O
O
I
III
anti attack
1
syn insertion
XPdII CO R
1
II
2
R O C
2
Pd X
H
H
R
R
O
O
II
IV
syn elimination
syn elimination
1
1
CO R
R O2C
2
R
R
O
O
2
(Z-2, not observed)
Scheme 2. Possible pathways for palladation: arene palladation vs. alkene activation
H CO C
3
2
CO CH3
2
CH O
CH O
3
3
PdCl (CH CN)
2
2
3
(
5 mol %)
BQ (1 equiv.)
p-TsOH (1 equiv.)
Dioxane, rt, 24 h
H CO
3
O
H CO
3
O
(Z)-1a
2a (80%)
Scheme 3. Intramolecular C-H alkenylation of (Z)-1a
We next decided to expand the scope of the reaction to non substituted alkenes tethered to the aromatic
ring. Thus, a series of substituted homoallyl aryl ethers 3a-w were selected in order to access highly and
diversely substituted 2H-chromenes 4a-w (Table 3). First, the cyclization of unsubstituted homoallyl
aryl ether 3a was tested. In this case, the reaction was much faster, and it was completed in 2 h at rt,
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The Journal of Organic Chemistry
1
obtaining 2H-chromene 4a, as expected, with a good isolated yield (74%) (Table 3). However, the H
1
2
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4
5
6
7
8
9
1
1
1
1
1
1
1
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1
1
2
2
2
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2
2
2
2
2
2
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3
4
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4
4
4
4
4
4
5
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5
5
6
1
3
and C NMR spectra showed the presence of a minor amount of the regioisomeric methylenechromane,
1
with an exocyclic double bond. A 93:7 endo/exo ratio was established by H NMR. This was confirmed,
as hydrogenation of the regioisomeric mixture gave 4-methylchromane 5a in high yield a single product
(Scheme 4). 2-Substitued chromenes, including flavenes 4d or 4e or a heteroaryl analog 4f, were
0
1
2
3
4
5
6
7
8
9
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8
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0
efficiently obtained under these reaction conditions (Table 3), in high isolated yields. The reaction could
also be extended to different substitution patterns on the aromatic ring, obtaining 5,6,7-trimethoxy
substituted chromenes 4g-4p, although an increase of the catalyst loading was required to maintain the
reactivity. Thus, a series of both alkyl and aryl substituted 2H-chromenes were easily accessed.
Table 3. Synthesis of chromenes 4a-w
CH3
PdCl (CH CN)
2
3
2
R3
R2
R3
O
(5 mol %)
BQ (1 equiv.)
p-TsOH (1 equiv.)
R2
R1
R1
O
Dioxane, rt, time
3a-w
4a-w
CH3O
CH3
O
CH3O
CH3
CH3O
CH3
O
CH3O
CH3
O
CH3O
CH3
O
CH3O
CH3O
O
CH3 CH3O
CH3 CH3O
Ph CH3O
4
b, 83% (83:17)a (2 h)
4c, 85% (93:7)a (2 h)
4d, 83% (9:1)a (2 h)
4e, 87% (9:1)a (2 h) OBn
CH3O
CH3
CH3O
CH3O
CH3
CH3O
CH3O
CH3
CH3O
CH3
R
CH3O
CH3O
CH3O
O
CH3O
O
O
CH3O
O
CH3
O
CH3
4
f, 86% (85:15)a (2 h) 4g, 61% (94:6)a (6 h)b
4h, 88% (92:8)a (2 h)b
4i, R = H, 86% (96:4)a (2.5 h)
j, R = CH3, 79% (94:6) (2.5 h)b
b
a
4
CH3O
CH3O
CH3
O
CH3O
CH3O
CH3
CH3O
CH3O
CH3
O
CH3
CH3O
CH3O
CH3O
CH3O
O
CH3O
O
CH3
R
O
b
4q, 61% (1 h)b,c
4
4
4
k, R = H 79% (94:6)a (2 h)b
4o, 81% (89:11)a) (2.5 h)b
4p, 72% (9:1)a (3 h)
l, R = 4-CH3 87% (9:1)a (3 h)
b
a
b
m, R = 4-CF3 91% (92:8) (5.5 h)
a
b
4n, R = 3-OBn 84% (93:7) (2.5 h)
X
CH3
CH3
O
CH3O
CH3
CH3O
CH3
O
CH3O
CH3
O
CH3O
CH3O
CH3
Ph
O
O
O
Ph
CH3
CH3O
O
CH3O
4u, 87% (2.5 h)
CH3O
r, 55% (3 h)b,c
4s, 60% (2.5 h)b,c
4t, 83% (1 h)
4v, X = F, 79% (4 h)
w, X = Cl, 73% (5.5 h)
4
4
a
1
Yield of isolated compound. Endo/exo regioisomer ratio determined by H
b
c
NMR. PdCl (CH CN) (10 mol %) was used. Performed at 70 ºC.
2
3
2
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3
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5
6
This type of alkenylation reaction requires an activated electron rich aromatic ring. We have previously
shown that non substituted or alkyl substituted aromatic rings gave only low yields of the cyclized
compounds on related reactions.11,24 However, the reaction works efficiently with different oxygenated
substitution patterns on the aromatic ring. The 6,7-disubstituted chromenes 4q-s were obtained as single
regioisomers by this procedure. This is interesting, as previous reports showed that, under related
conditions, catalyst loadings up to 20 and 25 % mol were required to obtain comparable yields with this
type of substitution on the aromatic ring.22 When a substituent is present on the position 3 of the
0
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0
3
homoallyl ether (3t-w, R = Me, aryl), the reaction completed in just 1 to 5 hours with 5 mol % of
catalyst. The endocyclic double bond is favored by this substitution pattern, and 3-substituted 2H-
chromenes, including isoflavenes 4u-w were obtained in high yield with complete regioselectivity. The
structure of the 2H-chromenes was unambiguously confirmed by single-crystal X-ray analysis of 4v
3
0
(See Supporting information). Finally, we tested this intramolecular alkenylation on an aryl butenoate,
such as 6, to check the applicability of this procedure for the synthesis of coumarins. Thus, coumarin 7
was obtained, although heating to 70 ºC was required to obtain full conversion in a reasonable reaction
time (Scheme 5).
CH O
CH3
CH3O
CH3
3
H2 (1 atm)
Pd/C
MeOH, rt, 16 h
CH O
O
CH3O
O
3
4a (endo:exo 93:7)
5 (89%)
Scheme 4. Hydrogenation of 4a.
CH O
CH3O
3
PdCl (CH CN)
2
2
3
(10 mol %)
BQ (1 equiv.)
p-TsOH (1 equiv.)
CH O
O
O
CH3O
O
O
3
Dioxane, 70 ºC, 5 h
6
7 (70%)
Scheme 5. Synthesis of coumarin 7
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In conclusion, an improved and mild protocol for Pd(II)-catalyzed C-H alkenylation of aryl homoallyl
ethers has been developed. The use of p-TsOH as additive accelerates the reaction, probably generating
more electrophilic Pd(II) species, and gives the procedure a significant improvement in substrate scope
and reaction conditions. Thus, in most cases, the reactions could be run at room temperature using
catalyst loadings of 5-10 mol % depending on the aromatic substitution pattern. This procedure would
be complementary to the related Mizoroki-Heck reaction that led to the formation of 4-methylidene
chromanes, with exocyclic double bonds,31 with the advantage that it does not require the prior
functionalization of the substrates. An additional feature of the process is the easy preparation of the
substrates, the polysubstituted aryl homoallyl ethers 3, which in most cases can be prepared in one step
by a Mitsunobu reaction between readily available alcohols and phenols. A cross-metathesis is required
to prepare the pent-2-enoates 1 (See Experimental Section). The procedure is very versatile, since it
allows the synthesis of alkylidenechromanes 2 and 2H-chromenes 4 with different types of substituents
(alkyl, electron-rich and electron-deficient aryl, heteroaryl) at C-2 or C-3 of the chromene moiety, thus
accessing relevant flavenes and isoflavenes, and even coumarins. Therefore, this procedure would be an
1
2
3
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5
6
7
8
9
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3
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5
6
0
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
efficient alternative to previously reported catalytic approaches, which usually give access either to 2-
3
2
33,34
substituted or to 3-substituted chromene derivatives.
Experimental Section
General experimental methods. Melting points were determined in unsealed capillary tubes and are
uncorrected. IR spectra were obtained using an ATR. NMR spectra were recorded at 20-25 ˚C, at 300
1
13
1
13
MHz for H and 75.5 MHz for C or at 500 MHz for H and 125.7 MHz for C in CDCl solutions.
3
Assignments of individual 13C and H resonances are supported by DEPT experiments and 2D
1
correlation experiments (COSY, HSQCed or HMBC). Mass spectra were recorded under electron
+
impact (EI) at 70 eV or with an ESI source. Exact mass was obtained using a TOF detector. TLC was
carried out with 0.2 mm thick silica gel plates. Visualization was accomplished by UV light. Flash
column chromatography was performed on silica gel (230-400 mesh). All solvents used in reactions
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were anhydrous and purified according to standard procedures. All air- or moisture-sensitive reactions
were performed under argon; the glassware was dried (130 ˚C) and purged with argon. Palladium
catalysts were commercially available, and were used without further purification: PdCl (CH CN) ,
1
2
3
4
5
6
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
2
3
2
9
9% purity; Pd(OAc) 98% purity.
2
Synthesis aryl homoallyl ethers 3a-w. General Procedure. Over a solution of the corresponding
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
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2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
homoallylic alcohol (1 mmol) in THF (3.3 mL) the corresponding phenol (3 mmol), PPh (1.3 mmol)
3
and DEAD (40 % wt solution in toluene) (1.3 mmol) were added under argon atmosphere. The resulting
solution was heated at reflux for 3-16 h. The reaction mixture was allowed to cool down to room
temperature and it was concentrated in vacuo. Purification by flash column chromatography (silica gel,
petroleum ether/AcOEt 9/1 or 8/2) afforded the corresponding aryl alkenyl ethers 3a-w.
1
-(But-3-en-1-yloxy)-3,5-dimethoxybenzene (3a).22 Prepared from 3-buten-1-ol (0.17 mL, 2.0
mmol), 3,5-dimethoxyphenol (0.92 g, 6.0 mmol), PPh (0.68 g, 2.6 mmol) and DEAD (1.1 g, 2.6 mmol)
3
in THF (6.6 mL). The reaction mixture was heated at reflux for 4 h. After purification by flash column
chromatography (silica gel, petroleum ether/AcOEt 9/1), 3a was obtained as an oil (0.35 g, 83 %): IR
-1 1
(
ATR) 2937, 3078 cm ; H NMR (300 MHz, CDCl ):  2.53 (q, J = 6.7 Hz, 2H), 3.77 (s, 6H), 3.98 (t, J
3
1
3
= 6.7 Hz, 2H), 5.07-5.22 (m, 2H), 5.90 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 6.09 (s, 3H); C NMR (75.5
MHz, CDCl ):  33.6, 55.3, 67.2, 93.0, 93.4, 117.0, 134.4, 160.8, 161.5; MS (EI) m/z (rel intensity):
3
+
+
2
08.1 (M , 28), 154.1 (100), 126.1 (62). HRMS (ESI-TOF) calcd. for C H O [MH ], 209.1178;
12 17 3
found, 209.1169.
1
,3-Dimethoxy-5-(pent-4-en-2-yloxy)benzene (3b).23 Prepared from 4-penten-2-ol (0.14 mL, 1.4
mmol), 3,5-dimethoxyphenol (0.64 g, 4.1 mmol), PPh (0.47 g, 1.8 mmol) and DEAD (0.78 g, 1.8
3
mmol) in THF (4.6 mL). The reaction mixture was heated at reflux for 3 h. After purification by flash
column chromatography (silica gel, petroleum ether/AcOEt 9/1), 3b was obtained as an oil (0.22 g, 73
-1 1
%
): IR (ATR) 2841, 2934, 2970, 3002, 3077 cm ; H NMR (300 MHz, CDCl ): δ 1.32 (d, J = 6.1 Hz,
3
3
7
H), 2.26-2.59 (m, 2H), 3.77 (s, 6H), 4.16-4.34 (m, 1H), 5.02-5.21 (m, 2H), 5.86 (ddt, J = 17.2, 10.2,
1
3
.0 Hz, 1H), 6.06-6.14 (m, 3H); C NMR (75.5 MHz, CDCl ): δ 19.4, 40.5, 55.3, 73.2, 92.9, 94.7,
3
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+
1
17.5, 134.2, 159.8, 161.5; MS (EI) m/z (rel intensity): 222.1 (M , 12), 181.1 (15), 154.1 (100), 153.1
1
2
3
4
5
6
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
+
(
18), 125.1 (65); HRMS (ESI-TOF): calcd. for C H O [MH ], 223.1334, found, 223.1335.
1
3
19
3
1-(Hept-1-en-4-yloxy)-3,5-dimethoxybenzene (3c). Prepared from 1-hepten-4-ol (0.10 mg, 0.90
mmol), 3,5-dimethoxyphenol (0.42 g, 2.7 mmol), PPh (0.30 g, 1.2 mmol) and DEAD (0.51 g, 1.2
3
mmol) in THF (3.0 mL). The reaction mixture was heated at reflux for 16 h. After purification by flash
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
column chromatography (silica gel, petroleum ether/AcOEt 9/1), 3c was obtained as an oil (0.14 g, 63
-1 1
%
): IR (ATR) 2841, 2934, 2959, 3006, 3081 cm ; H NMR (300 MHz, CDCl ): δ 0.95 (t, J = 7.3 Hz,
3
3
H), 1.30-1.76 (m, 4H), 2.35-2,52 (m, 2H), 3.77 (s, 6H), 4.18-4.33 (m, 1H), 5.04-5.19 (m, 2H), 5.87
1
3
(
ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 6.07-6.12 (m, 3H); C NMR (75.5 MHz, CDCl ): δ 14.1, 18.7, 35.9,
3
+
38.2, 55.3, 77.0, 92.8, 94.7, 117.4, 134.2, 160.3, 161.5; MS (ESI) m/z (rel intensity): 251.2 (MH , 100),
+
1
55.1 (30); HRMS (ESI-TOF): calcd. for C H O [MH ], 251.1647; found, 251.1650.
1
5
23
3
1
,3-Dimethoxy-5-((1-phenylbut-3-en-1-yl)oxy)benzene (3d)22 Prepared from 4-phenyl-1-buten-4-ol
(0.25 mg, 1.7 mmol), 3,5-dimethoxyphenol (0.79 g, 5.1 mmol), PPh (0.58 g, 2.2 mmol) and DEAD
3
(
0.96 g, 2.2 mmol) in THF (5.7 mL). The reaction mixture was heated at reflux for 16 h. After
purification by flash column chromatography (silica gel, petroleum ether/AcOEt 9/1), 3d was obtained
-1 1
as an oil (0.23 g, 47 %): IR (ATR) 2837, 2898, 2937, 2991, 3002, 3066 cm ; H NMR (300 MHz,
CDCl ): δ 2.52-2.87 (m, 2H), 3.71 (s, 6H), 5.04-5.21 (m, 3H), 5.88 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H),
3
1
3
6
5
.05 (t, J = 2.0, 1H), 6.08 (d, J = 2.0 Hz, 2H), 7.23-7.42 (m, 5H); C NMR (75.5 MHz, CDCl ): δ 42.8,
3
5.2, 79.9, 93.1, 94.9, 117.6, 126.0, 127.6, 128.6, 134.1, 141.4, 160.0, 161.3; MS (EI) m/z (rel
+
intensity): 284.2 (M , 6), 155.1 (10), 154.0 (100), 131.1 (42), 129.1 (32), 125.1 (30), 115.1 (23), 91.1
+
(
38); HRMS (ESI-TOF): calcd. for C H O [MH ], 285.1491; found, 285.1495.
1
8
21
3
5
-((1-(3-(Benzyloxy)phenyl)but-3-en-1-yl)oxy)-1,3-dimethoxybenzene (3e). Prepared from 1-(3-
(benzyloxy)phenyl)but-3-en-1-ol (0.17 g, 0.68 mmol), 3,5-dimethoxyphenol (0.31 g, 2.0 mmol), PPh3
0.23 g, 0.88 mmol) and DEAD (0.39 g, 0.88 mmol) in THF (2.3 mL). The reaction mixture was heated
at reflux for 16 h. After purification by flash column chromatography (silica gel, petroleum ether/AcOEt
(
-1 1
8
/2), 3e was obtained as an oil (0.13 g, 50 %): IR (ATR) 2841, 2901, 2934, 3009, 3031, 3074 cm ; H
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NMR (300 MHz, CDCl ): δ 2.70 (m, 2H), 3.73 (s, 6H), 5.02-5.25 (m, 5H), 5.90 (ddt, J = 17.1, 10.2, 6.8
3
1
2
3
4
5
6
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
1
3
Hz, 1H,), 6.07-6.10 (m, 1H), 6.12 (d, J = 2.1 Hz, 2H), 6.82-7.08 (m, 3H), 7.20-7.51 (m, 6H); C NMR
(75.5 MHz, CDCl ): δ 42.8, 55.3, 70.0, 79.8, 93.2, 94.9, 112.6, 113.9, 117.6, 118.7, 127.6, 128.0, 128.6,
3
+
1
29.7, 134.1, 137.0, 143.2, 159.1, 160.0, 161.4; MS (ESI) m/z (rel intensity): 391.2 (MH , 76), 156.1
+
(
5), 155.1 (100); HRMS (ESI-TOF): calcd. for C H O [MH ], 391.1909; found, 391.1907.
2
5
27
4
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
-(1-(3,5-Dimethoxyphenoxy)but-3-en-1-yl)furan (3f). Prepared from 1-(furan-3-yl)but-3-en-1-ol35
(
0.21 g, 1.5 mmol), 3,5-dimethoxyphenol (0.70 g, 4.5 mmol), PPh (0.51 g, 2.0 mmol) and DEAD (0.85
3
g, 2.0 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h. After purification by
flash column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3f was obtained as an oil (0.12 g,
-1 1
29 %): IR (ATR) 2841, 2901, 2941, 2999, 3074 cm ; H NMR (300 MHz, CDCl ): δ 2.52-2.83 (m,
3
2
H,), 3.77 (s, 6H), 5.04-5.23 (m, 3H), 5.85 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 6.06-6.10 (m, 1H), 6.12 (d,
1
3
J = 1.9 Hz, 2H), 6.41 (s, 1H), 7.38 (s, 1H ), 7.40 (s, 1H); C NMR (75.5 MHz, CDCl ): δ 40.9, 55.3,
´
3
72.9, 93.3, 94.9, 108.9, 117.8, 125.6, 133.7, 139.7, 143.3, 159.9, 161.4; MS (ESI) m/z (rel intensity):
+
+
2
75.1 (MH , 100), 233.1 (9), 155.1 (31); HRMS (ESI-TOF): calcd. for C H O [MH ], 275.1283;
16 19 4
found, 275.1289.
2
2
5
-(But-3-en-yloxy)-1,2,3-trimethoxybenzene (3g). Prepared from 3-buten-1-ol (0.22 mL, 2.5 mmol),
,4,5-trimethoxyphenol (1.4 g, 7.6 mmol), PPh (0.86 g, 3.3 mmol) and DEAD (1.4 g, 3.3 mmol) in
3
3
THF (8.4 mL). The reaction mixture was heated at reflux for 5.5 h. After purification by flash column
chromatography (silica gel, petroleum ether/AcOEt 8/2), 3g was obtained as an oil (0.47 g, 78 %): IR
-1 1
(ATR) 2833, 2934, 2995, 3077 cm ; H NMR (300 MHz, CDCl ): δ 2.49 (q, J = 6.7 Hz, 2H), 3.75 (s,
3
3
6
H), 3.79 (s, 6H), 3.94 (t, J = 6.7 Hz, 2H), 5.02-5.21 (m, 2H), 5.87 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H),
1
3
.12 (s, 2H); C NMR (75.5 MHz, CDCl ): δ 33.7, 56.0, 60.9, 67.5, 92.3, 117.0, 132.3, 134.4, 153.7,
3
+
155.5; MS (EI) m/z (rel intensity): 238.1 (M , 91), 223.1 (22), 184.0 (32), 169.00 (89), 153.1 (10), 141.0
+
(
36), 55.1 (100); HRMS (ESI-TOF): calcd. for C H O [MH ], 239.1283, found, 239.1292.
1
3
19
4
1
,2,3-Trimethoxy-5-(pent-4-en-2-yloxy)benzene (3h). Prepared from 4-penten-2-ol (0.12 mL, 1.2
mmol), 3,4,5-trimethoxyphenol (0.66 g, 3.6 mmol), PPh (0.41 g, 1.6 mmol) and DEAD (0.68 g, 1.6
3
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mmol) in THF (4.0 mL). The reaction mixture was heated at reflux for 6 h. After purification by flash
1
2
3
4
5
6
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
column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3h was obtained as an oil (0.24 g, 78
-1 1
%): IR (ATR) 2844, 2977, 3077 cm ; H NMR (300 MHz, CDCl ): δ 1.29 (d, J = 6.1 Hz, 3H), 2.26-
3
2
7
1
.55 (m, 2H), 3.77 (s, 3H), 3.81 (s, 6H), 4.27-4.39 (m, 1H), 5.05-5.18 (m, 2H), 5.85 (ddt, J = 17.2, 10.2,
1
3
.0 Hz, 1H), 6.14 (s, 2H); C NMR (75.5 MHz, CDCl ): δ 19.5, 40.6, 56.0, 60.7, 73.9, 93.9, 117.5,
3
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
+
32.4, 134.2, 153.7, 154.4; MS (EI) m/z (rel intensity): 252.1 (M , 36), 184.1 (43), 169.0 (100), , 141.0
+
(
27); HRMS (ESI-TOF): calcd. for C H O [MH ], 253.1440; found, 253.1449.
1
4
21
4
5
-(Hept-1-en-4-yloxy)-1,2,3-trimethoxybenzene (3i). Prepared from 1-hepten-4-ol (0.10 mg, 0.90
mmol), 3,4,5-trimethoxyphenol (0.49 g, 2.7 mmol), PPh (0.30 g, 1.2 mmol) and DEAD (0.51 g, 1.2
3
mmol) in THF (3.0 mL). The reaction mixture was heated at reflux for 16 h. After purification by flash
column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3i was obtained as an oil (0.16 g, 63
-1 1
%
): IR (ATR) 2841, 2872, 2937, 2962, 3074 cm ; H NMR (300 MHz, CDCl ): δ 0.93 (t, J = 7.2 Hz,
3
3H), 1.30-1.76 (m, 4H), 2.28-2.50 (m, 2H), 3.77 (s, 3H), 3.81 (s, 6H), 4.13-4.28 (m, 1H), 5.02-5.19 (m,
13
2
3
2
H), 5.85 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 6.14 (s, 2H); C NMR (75.5 MHz, CDCl ): δ 14.1, 18.7,
3
6.0, 38.3, 56.0, 61.0, 77.7, 93.9, 117.4, 132.3, 134.2, 153.7, 154.9; MS (EI) m/z (rel intensity): 281.2,
+
80.2 (M , 28), 184.0 (62), 169.0 (100), 141.0 (18), 69.0 (15); HRMS (ESI-TOF): calcd. for C H O
16 25
4
+
[
MH ], 281.1753; found, 281.1753.
1
,2,3-Trimethoxy-5-((6-methylhept-1-en-4-yl)oxy)benzene (3j). Prepared from 6-methylhept-1-en-4-
3
6
ol (0.12 mg, 0.95 mmol), 3,4,5-trimethoxyphenol (0.52 g, 2.9 mmol), PPh (0.32 g, 1.2 mmol) and
3
DEAD (0.54 g, 1.2 mmol) in THF (3.2 mL). The reaction mixture was heated at reflux for 16 h. After
purification by flash column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3j was obtained
-1 1
as an oil (0.10 g, 36 %): IR (ATR) 2833, 2872, 2934, 2959, 3070 cm ; H NMR (300 MHz, CDCl ): δ
3
0.91 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.30-1.49 (m, 1H), 1.55-1.90 (m, 2H), 2.39 (t, J = 6.1
Hz, 2H), 3.78 (s, 3H), 3.82 (s, 6H), 4.15-4.32 (m, 1H), 5.04-5.18 (m, 2H), 5.85 (ddt, J = 17.4, 10.4, 7.1
1
3
Hz, 1H), 6.14 (s, 2H); C NMR (75.5 MHz, CDCl ): δ 22.5, 23.1, 24.6, 38.6, 43.1, 56.0, 61.0, 76.0,
3
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+
9
1
3.7, 117.5, 132.2 (C ), 134.1, 153.7, 154.8; MS (EI) m/z (rel intensity): 294.2 (M , 23), 184.1 (64),
4
1
2
3
4
5
6
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
+
69.0 (100); HRMS (ESI-TOF): calcd. for C H O [MH ], 295.1909; found, 295.1910.
1
7
27
4
1,2,3-Trimethoxy-5-((1-phenylbut-3-en-1-yl)oxy)benzene (3k). Prepared from 4-phenyl-1-buten-4-ol
0.39 g, 2.6 mmol), 3,4,5-trimethoxyphenol (1.4 g, 7.9 mmol), PPh (0.89 g, 3.4 mmol) and DEAD (1.5
(
3
g, 3.4 mmol) in THF (8.7 mL). The reaction mixture was heated at reflux for 16 h. After purification by
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
flash column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3k was obtained as an oil (0.37 g,
-1 1
4
1 %): IR (ATR): 2841, 2901, 2937, 2959, 2987, 3070 cm ; H NMR (300 MHz, CDCl ): δ 2.50-2.88
3
(m, 2H), 3.72 (s, 6H), 3.74 (s, 3H), 5.02-5.21 (m, 3H), 5.76-5.96 (m, 1H), 6.11 (s, 2H), 7.20-7.44 (m,
1
3
5
H); C NMR (75.5 MHz, CDCl ): δ 42.8, 55.9, 60.9, 80.5, 93.9, 117.6, 126.0, 127.7, 128.6, 132.2,
3
+
134.5, 141.5, 153.5, 154.7; MS (EI) m/z (rel intensity): 314.1 (M , 13), 184.1 (100), 169.0 (85), 131.1
+
(
33), 129.1 (35), 115.0 (27), 91.1 (38); HRMS (ESI-TOF): calcd. for C H O [MH ], 315.1596; found,
1
9
23
4
3
15.1602.
1,2,3-Trimethoxy-5-((1-(p-tolyl)but-3-en-1-yl)oxy)benzene (3l). Prepared from 1-(4-methylphenyl)-3-
buten-1-ol (0.29 g, 1.8 mmol), 3,4,5-trimethoxyphenol (1.0 g, 5.4 mmol), PPh (0.62 g, 2.3 mmol) and
3
DEAD (1.0 g, 2.3 mmol) in THF (6.0 mL). The reaction mixture was stirred at reflux for 16 h. After
purification by flash column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3l was obtained
sp3
-1 1
as an oil (0.23 g, 42 %): IR (ATR) 2837, 2937 ( C-H), 3002, 3077 cm ; H NMR (300 MHz, CDCl ):
3
δ 2.33 (s, 3H), 2.51-2.83 (m, 2H), 3.73 (s, 9H), 5.01-5.17 (m, 3H), 5.86 (ddt, J = 24.1, 10.6, 6.9 Hz, 1H),
1
3
6
.11 (s, 2H), 7.15 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H); C NMR (75.5 MHz, CDCl ): δ 21.1,
3
42.8, 55.9, 60.9, 80.3, 93.8, 117.5, 126.0, 129.3, 132.2, 134.2, 137.4, 138.5, 153.4, 154.7; MS (ESI) m/z
+
+
(
rel intensity): 329.2 (MH , 18), 186.1 (7), 185.1 (100). HRMS (ESI-TOF): calcd. for C H O [MH ],
20 25 4
3
29.1753; found, 329.1759.
1,2,3-Trimethoxy-5-((1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)oxy)benzene (3m). Prepared from
-(4-(trifluoromethyl)phenyl)but-3-en-1-ol37 (0.40 g, 1.9 mmol), 3,4,5-trimethoxyphenol (1.0 g, 5.6
1
mmol), PPh (0.64 g, 2.4 mmol) and DEAD (1.1 g, 2.4 mmol) in THF (6.2 mL). The reaction mixture
3
was stirred at reflux for 16 h. After purification by flash column chromatography (silica gel, petroleum
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-1
1
ether/AcOEt 8/2), 3m was obtained as an oil (0.49 g, 68 %): IR (ATR) 2833, 2941, 3002, 3077 cm ; H
1
2
3
4
5
6
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
NMR (300 MHz, CDCl ): δ 2.50-2.85 (m, 2H), 3.73 (s, 6H), 3.74 (s, 3H), 5.04-5.18 (m, 3H), 5.83 (ddt,
3
1
3
J = 16.7, 9.7, 7.0 Hz, 1H), 6.07 (s, 3H), 7.48 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H); C NMR
(
75.5 MHz, CDCl ): δ 42.5, 56.0, 60.9, 79.7, 93.8, 118.2, 124.3 (q, J = 271.3 Hz), 125.6 (q, J = 3.7 Hz),
3
1
26.4, 130.4 (q, J = 32.5 Hz), 132.6 133.3, 145.5, 153.6, 154.2; MS (ESI) m/z (rel intensity): 383.1
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
+
+
(
MH , 100), 185.1 (21). HRMS (ESI-TOF): calcd. for C H F O [MH ], 383.1470; found: 383.1479.
20 22 3 4
5
-((1-(3-(Benzyloxy)phenyl)but-3-en-1-yl)oxy)-1,2,3-trimethoxybenzene (3n). Prepared from 1-(3-
(
benzyloxy)phenyl)but-3-en-1-ol (0.21 g, 0.83 mmol), 3,4,5-dimethoxyphenol (0.46 g, 2.5 mmol), PPh3
0.28 g, 1.1 mmol) and DEAD (0.47 g, 1.1 mmol) in THF (2.8 mL). The reaction mixture was heated at
(
reflux for 16 h. After purification by flash column chromatography (silica gel, petroleum ether/AcOEt
-1
1
8
/2), 3n was obtained as an oil (0.16 g, 45 %): IR (ATR): 2841, 2934, 2970, 3002, 3077 cm ; H NMR
(
300 MHz, CDCl ): δ 2.50-2.85 (m, 2H), 3.73 (s, 6H), 3.77 (s, 3H), 5.00-5.23 (m, 5H), 5.88 (ddt, J =
3
1
3
17.2, 10.3, 6.9 Hz, 1H), 6.12 (s, 2H), 6.82-7.08 (m, 3H), 7.20-7.51 (m, 6H); C NMR (75.5 MHz,
CDCl ): δ 42.7, 55.9, 61.0, 70.0, 80.4, 93.8, 112.6, 114.0, 117.6, 118.7, 127.9, 128.0, 128.6, 129.7,
3
+
1
1
2
32.3, 134.1, 136.9, 143.3, 153.9, 154.7, 159.1; MS (EI) m/z (rel intensity): 420.2 (M , 2), 184.1 (49),
+
69.0 (26), 91.1 (100); HRMS (ESI-TOF): calcd. for C H O [MH ], 421.2015; found, 421.2014.
26 29
5
-(1-(3,4,5-Trimethoxyphenoxy)but-3-en-1-yl)naphthalene (3o). Prepared from 1-(naphthalen-2-
3
8
yl)but-3-en-1-ol (0.21 g, 1.1 mmol), 3,4,5-trimethoxyphenol (0.60 g, 3.2 mmol), PPh (0.37 g, 1.4
3
mmol) and DEAD (0.61 g, 1.4 mmol) in THF (3.6 mL). The reaction mixture was heated at reflux for
16 h. After purification by flash column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3o
-1
1
was obtained as an oil (0.12 g, 31 %): IR (ATR) 2851, 2930, 2959, 2999, 3060, 3077 cm ; H NMR
300 MHz, CDCl ): δ 2.62-2.95 (m, 2H), 3.73 (s, 6H), 3.75 (s, 3H), 5.04-5.37 (m, 3H), 5.92 (ddt, J =
(
3
1
3
17.1, 10.2, 6.9 Hz, 1H), 6.19 (s, 2H), 7.43-7.60 (m, 3H), 7.79-7.90 (m, 4H); C NMR (75.5 MHz,
CDCl ): δ 42.7, 56.0, 60.9, 80.7, 94.0, 117.8, 123.9, 125.1, 126.0, 126.3, 127.8, 127.9, 128.6, 132.4,
3
+
1
33.1, 133.3, 134.0, 139.0, 153.5, 154.7; MS (ESI) m/z (rel intensity): 365.2 (MH , 15), 185.1 (100).
+
HRMS (ESI-TOF): calcd. for C H O [MH ], 365.1753; found: 365.1754.
23 25
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3
-(1-(3,4,5-Trimethoxyphenoxy)but-3-en-1-yl)furan (3p). Prepared from 1-(furan-3-yl)but-3-en-1-
1
2
3
4
5
6
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
3
5
ol (0.38 g, 2.7 mmol), 3,4,5-trimethoxyphenol (1.5 g, 8.2 mmol), PPh (0.93 g, 3.6 mmol) and DEAD
3
(1.5 g, 3.6 mmol) in THF (9.1 mL). The reaction mixture was heated at reflux for 16 h. After
purification by flash column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3p was obtained
-1 1
as an oil (0.22 g, 27 %): IR (ATR) 2841, 2934, 2987, 3009, 3074 cm ; H NMR (300 MHz, CDCl ): δ
3
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
2
.50-2.83 (m, 2H), 3.76 (s, 3H), 3.77 (s, 6H), 5.04-5.21 (m, 3H), 5.73-5.95 (m, 1H), 6.15 (s, 2H), 6.41
1
3
(s, 1H), 7.38 (s, 2H); C NMR (75.5 MHz, CDCl ): δ 41.0, 56.0, 60.9, 73.5, 94.1, 108.7, 117.9, 125.8,
3
+
1
32.6, 133.7, 139.7, 143.4, 153.3, 154.5; MS (EI) m/z (rel intensity): 304.1 (M , 7), 263.1 (17), 184.1
+
(100), 169.0 (85), 91.1 (56); HRMS (ESI-TOF): calcd. for C H O [MH ], 305.1389; found: 305.1398.
17 21
5
1,2-Dimethoxy-4-(pent-4-en-2-yloxy)benzene (3q). Prepared from 4-penten-2-ol (0.28 mL, 3.3 mmol),
,4-dimethoxyphenol (1.5 g, 9.8 mmol), PPh (1.1 g, 4.2 mmol) and DEAD (1.8 g, 4.2 mmol) in THF
3
3
(10.9 mL). The reaction mixture was heated at reflux for 16 h. After purification by flash column
chromatography (silica gel, petroleum ether/AcOEt 8/2), 3q was obtained as an oil (0.49 g, 67 %): IR
-1
1
(ATR) 2833, 2908, 2930, 2977, 3002, 3070 cm ; H NMR (300 MHz, CDCl ): δ 1.26 (d, J = 6.1 Hz,
3
3
H), 2.21-2.55 (m, 2H,), 3.80 (s, 3H), 3.81 (s, 3H), 4.29 (h, J = 6.1 Hz, 1H), 5.00-5.18 (m, 2H), 5.84
(ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 6.39 (dd, J = 8.7, 2.5 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.74 (d, J =
1
3
8
1
.7, 1H); C NMR (75.5 MHz, CDCl ): δ 19.5, 40.6, 55.8, 56.4, 74.1, 102.5, 106.0, 111.9, 117.4, 134.3,
3
+
43.5, 149.9, 152.3; MS (EI) m/z (rel intensity): 222.1 (M , 41), 154.1 (100), 139.0 (88), 111.0 (23);
+
HRMS (ESI): calcd. for C H O [MH ], 223.1334; found: 223.1334.
13 19
3
1,2-Dimethoxy-4-((1-phenylbut-3-en-1-yl)oxy)benzene (3r). Prepared from 4-phenyl-1-buten-4-ol
0.64 mL, 4.3 mmol), 3,4-dimethoxyphenol (2.0 g, 13.0 mmol), PPh (1.5 g, 5.6 mmol) and DEAD (2.6
(
3
g, 5.6 mmol) in THF (14.4 mL). The reaction mixture was heated at reflux for 16 h. After purification
by flash column chromatography (silica gel, petroleum ether/AcOEt 8/2), 3r was obtained as an oil
-1
1
(0.38 g, 31 %): IR (ATR) 2830, 2937, 3006, 3031, 3077 cm ; H NMR (300 MHz, CDCl ): δ 2.52-2.90
3
(m, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 5.00-5.23 (m, 3H), 5.88 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 6.30 (dd, J
1
3
=
8.8, 2.8 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 6.65 (d, J = 8.8, 1H), 7.20-7.42 (m, 5H); C NMR (75.5
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MHz, CDCl ): δ 42.8, 55.7, 56.3, 80.6, 102.1, 106.1, 111.7, 117.9, 126.1, 127.6, 128.5, 134.3, 141.6,
3
1
2
3
4
5
6
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
+
1
43.5, 149.7, 152.6; MS (EI) m/z (rel intensity): 284.1 (M , 6), 154,1 (100), 139.0 (36), 131.1 (24),
+
129.1 (23), 91.1 (29); HRMS (ESI-TOF): calcd. for C H O Na [MNa ], 307.1310; found: 307.1315.
1
8
20
3
5
-(Pent-4-en-2-yloxy)benzo[d][1,3]dioxole (3s). Prepared from 4-penten-2-ol (0.17 mL, 2.0 mmol),
sesamol (0.83 g, 6.0 mmol), PPh (0.69 g, 2.6 mmol) and DEAD (1.1 g, 2.6 mmol) in THF (6.7 mL).
3
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 reaction mixture was heated at reflux for 8 h. After purification by flash column chromatography
(silica gel, petroleum ether/AcOEt 9/1), 3s was obtained as an oil (0.36 g, 86 %): IR (ATR) 2833, 2908,
-
1 1
2
4
930, 2977, 3002, 3070 cm ; H NMR (300 MHz, CDCl ): 1.28 (d, J = 6.1 Hz, 3H), 2.24-2.55 (m, 2H),
3
.26 (h, J = 6.1 Hz, 1H), 5.05-5.21 (m, 2H), 5.91 (s, 2H), 5.75-5.99 (m, 1H), 6.35 (dd, J = 8.4, 2.5 Hz,
1
3
1H), 6.51 (d, J = 2.5 Hz, 1H), 6.70 (d, J = 8.4, 1H); C NMR (75.5 MHz, CDCl ): δ 19.4, 40.6, 74.9,
3
+
9
1
9.8, 101.1, 108.0, 108.3, 117.4, 134.3, 141.8, 148.2, 153.3; MS (EI) m/z (rel intensity): 206.1 (M , 24),
+
38.0 (100), 137.0 (54); HRMS (ESI-TOF): calcd. for C H O [MH ], 207.1021; found, 207.1022.
1
2
15
3
1,3-Dimethoxy-5-((2-methylbut-3-en-1-yl)oxy)benzene (3t). Prepared from 2-methyl-3-buten-1-ol
0.23 mL, 2.6 mmol), 3,5-dimethoxyphenol (1.2 g, 7.9 mmol), PPh (0.90 g, 3.4 mmol) and DEAD (1.5
(
3
g, 3.4 mmol) in THF (8.8 mL). The reaction mixture was heated at reflux for 3.5 h. After purification by
flash column chromatography (silica gel, petroleum ether/AcOEt 9/1), 3t was obtained as an oil (0.47 g,
-1 1
7
9 %): IR (ATR) 2841, 2872, 2912, 2926, 2959, 2987, 3005 cm ; H NMR (300 MHz, CDCl ): δ 1.15
3
(d, J = 6.8 Hz, 3H), 2.59-2.80 (m, 1H), 3.77 (s, 6H), 3.69-3.94 (m, 2H), 5.04-5.25 (m, 2H), 5.88 (ddd, J
1
3
=
17.3, 10.4, 6.8 Hz, 1H), 6.10 (s, 3H); C NMR (75.5 MHz, CDCl ): δ 16.5, 37.3, 55.3, 72.4, 93.0,
3
+
93.5, 114.7, 140.4, 161.0, 161.5; MS (EI) m/z (rel intensity): 222.1 (M , 10), 154.0 (100), 126.1 (37),
+
1
25.1 (43); HRMS (ESI-TOF): calcd. for C H O [MH ], 223.1334; found: 223.1328.
1
3
19
3
2
2
39
1
,3-Dimethoxy-5-((2-phenylbut-3-en-1-yl)oxy)benzene (3u). Prepared from 2-phenylbut-3-en-1-ol
(0.35 g, 2.4 mmol), 3,5-dimethoxyphenol (1.1 g, 7.1 mmol), PPh (0.81 g, 3.1 mmol) and DEAD (1.3 g,
3
3
.1 mmol) in THF (7.9 mL). The reaction mixture was heated at reflux for 16 h. After purification by
flash column chromatography (silica gel, petroleum ether/AcOEt 9/1), 3u was obtained as an oil (0.20 g,
-1 1
3
0 %): IR (ATR) 2841, 2880, 2930, 2955, 3002, 3063, 3085 cm ; H NMR (300 MHz, CDCl ): δ 3.76
3
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(
s, 6H), 3.84 (q, J = 7.0 Hz, 1H), 4.11-4.23 (m, 2H), 5.11-5.28 (m, 2H), 6.01-6.21 (m, 4H), 7.20-7.42
1
2
3
4
5
6
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
1
3
(m. 5H); C NMR (75.5 MHz, CDCl ): δ 49.0, 55.3, 71.1, 93.0, 93.6, 116.5, 126.9, 128.1, 128.6, 138.3,
3
+
140.4 (C ), 160.7, 161.5; MS (ESI) m/z (rel intensity): 285.2 (MH , 100), 15.1 (6); HRMS (ESI-TOF):
1
´
+
calcd. for C H O [MH ], 285.1491; found: 285.1501.
1
8
21
3
1
-((2-(4-Fluorophenyl)but-3-en-1-yl)oxy)-3,5-dimethoxybenzene (3v). Prepared from 2-(4-
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
4
0
fluorophenyl)but-3-en-1-ol (0.34, 2.0 mmol), 3,5-dimethoxyphenol (0.95 g, 6.1 mmol), PPh (0.70 g,
3
2
5
.7 mmol) and DEAD (1.2 g, 2.7 mmol) in THF (6.8 mL). The reaction mixture was heated at reflux for
h. After purification by flash column chromatography (silica gel, petroleum ether/AcOEt 9/1), 3v was
-1 1
obtained as an oil (0.18 g, 30 %): IR (ATR) 2841, 2926, 2959, 3006, 3081 cm ; H NMR (300 MHz,
CDCl ): δ 3.77 (s, 6H), 3.84 (q, J = 6.9 Hz, 1H), 4.11-4.23 (m, 2H), 5.09-5.32 (m, 2H), 6.01-6.21 (m,
3
13
4
5
H), 7.05 (t, J = 8.7 Hz, 2H), 7.27 (dd, J = 8.7, 5.4 Hz, 2H ); C NMR (75.5 MHz, CDCl ): δ 48.2,
´
3
5.3, 71.0, 93.3, 93.6, 115.4 (d, J = 21.2 Hz), 116.7, 129.6 (d, J = 7.9 Hz), 136.4 (d, J = 3.2 Hz), 138.0,
+
160.6, 161.5, 161.8 (d, J = 247.4 Hz); MS (ESI) m/z (rel intensity): 303.1 (MH , 100), 155.1 (7). HRMS
+
(ESI-TOF): calcd. for C H O F [MH ], 303.1396; found: 303.1395.
1
8
20
3
1
-((2-(4-Chlorophenyl)but-3-en-1-yl)oxy)-3,5-dimethoxybenzene (3w). Prepared from 2-(4-
4
1
chlorophenyl)but-3-en-1-ol (0.32, 1.8 mmol), 3,5-dimethoxyphenol (0.81 g, 5.3 mmol), PPh (0.60 g,
3
2
.3 mmol) and DEAD (0.99 g, 2.3 mmol) in THF (5.8 mL). The reaction mixture was heated at reflux
for 5 h. After purification by flash column chromatography (silica gel, petroleum ether/AcOEt 9/1), 3w
-1
1
was obtained as an oil (0.13 g, 23 %): IR (ATR) 2841, 2876, 2934, 2955, 3006, 3085 cm ; H NMR
(300 MHz, CDCl ): δ 3.76 (s, 6H), 3.77-3.85 (m, 1H), 4.04-4.23 (m, 2H), 5.09-5.26 (m, 2H), 5.95-6.15
3
13
(m, 4H), 7.22 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H); C NMR (75.5 MHz, CDCl ): δ 48.3, 55.3,
3
7
0.8, 93.3, 93.6, 116.9, 128.7, 129.5, 132.6, 137.7, 139.3, 160.5, 161.5; MS (ESI) m/z (rel intensity):
+
+
+
321.1 (MH + 2, 28), 319.1 (MH , 100), 155.1 (4). HRMS (ESI-TOF): calcd. for C H O Cl [MH ],
1
8
20
3
3
19.1101; found: 319.1099.
Synthesis aryl aryloxypentenoates 1a-h. General Procedure. Over a solution of the corresponding
nd
aryl alkenyl ether 3 (1 mmol) and acrylate (20 mmol) in dry CH Cl (2 mL), 2 generation Grubbs
2
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catalyst (0.05 mmol) was added under argon atmosphere. The reaction mixture was stirred at room
temperature for 24 h, after which DMSO (2.5 mmol) was added. The resulting mixture was further
stirred for 20 h. The volatile compounds were evaporated in vacuo and the residue obtained was purified
by flash column chromatography (petroleum ether/AcOEt 8/2 or 9/1) to obtain the corresponding esters
1
2
3
4
5
6
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
1
a-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
Methyl (E)-5-(3,5-dimethoxyphenoxy)pent-2-enoate (1a). Prepared from 3a (0.27 g, 1.3 mmol),
nd
methyl acrylate (2.3 mL, 25.4 mmol) and 2 generation Grubbs catalyst (54.0 mg, 0.06 mmol) in dry
CH Cl (2.6 mL). After stirring the reaction mixture for 24 h, DMSO (0.23 mL, 3.2 mmol) was added
2
2
and the resulting solution was further stirred for 20 h. After evaporating the volatile compounds in
vacuo and purification by flash column chromatography (petroleum ether/AcOEt 9/1), 3a was obtained
-1
1
as a solid (0.29 g, 87 %): mp (CH Cl ) 47-49 ºC; IR (ATR) 1724 cm ; H NMR (500 MHz, CDCl ): δ
2
2
3
2
.64-2.70 (m, 2H), 3.74 (s, 3H), 3.76 (s, 6H), 4.03 (t, J = 5.8 Hz, 2H), 5.95 (d, J = 15.7 Hz, 1H,), 6.07
1
3
(s, 3H), 7.03 (dt, J = 15.7, 6.9 Hz, 1H,); C NMR (125.7 MHz, CDCl ): δ 32.0, 51.5, 55.3, 65.9, 93.2,
3
+
9
3.4, 123.0, 144.5, 160.4, 161.5, 166.; MS (EI) m/z (rel intensity): 266.1 (M , 38), 154.1 (96), 126.1
+
(
50), 113.1 (100); HRMS (ESI-TOF): calcd. for C H O [MH ], 267.1233; found: 267.1232.
1
4
19
5
Methyl (Z)-5-(3,5-dimethoxyphenoxy)pent-2-enoate [(Z)-1a]. Obtained as a side-product in the
-1
1
obtention of 1a (19 mg, 6 %): mp (CH Cl ) 62-64 ºC; IR (ATR) 1720 cm ; H NMR (500 MHz,
2
2
CDCl ): δ 3.07-3.19 (m, 2H), 3.72 (s, 3H), 3.76 (s, 6H), 4.04 (t, J = 5.8 Hz, 2H), 5.91 (d, J = 11.5 Hz,
3
1
3
1
H), 6.09 (s, 3H), 6.40 (dt, J = 11.5, 7.3 Hz, 1H); C NMR (125.7 MHz, CDCl ): δ 29.1, 51.1, 55.3,
3
+
66.8, 93.2, 93.4, 121.2, 146.1, 160.7, 161.5, 166.6; MS (EI) m/z (rel intensity): 266.2 (M , 24), 154.1
+
(
84), 113.1 (100), 81.1 (34); HRMS (ESI-TOF): calcd. for C H O [MH ], 267.1233; found: 267.1232.
1
4
19
5
Methyl (E)-5-(3,5-dimethoxyphenoxy)hex-2-enoate (1b). Prepared from 1 3b (1.9 g, 8.4 mmol),
nd
methyl acrylate (15.1 mL, 0.17 mol) and 2 generation Grubbs catalyst (0.36 g, 0.42 mmol) in dry
CH Cl (16.7 mL). After stirring the reaction mixture for 24 h, DMSO (1.5 mL, 20.9 mmol) was added
2
2
and the resulting solution was further stirred for 20 h. After evaporating the volatile compounds in
vacuo and purification by flash column chromatography (petroleum ether/AcOEt 8/2), 1b was obtained
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-1 1
as an oil (1.3 g, 55 %): IR (ATR) 1720 cm ; H NMR (300 MHz, CDCl ): δ 1.32 (d, J = 6.1 Hz, 3H),
3
1
2
3
4
5
6
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
2
.42-2.69 (m, 2H), 3.72 (s, 3H), 3.75 (s, 6H), 4.45 (h, J = 6.0 Hz , 1H), 5.91 (dt, J = 15.7, 1.4 Hz, 1H),
1
3
6.06 (s, 3H), 6.99 (dt, J = 15.7, 7.3 Hz, 1H); C NMR (75.5 MHz, CDCl ): δ 19.6, 38.8, 51.5, 55.3,
3
+
7
2.2, 93.2, 93.7, 123.5, 144.5, 159.3, 161.6, 166.7; MS (EI) m/z (rel intensity): 280.1 (M , 20), 207.1
(28), 181.1 (29), 154.0 (100), 127.1 (72), 125.1 (74), 95.1 (32); HRMS (ESI-TOF): calcd. for C H O
15 21 5
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
+
[MH ], 281.1389; found: 281.1399.
Methyl (E)-5-(3,5-dimethoxyphenoxy)-5-phenylpent-2-enoate (1c). Prepared from 3d (0.30 g, 1.1
nd
mmol), methyl acrylate (1.9 mL, 21.2 mol) and 2 generation Grubbs catalyst (45.0 mg, 0.053 mmol) in
dry CH Cl (2.1 mL). After stirring the reaction mixture for 24 h, DMSO (0.19 mL, 2.6 mmol) was
2
2
added and the resulting solution was further stirred for 20 h. After evaporating the volatile compounds
in vacuo and purification by flash column chromatography (petroleum ether/AcOEt 8/2), 1c was
-1 1
obtained as a solid (0.27 g, 75 %): mp (CH Cl ) 67-69 ºC; IR (ATR) 1713 cm ; H NMR (300 MHz,
2
2
CDCl ): δ 2.62-2.95 (m, 2H), 3.69 (s, 6H), 3.72 (s, 3H), 5.20 (dd, J = 7.6, 5.0 Hz, 1H), 5.90 (d, J = 15.7
3
13
Hz, 1H), 6.03 (s, 3H), 7.01 (dt, J = 15.7, 7.6 Hz, 1H), 7.20-7.39 (m, 5H); C NMR (75.5 MHz, CDCl ):
3
δ 41.1, 51.5, 55.5, 78.6, 93.3, 94.9, 123.6, 125.8, 127.9, 128.8, 140.6, 144.3, 159.6, 161.3, 166.6; MS
+
+
(ESI) m/z (rel intensity): 343.2 (MH , 60), 155.1 (100); HRMS (ESI-TOF): calcd. for C H O [MH ],
20 23 5
3
43.1546; found: 343.1557.
Ethyl (E)-5-(3,5-dimethoxyphenoxy)pent-2-enoate (1d). Prepared from 3a (0.30 g, 1.5 mmol), ethyl
nd
acrylate (3.2 mL, 29.1 mmol) and 2 generation Grubbs catalyst (61.7 mg, 0.07 mmol) in dry CH Cl
2
2
(2.9 mL). After stirring the reaction mixture for 24 h, DMSO (0.26 mL, 3.6 mmol) was added and the
resulting solution was further stirred for 20 h. After evaporating the volatile compounds in vacuo and
purification by flash column chromatography (petroleum ether/AcOEt 8/2), 1d was obtained as an oil
-1 1
(0.23 g, 57 %): IR (ATR) 1716 cm ; H NMR (300 MHz, CDCl ): δ 1.29 (t, J = 7.1 Hz, 3H), 2.64-2.70
3
(m, 2H), 3.76 (s, 6H), 4.03 (t, J = 5.8 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 5.95 (d, J = 15.7 Hz, 1H), 6.07
1
3
(s, 3H), 7.02 (dt, J = 15.7, 6.9 Hz, 1H); C NMR (75.5 MHz, CDCl ): δ 14.3, 31.9, 55.3, 60.3, 65.9,
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+
9
3.2, 93.4, 123.5, 144.5, 160.5, 161.5, 166.3; MS (ESI) m/z (rel intensity): 281.1 (MH , 100), 127.1
1
2
3
4
5
6
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
+
(
35); HRMS (ESI-TOF): calcd. for C H O [MH ], 281.1389; found: 281.1390.
1
5
21
5
Butyl (E)-5-(3,5-dimethoxyphenoxy)pent-2-enoate (1e). Prepared from 3a (0.49 g, 2.4 mmol), n-butyl
nd
acrylate (6.8 mL, 47.1 mmol) and 2 generation Grubbs catalyst (99.9 mg, 0.12 mmol) in dry CH Cl
2
2
(
4.7 mL). After stirring the reaction mixture for 24 h, DMSO (0.42 mL, 5.9 mmol) was added and the
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
resulting solution was further stirred for 20 h. After evaporating the volatile compounds in vacuo and
purification by flash column chromatography (petroleum ether/AcOEt 9/1), 1e was obtained as an oil
-1 1
(
0.59 g, 82 %): IR (ATR) 1716 cm ; H NMR (300 MHz, CDCl ): δ 0.93 (t, J = 7.3 Hz, 3H), 1.28-1.47
3
(
m, 2H), 1.54-1.70 (m, 2H), 2.59-2.71 (m, 2H), 3.75 (s, 6H), 4.02 (t, J = 6.4 Hz, 2H), 4.13 (t, J = 6.7 Hz,
1
3
2H), 5.94 (dt, J = 15.7, 1.5 Hz, 1H), 6.04-6.10 (s, 3H), 7.01 (dt, J = 15.7, 6.8 Hz, 1H); C NMR (75.5
MHz, CDCl ): δ 13.7, 19.2, 30.7, 31.9, 55.3, 64.2, 65.9, 93.2, 93.4, 123.4, 144.5, 160.5, 161.5, 166.4;
3
+
MS (ESI) m/z (rel intensity): 309.2 (MH , 100), 155.1 (23); HRMS (ESI-TOF): calcd. for C H O
1
7
25
5
+
[MH ], 309.1702; found: 309.1703.
t-Butyl (E)-5-(3,5-dimethoxyphenoxy)pent-2-enoate (1f). Prepared from 3a (0.41 g, 2.0 mmol), tert-
nd
butyl acrylate (5.8 mL, 39.3 mmol) and 2 generation Grubbs catalyst (83.4 mg, 0.098 mmol) in dry
CH Cl (4.0 mL). After stirring the reaction mixture for 24 h, DMSO (0.35 mL, 4.9 mmol) was added
2
2
and the resulting solution was further stirred for 20 h. After evaporating the volatile compounds in
vacuo and purification by flash column chromatography (petroleum ether/AcOEt 9/1), 1f was obtained
-1 1
as an oil (0.44 g, 73 %): IR (ATR) 1710 cm ; H NMR (300 MHz, CDCl ): δ 1.47 (s, 9H), 2.52-2.68
3
(m, 2H), 3.74 (s, 6H), 4.00 (t, J = 6.4 Hz , 2H), 5.86 (dt, J = 15.7, 1.4 Hz, 1H), 6.06 (s, 3H), 6.90 (dt, J =
13
1
1
5.7, 6.8 Hz, 1H); C NMR (75.5 MHz, CDCl ): δ 28.1, 31.8, 55.3, 66.0, 80.2, 93.2, 93.4, 125.1, 143.2,
3
+
60.5, 161.5, 165.6; MS (ESI) m/z (rel intensity): 309.2 (MH , 15), 253.1 (100); HRMS (ESI-TOF)
+
calcd. for C H O [MH ], 309.1702; found: 309.1697.
1
7
25
5
t-Butyl (E)-5-(3,5-dimethoxyphenoxy)hex-2-enoate (1g). Prepared from 3b (0.27 g, 1.2 mmol), tert-
nd
butyl acrylate (3.5 mL, 23.8 mmol) and 2 generation Grubbs catalyst (50.6 mg, 0.060 mmol) in dry
CH Cl (2.4 mL). After stirring the reaction mixture for 24 h, DMSO (0.21 mL, 2.9 mmol) was added
2
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and the resulting solution was further stirred for 20 h. After evaporating the volatile compounds in
vacuo and purification by flash column chromatography (petroleum ether/AcOEt 9/1), 1g was obtained
1
2
3
4
5
6
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
-1 1
as an oil (0.33 g, 87 %): IR (ATR) 1713 cm ; H NMR (300 MHz, CDCl ): δ 1.34 (d, J = 6.1 Hz, 3H),
3
1
6
1
1
.50 (s, 9H), 2.40-2.67 (m, 2H), 3.78 (s, 6H), 4.37-4.53 (m, 1H), 5.74-5.92 (m, 1H), 6.09 (s, 3H), 6.79-
1
3
.98 (m, 1H); C NMR (75.5 MHz, CDCl ): δ 19.6, 28.1, 38.7, 55.3, 72.3, 80.3, 93.2, 94.7, 125.7,
3
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
+
42.8, 159.4, 161.5, 165.6; MS (ESI) m/z (rel intensity): 323.2 (MH , 19), 268.1 (13), 267.1 (100),
+
55.1 (10); HRMS (ESI-TOF): calcd. for C H O [MH ], 323.1858; found, 323.1859.
1
8
27
5
Methyl (E)-5-(3,4,5-trimethoxyphenoxy)hex-2-enoate (1h). Prepared from 3h (0.29 g, 1.1 mmol),
nd
methyl acrylate (2.1 mL, 23.0 mmol) and 2 generation Grubbs catalyst (48.8 mg, 0.057 mmol) in dry
CH Cl (2.3 mL). After stirring the reaction mixture for 24 h, DMSO (0.2 mL, 2.9 mmol) was added
2
2
and the resulting solution was further stirred for 20 h. After evaporating the volatile compounds in
vacuo and purification by flash column chromatography (petroleum ether/AcOEt 8/2), 1h was obtained
-1 1
as an oil (0.29 g, 83 %): IR (ATR) 1720 cm ; H NMR (300 MHz, CDCl ): δ 1.22 (d, J = 6.0 Hz, 3H),
3
2
6
6
1
3
.33-2.59 (m, 2H), 3.62 (s, 3H), 3.68 (s, 3H), 3.72 (s, 6H), 4.26-4.44 (m, 1H), 5.82 (d, J = 15.7 Hz, 1H),
1
3
.06 (s, 2H), 6.91 (dt, J = 15.7, 7.3 Hz, 1H); C NMR (75.5 MHz, CDCl ): δ 19.6, 38.8, 51.3, 55.9,
3
+
0.8, 72.8, 94.0, 123.4, 132.5, 144.5, 153.6, 153.9, 166.5; MS (EI) m/z (rel intensity): 310.1 (M , 23),
+
84.0 (34), 169.0 (100), 127.1 (57), 69.0 (22); HRMS (ESI-TOF): calcd. for C H O [MH ],
1
6
23
6
11.1495; found, 311.1499.
Pd(II)-Catalyzed cyclization of 1 and 3. Synthesis of chromanes 2a-h and 2H-chromenes 4a-w. A
solution of the corresponding ester 1a-h or ether 3a-w (1 mmol), p-TsOH (1 mmol), p-benzoquinone (1
mmol) and PdCl (CH CN) (0.05 or 0.1 mmol) in 1,4-dioxane (66.7 mL) was stirred at room
2
3
2
temperature (or 70 ºC) for 1 to 24 h. Then, the reaction was quenched by addition of water and the
mixture was extracted with CH Cl (3 × 10 mL). The combined organic extracts were washed with brine
2
2
(10 mL), dried (Na SO ) and concentrated in vacuo. After purification by flash column chromatography
2 4
(silica gel, petroleum ether/AcOEt 8/2 or 9/1) the corresponding chromanes 1a-h or 2H-chromenes 4a-
w were obtained.
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Methyl (E)-2-(5,7-dimethoxychroman-4-ylidene)acetate (2a). Prepared from 1a (43.8 mg, 0.16
mmol), p-TsOH (31.8 mg, 0.16 mmol), p-benzoquinone (18.2 mg, 0.16 mmol) and PdCl (CH CN) (2.1
1
2
3
4
5
6
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
2
3
2
mg, 0.008 mmol) in 1,4-dioxane (11.0 mL), 24 h at rt. 2a was obtained as a solid (31.5 mg, 73 %): mp
-1
1
(
CH Cl ) 96-98 ºC; IR (ATR) 1706 cm ; H NMR (300 MHz, CDCl ): δ 3.36 (t , J = 6.0 Hz, 2H), 3.71
2 2 3
1
3
(
s, 3H,), 3.77 (s, 3H), 3.84 (s, 3H), 4.16 (t, J = 6.0 Hz, 2H), 6.04 (s, 1H), 6.07 (s, 1H), 6.92 (s, 1H); C
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 (75.5 MHz, CDCl ): δ 27.3, 50.9, 55.3, 55.6, 65.8, 92.7, 93.9, 104.8, 112.4, 145.6, 159.4, 160.7,
3
+
1
62.0, 168.5; MS (EI) m/z (rel intensity): 264.2 (M , 75), 233.1 (100), 191.1 (80), 175.1 (20); HRMS
+
(
ESI-TOF): calcd. for C H O [MH ], 265.1076; found, 265.1073.
1
4
17
5
Methyl (E)-2-(5,7-dimethoxy-2-methyl-chroman-4-ylidene)acetate (2b). Prepared from 1b (89.6 mg,
0.32 mmol), p-TsOH (60.8 mg, 0.32 mmol), p-benzoquinone (34.6 mg, 0.32 mmol) and PdCl (CH CN)
2
2
3
(4.2 mg, 0.016 mmol) in 1,4-dioxane (21.3 mL), 24 h at rt. 2b was obtained as a solid (71.1 mg, 80 %):
-1 1
mp (CH Cl ) 76-78 ºC; IR (ATR) 1695 cm , H NMR (300 MHz, CDCl ): δ 1.40 (d, J = 6.2 Hz, 3H),
2
2
3
2.52-2.69 (m, 1H), 3.71 (s, 3H), 3.77 (s, 3H), 3.84 (s, 3H), 3.82-3.92 (m, 1H), 4.06-4.24 (m, 1H), 6.98-
13
6
9
2
.10 (m, 2H), 6.93 (s, 1H); C NMR (75.5 MHz, CDCl ): δ 20.8, 33.9, 50.9, 55.3, 55.6, 72.1, 92.6,
3
+
3.9, 104.4, 112.5, 145.9, 159.4, 160.6, 162.1, 168.4; MS (ESI) m/z (rel intensity): 279.1 (MH , 100),
+
47.1 (23); HRMS (ESI-TOF): calcd. for C H O [MH ], 279.1233; found, 279.1236.
15 19
5
Methyl (E)-2-(5,7-dimethoxy-2-phenylchroman-4-ylidene)acetate (2c). Prepared from 1c (65.2 mg,
.19 mmol), p-TsOH (36.2 mg, 0.19 mmol), p-benzoquinone (20.6 mg, 0.19 mmol) and PdCl (CH CN)
2
0
2
3
(2.5 mg, 0.01 mmol) in 1,4-dioxane (12.7 mL) 24 h at rt. 2c was obtained as a solid (38.3 mg, 59 %):
-1 1
mp (CH Cl ) 142-144 ºC; IR (ATR) 1695 cm ; H NMR (300 MHz, CDCl ): δ 2.86-3.03 (m, 1H), 3.71
2
2
3
(s, 3H), 3.79 (s, 3H), 3.87 (s, 3H), 4.10-4.25 (m, 1H), 5.00-5.14 (m, 1H), 6.13 (d, J = 2.1 Hz, 1H), 6.18
1
3
(
d, J = 2.1 Hz, 1H), 6.99 (s, 1H), 7.27-7.51 (m, 5H); C NMR (75.5 MHz, CDCl ): δ 34.1, 50.9, 55.4,
3
55.6, 77.6, 93.0, 94.1, 104.5, 112.9, 126.2, 128.2, 128.5, 140.1, 145.5, 159.5, 160.7, 162.2, 168.4; MS
+
+
(
ESI) m/z (rel intensity): 341.1 (MH , 100), 309.1 (13); HRMS (ESI-TOF): calcd. for C H O [MH ],
20 21 5
3
41.1389; found, 341.1388.
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Ethyl (E)-2-(5,7-dimethoxychroman-4-ylidene)acetate (2d). Prepared from 1d (68.3, 0.24 mmol), p-
TsOH (46.3 mg, 0.24 mmol), p-benzoquinone (26.3 mg, 0.24 mmol) and PdCl (CH CN) (6.3 mg,
1
2
3
4
5
6
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
2
3
2
0.024 mmol) in 1,4-dioxane (24.6 mL) 24 h at rt. 2d was obtained as a solid (51.7 mg, 77 %): mp
-1
1
(
CH Cl ) 107-108 ºC; IR (ATR)1739 cm ; H NMR (300 MHz, CDCl ): δ 1.30 (t, J = 7.1 Hz, 3H), 3.37
2
2
3
(t, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.85 (s, 3H), 4.08-4.25 (m, 4H), 6.05 (d, J = 2.3 Hz, 1H), 6.08 (d, J =
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
2
1
.3 Hz, 1H), 6.91 (s, 1H); C NMR (75.5 MHz, CDCl ): δ 14.4, 27.3, 55.3, 55.6, 59.5, 65.8, 92.7, 93.9,
3
+
04.8, 112.9, 145.2, 159.3, 160.7, 161.9, 168.1; MS (ESI) m/z (rel intensity):, 279.1 (MH , 100), 233.1
+
(
3); HRMS (ESI) Calcd. for C H O [MH ], 279.1233; found, 279.1240.
1
5
19
5
n-Butyl (E)-2-(5,7-dimethoxychroman-4-ylidene)acetate (2e). Prepared from 1e (0.11, 0.37 mmol),
p-TsOH (70.1 mg, 0.37 mmol), p-benzoquinone (39.8 mg, 0.37 mmol) and PdCl (CH CN) (9.6 mg,
2
3
2
0
.037 mmol) in 1,4-dioxane (24.6 mL) 24 h at rt. 2e was obtained as a solid (79.2 mg, 70 %): mp
-1 1
(
CH Cl ) 81-82 ºC; IR (ATR) 1691 cm ; H NMR (300 MHz, CDCl ): δ 0.95 (t, J = 7.3 Hz, 3H), 1.32-
2
2
3
1.49 (m, 2H), 1.56-1.73 (m, 2H), 3.27-3.41 (m, 2H), 3.77 (s, 3H), 3.84 (s, 3H), 4.11 (t, J = 6.8 Hz, 2H),
13
4
.17 (t, J = 6.0 Hz, 2H), 6.04 (d, J = 2.4 Hz, 1H), 6.07 (d, J = 2.4 Hz, 1H), 6.90 (s, 1H); C NMR (75.5
MHz, CDCl ): δ 13.8, 19.3, 27.3, 30.9, 55.3, 55.6, 63.5, 65.2, 92.7, 93.9, 104.8, 113.0, 145.1, 159.3,
3
+
1
60.7, 161.9, 168.2; MS (ESI) m/z (rel intensity): 307.2 (MH , 100), 305.1 (3); HRMS (ESI-TOF):
+
calcd. for C H O [MH ], 307.1546; found, 307.1546.
1
7
23
5
t-Butyl (E)-2-(5,7-dimethoxychroman-4-ylidene)acetate (2f). Prepared from 1f (0.13 g, 0.42 mmol),
p-TsOH (79.5 mg, 0.42 mmol), p-benzoquinone (45.2 mg, 0.42 mmol) and PdCl (CH CN) (10.8 mg,
2
3
2
0.042 mmol) in 1,4-dioxane (28.0 mL) 24 h at rt. 2f was obtained as an oil (75.8 mg, 59 %): IR (ATR)
-1
1
1
4
695 cm ; H NMR (300 MHz, CDCl ): δ 1.52 (s, 9H), 3.28-3.42 (m, 2H), 3.79 (s, 3H), 3.86 (s, 3H),
3
1
3
.18 (t, J = 6.0 Hz, 2H), 6.05 (d, J = 2.3 Hz, 1H), 6.09 (d, J = 2.3 Hz, 1H), 6.84 (s, 1H); C NMR (75.5
MHz, CDCl ): δ 27.2, 28.4, 55.3, 55.6, 65.2, 79.5, 92.6, 93.9, 104.9, 115.0, 143.8, 159.1, 160.6, 161.7,
3
+
1
67.7; MS (ESI) m/z (rel intensity): 307.2 (MH , 100), 251.1 (76); HRMS (ESI-TOF): calcd. for
C H O [MH+], 307.1546; found, 307.1563.
1
7
23
5
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The Journal of Organic Chemistry
t-Butyl (E)-2-(5,7-dimethoxy-2-methylchroman-4-ylidene)acetate (2g). Prepared from 1g (0.11 g,
.33 mmol), p-TsOH (63.0 mg, 0.33 mmol), p-benzoquinone (35.8 mg, 0.33 mmol) and PdCl (CH CN)
2
1
2
3
4
5
6
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
0
2
3
(8.6 mg, 0.033 mmol) in 1,4-dioxane (22.1 mL) 24 h at rt. 2g was obtained as a solid (74.1 mg, 69 %):
-1
1
mp (CH Cl ) 83-84 ºC; IR (ATR) 1685 cm ; H NMR (300 MHz, CDCl ): δ 1.40 (d, J = 6.2 Hz, 3H),
2
2
3
1
.50 (s, 9H), 2.55 (ddd, J = 15.8, 11.3, 1.8 Hz, 1H), 3.76 (s, 3H), 3.84 (s, 3H), 3.81-3.89 (m, 1H), 4.08-
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
4
.23 (m, 1H), 6.04 (d, J = 2.3 Hz, 1H), 6.06 (d, J = 2.3 Hz, 1H), 6.83 (s, 1H); C NMR (75.5 MHz,
CDCl ): δ 20.9, 28.4, 33.8, 55.3, 55.6, 72.1, 79.4, 92.6, 93.8, 104.5, 115.0, 144.2, 159.3, 160.5, 161.7,
3
+
1
67.8; MS (ESI) m/z (rel intensity): 321.2 (MH , 100), 284.1 (6); 265.1 (62). HRMS (ESI-TOF): calcd.
+
for C H O [MH ], 321.1702; found, 321.1708.
18 25
5
Methyl (E)-2-(5,6,7-trimethoxy-2-methyl-chroman-4-ylidene)acetate (2h). Prepared from 1h (0.11 g,
.38 mmol), p-TsOH (73.0 mg, 0.38 mmol), p-benzoquinone (41.5 mg, 0.38 mmol) and PdCl (CH CN)
2
0
2
3
(10.0 mg, 0.038 mmol) in 1,4-dioxane (25.6 mL) 24 h at rt. 2h was obtained as a solid (67.4 mg, 60 %):
-1 1
mp (CH Cl ) 90-92 ºC; IR (ATR) 1706 cm ; H NMR (300 MHz, CDCl ): δ 1.38 (d, J = 6.2 Hz, 3H),
2
2
3
2
.48-2.64 (m, 1H), 3.70 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 3.48-3.96 (m, 1H), 4.04-4.23
1
3
(
m, 1H), 6.19 (s, 1H), 6.97 (s, 1H); C NMR (75.5 MHz, CDCl ): δ 20.8, 33.7, 50.9, 55.8, 60.2, 61.0,
3
7
2.2, 96.6, 107.7, 112.7, 136.9, 145.8, 153.4, 154.1, 155.5, 168.4; MS (ESI) m/z (rel intensity): 309.1
+
+
(
MH , 100), 277.1 (27); HRMS (ESI-TOF): calcd. for C H O [MH ], 309.1338; found, 309.1347.
16 21 6
2
2
5
,7-Dimethoxy-4-methyl-2H-chromene (4a). Prepared from 3a (0.14 g, 0.66 mmol), p-TsOH (0.12
g, 0.66 mmol), p-benzoquinone (71.6 mg, 0.66 mmol) and PdCl (CH CN) (8.7 mg, 0.033 mmol) in
2
3
2
1,4-dioxane (44.6 mL) 2 h at rt. 4a was obtained and as an oil (0.10 g, 74 %) (mixture of regioisomers
-1
1
9
4
3:7): IR (ATR) 2837, 2959, 3009 cm ; H NMR (300 MHz, CDCl ): δ 2.15 (s, 3H), 3.78 (s, 6H), 4.42-
3
1
3
.54 (m, 2H), 5.35-5.47 (m, 1H), 6.09 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H); C NMR (75.5
MHz, CDCl ): δ 21.8, 55.3, 55.4, 65.0, 92.9, 93.8, 108.0, 115.2, 131.7, 157.2, 158.2, 160.6; MS (ESI)
3
+
+
m/z (rel intensity): 207.1 (MH , 100), 205.1 (3). HRMS (ESI-TOF): calcd. for C H O [MH ],
1
2
15
3
2
07.1021; found, 207.1022.
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5
,7-Dimethoxy-2,4-dimethyl-2H-chromene (4b). Prepared from 3b (0.15 g, 0.67 mmol), p-TsOH
1
2
3
4
5
6
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
(0.13 g, 0.67 mmol), p-benzoquinone (72.3 mg, 0.67 mmol) and PdCl (CH CN) (8.7 mg, 0.034 mmol)
2
3
2
in 1,4-dioxane (44.6 mL) 2 h at rt. 4b was obtained as an oil (0.13 g, 86 %) (mixture of regioisomers
-1
1
8
3:17): IR (ATR) 2837, 2934, 2966, 2999, 3034 cm ; H NMR (300 MHz, CDCl ): δ 1.41 (d, J = 6.6
3
Hz, 3H), 2.15 (s, 3H), 3.77 (s, 6H), 4.61-4.74 (m, 1H), 5.22-5.26 (m, 1H), 6.08 (d, J = 2.4 Hz, 1H), 6.12
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
(d, J = 2.4 Hz, 1H); C NMR (75.5 MHz, CDCl ): δ 20.4, 21.8, 55.2, 55.3, 71.1, 92.8, 94.0, 107.5,
3
+
1
21.0, 130.9, 156.8, 158.2, 161.5; MS (ESI) m/z (rel intensity): 221.1 (MH , 100), 219.1 (10). HRMS
+
(ESI-TOF): calcd. for C H O [MH ], 221.1178; found, 221.1178.
1
3
17
3
5
,7-Dimethoxy-4-methyl-2-propyl-2H-chromene (4c). Prepared from 3c (73.8 mg, 0.29 mmol), p-
TsOH (56.1 mg, 0.29 mmol), p-benzoquinone (31.9 mg, 0.29 mmol) and PdCl (CH CN) (3.8 mg,
2
3
2
0
.015 mmol) in 1,4-dioxane (19.7 mL) 2 h at rt. 4c was obtained as an oil (62.0 mg, 85 %) (mixture of
-1 1
regioisomers 93:7): IR (ATR) 2841, 2872, 2937, 2959, 3006 cm ; H NMR (300 MHz, CDCl ): δ 0.98
3
(t, J = 7.1 Hz, 3H), 1.40-1.90 (m, 4H), 2.17 (s, 3H), 3.79 (s, 6H), 4.51-4.60 (m, 1H), 5.30 (d, J = 1.6 Hz,
13
1
2
H), 6.09 (d, J = 2.1 Hz, 1H), 6.14 (d, J = 2.1 Hz, 1H); C NMR (75.5 MHz, CDCl ): δ 14.0, 18.3,
3
1.9, 36.5, 55.3, 55.4, 74.6, 92.7, 94.0, 107.6, 120.0, 130.8, 156.7, 158.1, 160.5; MS (ESI) m/z (rel
+
+
intensity): 249.1 (MH , 100), 247.1 (3); HRMS (ESI-TOF): calcd. for C H O [MH ], 249.1491;
15 21
3
found, 249.1489.
,7-Dimethoxy-4-methyl-2-phenyl-2H-chromene (4d). Prepared from 3d (77.2 mg, 0.27 mmol), p-
TsOH (51.6 mg, 0.27 mmol), p-benzoquinone (29.4 mg, 0.27 mmol) and PdCl (CH CN) (3.5 mg,
5
2
3
2
0.014 mmol) in 1,4-dioxane (18.0 mL) 2h at rt. 4d was obtained as an oil (63.4 mg, 83 %) (mixture of
-1
1
regioisomers 90:10): IR (ATR) 2837, 2930, 2973, 3009 cm ; H NMR (300 MHz, CDCl ): δ 2.25 (s,
3
3
H), 3.77 (s, 3H), 3.80 (s, 3H), 5.41-5.46 (m, 1H), 5.60-5.64 (m, 1H), 6.11 (d, J = 2.4 Hz, 1H), 6.18 (d,
1
3
J = 2.4 Hz, 1H), 7.24-7.54 (m, 5H); C NMR (75.5 MHz, CDCl ): δ 22.0, 55.3, 55.4, 76.8, 93.0, 94.1,
3
1
07.2, 119.1, 127.1, 128.1, 128.5, 131.4, 140.9, 156.2, 158.3, 160.8; MS (ESI) m/z (rel intensity): 283.1
+
+
(MH , 100), 155.1 (3); HRMS (ESI-TOF): calcd. for C H O [MH ], 283.1334; found, 283.1337.
18 19 3
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2
-(3-(Benzyloxy)phenyl)-5,7-dimethoxy-4-methyl-2H-chromene (4e). Prepared from 3e (0.10 g, 0.26
1
2
3
4
5
6
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
mmol), p-TsOH (50.0 mg, 0.26 mmol), p-benzoquinone (28.4 mg, 0.26 mmol) and PdCl (CH CN) (3.4
2
3
2
mg, 0.013 mmol) in 1,4-dioxane (17.5 mL) 2h at rt. 4e was obtained as an oil (88.3 mg, 87 %) (mixture
-1
1
of regioisomers 90:10): IR (ATR) 2837, 2930, 2959, 2999, 3031, 3066 cm ; H NMR (300 MHz,
CDCl ): δ 2.22 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 5.07 (s, 2H), 5.38-5.41 (m, 1H), 5.56-5.59 (m, 1H),
3
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
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4
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6
7
8
9
0
1
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6
7
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9
0
1
3
6
.09 (d, J = 2.4 Hz, 1H), 6.16 (d, J = 2.4 Hz, 1H), 6.86-7.17 (m, 3H), 7.22-7.51 (m, 6H); C NMR (75.5
MHz, CDCl ): δ 22.0, 55.3, 55.4, 70.0, 76.6, 93.0, 94.1, 107.2, 112.7, 113.5, 114.3, 118.7, 127.6, 128.0,
3
1
1
28.6, 129.6, 131.4, 137.0, 142.6, 156.2, 158.3, 159.0, 160.8; MS (ESI) m/z (rel intensity): 389.2 (MH+,
+
00), 363.2 (2); HRMS (ESI-TOF): calcd. for C H O [MH ], 389.1753; found, 389.1749.
25 25
4
2-(Furan-3-yl)-5,7-dimethoxy-4-methyl-2H-chromene (4f). Prepared from 3f (77.2 mg, 0.27 mmol),
p-TsOH (51.6 mg, 0.27 mmol), p-benzoquinone (29.4 mg, 0.27 mmol) and PdCl (CH CN) (3.5 mg,
2
3
2
0
.014 mmol) in 1,4-dioxane (18.0 mL) 2h at rt. 4f was obtained as an oil (63.4 mg, 86 %) (mixture of
-1 1
regioisomers 85:15): IR (ATR) 2841, 2926, 2962, 2991, 3006 cm ; H NMR (300 MHz, CDCl ): δ 2.21
3
(t, J = 1.5 Hz, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 5.38-5.47 (m, 1H), 5.50-5.59 (m, 1H), 6.09 (d, J = 2.4 Hz,
1
3
1
H), 6.13 (d, J = 2.4 Hz, 1H), 6.47-6.49 (m, 1H), 7.38 (t, J = 1.7 Hz, 1H ), 7.44-7.46 (m, 1H); C NMR
´
(75.5 MHz, CDCl ): δ 21.9, 55.3, 55.4, 69.2, 93.0, 94.2, 107.4, 109.6, 117.9, 125.2, 131.8, 140.8, 143.3,
3
+
1
56.0, 158.3, 160.8; MS (ESI): m/z (rel intensity): 273.1 (MH , 100), 171.1 (2). HRMS (ESI-TOF):
+
calcd. for C H O [MH ], 273.1127; found, 273.1123.
1
6
17
4
5
,6,7-Trimethoxy-4-methyl-2H-chromene (4g). Prepared from 3g (0.13 g, 0.53 mmol), p-TsOH (0.10
g, 0.53 mmol), p-benzoquinone (57.4 mg, 0.53 mmol) and PdCl (CH CN) (13.8 mg, 0.053 mmol) in
2
3
2
1
9
,4-dioxane (35.4 mL) 6 h at rt. 4g was obtained as an oil (76.5 mg, 61 %) (mixture of regioisomers
-1 1
4:6): IR (ATR) 2833, 2934, 2966, 3006 cm ; H NMR (300 MHz, CDCl ): δ 2.17 (s, 3H), 3.80 (s, 3H),
3
1
3
3.81 (s, 3H), 3.85 (s, 3H), 4.48 (d, J = 2.2 Hz, 2H), 5.46 (bs, 1H), 6.28 (s, 1H); C NMR (75.5 MHz,
CDCl ): δ 21.1, 55.9, 60.9, 61.2, 64.9, 96.3, 111.7, 117.0, 131.1, 137.1, 151.4, 151.7, 153.4; MS (ESI)
3
+
+
m/z (rel intensity): 237.1 (MH , 100), 236.1 (3). HRMS (ESI-TOF): calcd. for C H O [MH ],
1
3
17
4
2
37.1127; found, 237.1126.
ACS Paragon Plus Environment
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