Intramolecular Base-Free Catalytic Wittig Reaction: Synthesis of Benzoxepinones

Article abstract of DOI:10.1021/acs.joc.8b02789

A straightforward two-step synthesis of benzoxepinones was developed via base-free phosphane-catalyzed Wittig reaction. 3-Methyl-1-phenyl-2-phospholene 1-oxide was used as a precatalyst and trimethoxysilane as a reducing agent. Additionally benzoic acid is employed as a catalyst to facilitate the reduction of the phosphane oxide. Mechanistic investigation revealed the formation of a coumarin as a side product, which was identified by 2D NMR experiments. First results of metabolic activity tests on the prepared benzoxepinones are reported.

Full text of DOI:10.1021/acs.joc.8b02789

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Article
Intramolecular Base-Free Catalytic Wittig
Reaction: Synthesis of Benzoxepinones
Aiga Grandane, Lars Longwitz, Catrin Roolf, Anke Spannenberg, Hugo
Murua Escobar, Christian Junghanss, Edgars Suna, and Thomas Werner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02789 • Publication Date (Web): 17 Dec 2018
Downloaded from http://pubs.acs.org on December 17, 2018
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The Journal of Organic Chemistry
Intramolecular
Benzoxepinones
Base-Free
Catalytic
Wittig
Reaction:
Synthesis
of
1
2
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5
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Aiga Grandane†‡, Lars Longwitz‡, Catrin Roolf§, Anke Spannenberg‡, Hugo Murua Escobar§,
Christian Junghanss§, Edgars Suna†, Thomas Werner*‡
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†Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia
‡Leibniz Institute for Catalysis at the University of Rostock, Albert-Einstein-Straße 29a, 18059
Rostock, Germany
§Department of Internal Medicine, Medical Clinic III, Clinic for Hematology, Oncology and
Palliative Care, University Medical Center Rostock Ernst-Heydemann-Straße 6, 18057
Rostock, Germany
ABSTRACT
A straightforward two-step synthesis of benzoxepinones was developed via base-free
phosphane-catalyzed Wittig reaction. 3-Methyl-1-phenyl-2-phospholene 1-oxide was used as a
precatalyst and trimethoxysilane as a reducing agent. Additionally benzoic acid is employed as
a catalyst to facilitate the reduction of the phosphane oxide. Mechanistic investigation revealed
the formation of a coumarin as a side product, which was identified via 2D NMR experiments.
First results of metabolic activity tests on the prepared benzoxepinones are reported.
INTRODUCTION
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The Wittig reaction between phosphonium ylides and ketones or aldehydes is among
the most frequently used methods for the synthesis of alkenes.1, 2 A disadvantage of the Wittig
reaction is the need of a relatively strong base to generate stoichiometric amount of
phosphonium ylide: these conditions are not compatible with base-sensitive substrates.3-5
Furthermore, the formation of stoichiometric phosphane oxide waste from the phosphonium
ylide not only complicates purification of the product, but also reduces the atom economy of
the Wittig reaction.6, 7 The latter disadvantage was mitigated by the introduction of Wittig
reaction conditions, employing catalytic amount of phosphane.8, 9 Several applications of the
phosphane-catalyzed Wittig reaction were reported since then,10, 11 however the presence of
stoichiometric base was still required in these works. Lee et al. were the first to accomplish an
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intramolecular Wittig reaction using catalytic amount of base.12 Recently, we have developed a
base-free intermolecular phosphane-catalyzed Wittig reaction, which proceeded under virtually
neutral conditions.13, 14 The base-free phosphane-catalyzed Wittig reaction has already been
used for the synthesis of pyrrolizine and indole derivatives.15 Herein, we report an application
of our base-free phosphane-catalyzed Wittig reaction in the synthesis of benzoxepinones,
synthetically valuable and easy-to-modify precursors of benzoxepines.16-23
Me
Me
O
HO
Me
HO
Me
Cl
Me
Me
OH
O
O
O
OH
Me
Heliannuol B
Pterulone
Enokipodin A
Figure 1. Natural products based on benzoxepine core.
The benzoxepine scaffold is encountered in a number of biologically active natural
products.24-29 For example, fungi metabolite pterulone has antibacterial properties,30 and
Enokipodin A , a sesquiterpenoid from enokitake, shows antimicrobial activity.24 Further,
Heliannuol B was isolated from sunflowers showing allelopathic activity29 (Figure 1).
Furthermore, several benzoxepine derivatives have been synthesized as anticancer drugs.31,
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The Journal of Organic Chemistry
32 Thus, we were interested in developing an efficient synthetic route to access the
benzoxepine scaffold and evaluate the anti-proliferative activities. Benzoxepinones have been
synthesized by Lewis-acid mediated rearrangement of dihydrofurans33 or from cyclobutanone
by rhodium-catalyzed C–C bond cleavage in the presence of CO.34 These heterocycles were
also prepared in a long six-step sequence from 2-hydroxybenzaldehyde derivatives in 8–36 %
overall yield (Scheme 1).35 We realized that the long synthetic route from 2-
hydroxybenzaldehyde (1a) could be reduced to a two-step sequence comprising an initial
formation of ester 2a, followed by an intramolecular base-free catalytic Wittig as the key step
(Scheme 1).
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Scheme 1. Synthesis of Benzoxepinones from salicylic aldehydes.
OH
R
R
CO2Me
CN
CO2Me
OH
OBn
CO2Me
O
R
R
Lee et al. (2008): 8-36% yield in 6 steps
This work: 20-38% yield in 2 steps
O
OH
O
1
3
O
Base-free catalytic
Wittig reaction
R
O
O
CO2Me
2
RESULTS AND DISCUSSION
The Wittig reaction conditions from our previously published work13 were employed as
the starting point for the development of cyclization of 2a to benzoxepinone 3a. Accordingly,
the use of Bu3P as a catalyst, phenylsilane as a reducing agent, benzoic acid as an additive
and toluene as a solvent afforded the desired benzoxepinone 3a in 27% yield (Table 1, entry
1). The cyclization without the added benzoic acid led to slightly improved yield (34%, entry 2).
Further improvement was achieved by using phospholene 5 as the catalyst and (MeO)3SiH as
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the reducing agent leading to 3a in 41% yield under previously reported conditions14 (entry 3).
Structurally closely related phospholane 6 was equally efficient as the catalyst (38%, entry 4).
Variations in the amount of catalyst 5 had minor influence on the yield of lactone 3a. Thus,
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8
9
both increased (10 mol %) and reduced (2.5 mol %) catalyst loading afforded comparable yield
of lactone 3a.36 Further decrease of the catalyst amount to 1 mol % resulted in an incomplete
conversion of 2a.36 Phenylsilane and hexylsilane were less efficient as reducing agents
compared to (MeO)3SiH (19% and 33%, respectively; see entries 5 and 6). Variations of
(MeO)3SiH amount did not improve the yield of 3a.36 Attempted cyclization of 2a in various
solvents such as 1,4-dioxane, THF and MeOH resulted in reduced yields of the desired
benzoxepinone 3a.36 Prolongation of the reaction time to 48 h decreased the yield of lactone
3a to 33% (entry 7). Variations of the cyclization temperature did not help to increase yield of
lactone 3a. Thus, lowering the temperature to 80 °C gave 25% of 3a (entry 8), whereas at
higher temperature (120 °C) lactone 3a was formed in 33% yield (entry 9). Interestingly,
microwave heating allowed for the full conversion to be achieved within 3 h, giving the desired
lactone 3a in 38% yield (entry 10).
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We hypothesized that moderate yields of the desired lactone 3a could be attributed to
the concomitant formation of a six-membered side product 4 under all tested conditions (Table
1). Indeed, the formation of coumarin 4 (up to 10%) was observed using Bu3P as a catalyst
(entries 1 and 2). The 6-membered side product 4 was separated from the desired lactone 3a
by chromatography on silica gel and isolated in a pure form. Coumarin 4 was not observed by
NMR under the phospholene-catalyzed cyclization conditions (entry 3). However, its formation
cannot be excluded, because a control experiment showed that coumarin 4 is not stable under
the phospholene-catalyzed cyclization conditions (entry 3), and it undergoes rapid
decomposition. Possibly, the formation of transient coumarin 4 consumes the starting
aldehyde 2a, thus leading to moderate yields of the desired benzoxepinone 3a. We also
realized that the undesired Michael addition of phospholene 5 to position 2 of fumarate 2a
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The Journal of Organic Chemistry
(See graphics of Table 1) could be avoided by the replacement of methoxycarbonyl moiety in
2a with N,N-dialkylamide group. The presence of the less electron-withdrawing N,N-
dialkylamide substituent could improve the regioselectivity of Michael addition, favoring the
addition to position 3 of fumarate, which leads to the desired benzoxepinone. Unfortunately,
N,N-diethylamide moiety-containing analog of 2a turned out to be unstable, and it underwent
rapid decomposition under the standard Wittig cyclization conditions.
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Table 1. Catalyst screening and optimization of the reaction conditions.
5
6
Catalyst or (5 mol %)
PhCO2H (5 mol %)
Silane
CO2Me
O
CO2Me
O
3
+
O
O
O
O
CO2Me
O
toluene-d8
2
2a
3a
4
Me
Me
O
O
P
P
Ph
Ph
Catalyst
5
Catalyst
6
entry
1b
cat. (5 mol %)
Bu3P
silane (equiv)
PhSiH3 (1)
T (°C)
T (h)
yield 3a (%)a
125
24
27
2c
3
Bu3P
PhSiH3 (1)
125
100
100
100
100
100
80
24
16
16
16
16
48
20
20
3
34
41
38
19
33
33
25
33
38
5
6
5
5
5
5
5
5
(MeO)3SiH (3)
(MeO)3SiH (3)
PhSiH3 (3)
4
5
6
HexylSiH3 (3)
(MeO)3SiH (3)
(MeO)3SiH (3)
(MeO)3SiH (3)
(MeO)3SiH (3)
7
8
9
120
100
10d
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aYield was determined by NMR with mesitylene as an internal standard. Lactone 4 was formed as a side product (10%).
b
1
2
cWithout PhCO2H; 6-membered lactone 4 (9%) was formed. dMicrowave heating was used.
3
4
5
6
7
8
9
Structures of both benzoxepinone 3a and chromenone 4 were confirmed by NMR
experiments. Thus, an NOE correlation between the lactone proton HA (7.68 ppm) and
aliphatic protons HB and HB’ (3.60 ppm) was observed for coumarin 4 (Figure 2). In contrast,
the NOE crosspeaks between protons HA and HB could not be seen for the benzoxepinone 3a.
Additional structural support for the formation of lactone 3a was obtained by X-ray
crystallographic analysis.36
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NOE
HA HB
NOE
7.87
7.68
3.60
OMe
O
HA
OMe
HB
3.44
O
O
O
O
O
4
3a
Figure 2. NOESY experiments for benzoxepinone 3a and coumarin 4.
To evaluate the substrate scope and limitations a series of substituted 2-formylphenyl
fumarates 2a–m were prepared from various 2-hydroxybenzaldehydes 1a–m (Scheme 2).
Under standard base-free catalytic Wittig reaction conditions esters 2a–m were transformed
into lactones 3a,b,d–m (Scheme 2). It has to be mentioned that O-acylation of acceptor
substituted substrates proved to be difficult. Moreover, the conversion of the respective esters
under the standard reaction conditions usually led to complex reaction mixtures due to side
reactions such as reduction of the aldehyde. However, aldehydes 2a–h with electron donating
substituents such as MeO, methyl and t-Bu groups as well as with electron-withdrawing
substituents such as chloride (3k and 3l), ester moiety (3m) and protonated amine (3i)
afforded heterocycles 3a–m in 27-44% yield. An exception is substrate 2c, which contains a
methoxy substituent in the ortho position to the aldehyde. In this case no formation of
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The Journal of Organic Chemistry
benzoxepinone 3c was observed. In contrast, aldehyde 2b and 2j possessing a substituent
ortho to the phenolic oxygen are suitable as substrates for the base-free Wittig reaction.
Scheme 2. Substrate scope of the intramolecular base-free catalytic Wittig reaction.a
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5
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9
Me
O
O
(5 mol %)
P
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Ph
CO2Me
O
O
O
Cl
CO2Me
R
R
R
PhCO2H (5 mol %)
8
(E)-
O
NEt3
(MeO)3SiH, toluene,
100 °C, 16 h
O
OH
CO2Me
O
CH2Cl2, rt, 16 h
61–99%
1a–m
2a–m
3a–m
CO2Me
OMe
CO2Me
CO2Me
CO2Me
CO2Me
MeO
O
MeO
O
O
O
O
O
O
O
O
O
OMe
3a
3b
3c
3d
, 44%
3e
, 35%
, 36%
, 29%
, 0%
CO2Me
CO2Me
CO2Me
CO2Me
Me
tBu
Me
Et2HN
Cl
O
O
O
O
, 27%
O
O
O
O
3f
3g
3h
3i
, 36%
CO2Me
, 40%
CO2Me
, 34%
CO2Me
O
CO2Me
Cl
MeO
O
Cl
O
O
O
O
3m, 31%
O
O
O
3j, 43%
3k, 32%
3l, 42%
aStandard reaction conditions: 2a–m (1.00 equiv), catalyst 5 (0.05 equiv), co-catalyst PhCO2H (0.05 equiv), silane
(3.00 equiv), toluene (0.5 M), 100 °C for 16 h. Isolated yields are given.
To gain more insight into the reaction mechanism, we synthesized Z-isomer (Z-2a) of
the model substrate. Under the standard reaction conditions, the same reactivity was observed
and NMR experiments showed no significant difference in the reaction outcome for E-2a and
Z-2a (Scheme 3). Additionally, compounds 11 and 14 were also prepared as substrates for the
cyclization. Ester 11 was synthesized by an initial reaction of sodium pyruvate with trimethyl
phosphonoacetate under Horner-Emmons conditions, followed by formation of acid chloride 10
and condensation with aldehyde 2a (Scheme 3). The first step in the synthesis of isomeric
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ester 14 was the condensation of methyl pyruvate with phosphorus ylide under Wittig reaction
conditions. Subsequent synthesis involved the formation of acid chloride 13 and condensation
with 2a (Scheme 3, equations 2 and 3). Unfortunately, the formation of the cyclization product
from both esters 11 and 14 was not observed under the standard Wittig reaction conditions
and only starting material or a mixture of several side products were observed. This is likely
due to the increased steric hindrance hampering the initial step (the Michael addition of the
phosphane).
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Scheme 3. Control experiments and investigation of the reaction mechanism.
O
CO2Me
standard
SOCl2
O
CO2Me
2a
O
CO2Me
O
CO2Me
conditions
(1)
(2)
(3)
NEt3
CH2Cl2
31%
HO
DMF (cat.)
Cl
O
O
O
21%
7
8
2a
3a
(Z)-
(Z)-
(Z)-
O
O
O
P
CO2Me
standard
conditions
O
O
MeO
2a
OMe
O
no cyclization
observed
O
NaO
X
CO2Me
SOCl2
DBU, LiCl
DMSO, 100 oC
35%
NEt3
CH2Cl2
42%
CO2Me
Me
Me
Me
11
9
, X= OH
DMF (cat.)
10
, X= Cl
O
O
O
PPh3
standard
conditions
1. t
BuO
CHCl3
Me
O
X
Me
CO2Me
2a
no cyclization
observed
O
Me
CO2Me
KOH
CH2Cl2
17%
CO2Me
O
2. TFA, CH2Cl2
76%
12
13
14
, X= OH
, X= Cl
SOCl2
DMF (cat.)
O
O
O
O
O
CO2Me
standard
conditions
O
D
D
2a
1. MeOH
O
D
H/D
H/D
(4)
X
CO2Me
2. AlCl3 (4 mol %)
80 °C
NEt3
CH2Cl2
70%
CO2Me
D
O
D
O
D
60% (99:1 E:Z)
15
16
2a
3a
H2:HD:D2= 0.15:0.8:1
, X= OH
, X=Cl
-D2
SOCl2
DMF (cat.)
Based on our previous findings and the above control experiments, a plausible catalytic
cycle starts with the reduction of precatalyst 5 to phosphane 17 (step I, Scheme 4). This is
probably promoted by the Brønsted acid additive.13, 37, 38 The second step is the Michael
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addition of the in situ formed phosphane to the activated olefin 2a, which leads to the
formation of enolate 18 (step II).14 The product of the Michael addition was not observed by in
situ NMR spectroscopy. However, the control experiments with the corresponding Z isomer (Z-
2a) clearly indicate the formation of such an adduct. Subsequent 1,2-proton shift or a
protonation/ deprotonation sequence generates ylide 19. This step might also be catalyzed by
the Brønsted acid (step III).39, 40 Finally, the intramolecular Wittig reaction between the
aldehyde and the phosphonium ylide affords the desired lactone 3a and liberates precatalyst
5, which re-enters the catalytic cycle (step IV).
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Scheme 4. Plausible catalytic cycle for intramolecular base-free catalytic Wittig reaction.
CO2Me
Ph
P
O
2 HSi(OMe) 3
O
O
O
3a
(MeO)3Si
Si(OMe)3
Me
5
IV
I
Ph
Me
O
P
O
P
Ph
CO2Me
Me
17
O
O
O
19
Me
III
II
O
CO2Me
O
2a
O
P
Ph
CO2Me
O
18
To gain more insight into the reaction mechanism, we synthesized the deuterated
analogue 2a-D2 in a three-step sequence from maleic anhydride-d2 (Scheme 3, equation 4).
Under the standard reaction conditions a significant amount of hydrogen in the product 3a at
the -position was observed, excluding a purely intramolecular mechanism of the ylide
formation. Other control experiments using a 1:1 mixture of 2a-H2 and 2a-D2 as starting
materials showed a similar result, indicating at least a partial involvement of another molecule
in the ylide forming step. For this reason, we investigated the reaction using PhCO2D (50 mol
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%) as a Brønsted acid additive and could detect a significantly increased deuterium
incorporation in the product.36 Apparently, the Brønsted acid additive is involved in the
1
2
3
4
5
6
7
8
9
formation of ylide 19 from enolate 18 (step III, see Scheme 4), however extensive mechanistic
studies are required to get better insight into this intriguing mechanistic question.
Due to the use of benzoxepine derivates as anticancer drugs, we investigated the anti-
proliferative activities of the synthesized substrates 3a, b, d–m using human leukemia cell line
SEM as an experimental model.36 The data was obtained from one experiment performed in
triplicates. Our results demonstrated that none of the tested compound influenced metabolic
activity compared to DMSO treated control cells (= 100%) significantly.36 Metabolic activity in
the compound-treated cells ranged from 95.1 to 108.5 (5 µM) as well as from 91.0 to 108.5 (10
µM). However further studies concerning the biological activity of these compounds are
currently in progress.
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CONCLUSION
Herein we reported a straightforward two-step synthesis of benzoxepinones from 2-
hydroxybenzaldehydes using an intramolecular base-free catalytic Wittig reaction. A
commercially available phospholene oxide was used as a precatalyst (5 mol %) in a
combination with benzoic acid as co-catalyst (5 mol %) and trimethoxysilane as a reducing
agent. Moderate cyclization yields (29–44%) are compensated by the short synthesis and
simplified workup due to the reduced amounts of phosphane and phosphaneoxide byproduct
(5 mol %).
EXPERIMENTAL SECTION
General Information. All reagents were purchased from commercial sources and used
as received without further purification. Thin layer chromatography was performed on Merck
TLC-plates with fluorescence indication (silica type 60, F254), spots were visualized using UV-
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light or KMnO4 stains. Flash chromatography was performed using silica with a grain size of
40–63 µm from Macherey-Nagel. Deuterated chloroform was purchased from Deutero. NMR
spectra were recorded on Bruker 300 Fourier, Bruker AV 300 and Bruker AV 400
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spectrometers. The chemical shifts () for 1H and 13C in CDCl3 are given in parts per million
(ppm) and referenced to 7.26 and 77.16 ppm, respectively. Coupling constants are expressed
in Hertz (Hz). The following abbreviations are used: s= singlet, d= doublet, t= triplet, q=
quadruplet, m= multiplet. IR spectra were recorded on a Nicolet iS10 MIR FT-IR-spectrometer
from Thermo Fisher Scientific. Gas chromatography was performed on Agilent 7890A GC
System, mass spectra were measured on downstream 5975C inert XL MSD mass detector
also from Agilent. Elementary analysis was performed on a TruSpec CHNS Micro from Leco.
High resolution mass spectra (HRMS) were obtained either from a MAT 95 XP from Thermo
(EI) or from an HPLC system 1200 and downstream ESI-TOF-MS 6210 from Agilent (ESI).
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General procedure 1 (GP1) for the synthesis of fumarates 2a-m. Fumaric acid
monomethyl ester (1 equiv) was dissolved in CH2Cl2 (2 mL·mmol–1). After DMF (0.03
mL·mmol–1) was added the mixture was cooled to 0 °C and thionyl chloride (1.1 equiv) was
added dropwise. The resulting mixture was refluxed for 3 h. The solvent was distilled off and
the obtained (E)-4-methoxy-4-oxobut-2-enoic acid chloride (E)-8 was used without further
purification. Salicylderivative 1a–m (1 equiv) was dissolved in CH2Cl2 (5 mL·mmol–1) and acid
chloride (E)-8 (1.1–2.0 equiv) was added dropwise. The mixture was cooled to 0 °C and NEt3
(1.6–2.0 equiv) was added dropwise. The resulting mixture was stirred at 23 °C for 16 h. The
mixture was carefully quenched with H2O (2.5 mL·mmol–1) and washed with saturated
aqueous KHCO3 solution (2  2.5mL·mmol–1). The organic layer was dried over Na2SO4. All
volatiles were removed in vacuum and the product was purified by column chromatography on
silica gel (cyclohexane:EtOAc).
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2-Formylphenyl methyl fumarate (2a).41 Obtained according GP1 from 2-
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hydroxybenzaldehyde (1a, 500 mg, 0.44 mL, 4.09 mmol), (E)-4-methoxy-4-oxobut-2-enoic
acid chloride ((E)-8, 668 mg, 4.50 mmol) and NEt3 (662 mg, 0.91 mL, 6.54 mmol). Purification
by column chromatography on silica gel (cyclohexane:EtOAc= 20:1) gave 2a as a yellow oil
(925 mg, 3.95 mmol, 97 %). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.32; 1H NMR (400 MHz,
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CDCl3, δ): 3.87 (s, 3H), 7.08 (d, 1H, J = 15.8 Hz), 7.13 (d, 1H, J =15.8 Hz), 7.23–7.26 (m, 1H),
7.43–7.48 (m, 1H), 7.65–7.70 (m, 1H), 7.92 (dd, 1H, J = 7.7, 1.7 Hz), 10.10 (s, 1H).
2-Formyl-6-methoxyphenyl methyl fumarate (2b). Obtained according GP1 from 2-
hydroxy-4-methoxybenzaldehyde (1b, 400 mg, 2.63 mmol), (E)-4-methoxy-4-oxobut-2-enoic
acid chloride ((E)-8, 430 mg, 2.89 mmol) and NEt3 (426 mg, 0.59 mL, 4.21 mmol). Purification
by column chromatography on silica gel (cyclohexane:EtOAc 5:1) gave 2b as a colorless solid
(605 mg, 2.29 mmol, 87%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.18; Mp 122–124 °C; IR
(neat, cm–1): 1721 (C=O), 1694 (C=O). 1H NMR (300 MHz, CDCl3, δ): 3.86 (s, 3H), 3.37 (s,
3H), 7.08 (d, 1H, J = 15.8 Hz), 7.15 (d, 1H, J = 15.8 Hz), 7.22–7.26 (m, 1H), 7.34–7.41 (m,
1H), 7.46–7.50 (m, 1H), 10.11 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 52.7, 56.5, 118.0,
121.6, 127.4, 129.2, 132.1, 135.6, 140.9, 151.7, 162.7, 165.2, 188.5. HRMS-ESI (m/z) calcd
for C13H12O6 [M]+ 264.0628, found 264.0628; MS (EI, 70 eV): m/z (%) = 264 (2) [M+], 152 (15),
113 (100), 85 (19), 54 (12), 40 (41).
2-Formyl-3-methoxyphenyl methyl fumarate (2c). Obtained according GP1 from 2-
hydroxy-6-methoxybenzaldehyde (1c, 400 mg, 2.63 mmol), (E)-4-methoxy-4-oxobut-2-enoic
acid chloride ((E)-8, 430 mg, 2.89 mmol) and NEt3 (426 mg, 0.59 mL, 4.21 mmol). Purification
by column chromatography on silica gel (cyclohexane:EtOAc 5:1) gave 2c as a colorless solid
( 546 mg, 2.07 mmol, 79%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.18; IR (neat, cm-1): 1720
(C=O), 1684 (C=O). 1H NMR (400 MHz, CDCl3, δ): 3.84 (s, 3H), 3.94 (s, 3H), 6.71–6.74 (m,
1H), 6.92–6.95 (m, 1H), 7.04 (d, 1H, J = 15.8 Hz), 7.10 (d, 1H, J = 15.8 Hz), 7.53–7.58 (m,
1H), 10.40–10.41 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3, δ): 52.5, 56.4, 110.0, 115.6, 117.0,
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133.0, 135.0, 135.9, 150.0, 163.26, 163.34, 165.4, 188.1. Anal. calcd for C13H12O6: C, 59.09;
H, 4.58. Found: C, 59.08; H, 4.51.
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2-Formyl-5-methoxyphenyl methyl fumarate (2d). Obtained according GP1 from 2-
hydroxy-3-methoxybenzaldehyde (1d, 400 mg, 2.63 mmol), (E)-4-methoxy-4-oxobut-2-enoic
acid chloride ((E)-8, 430 mg, 2.89 mmol) and NEt3 (426 mg, 0.59 mL, 4.21 mmol). Purification
by column chromatography on silica gel (cyclohexane:EtOAc 5:1) gave 2d as a colorless solid
(472 mg, 1.79 mmol, 68%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.18; Mp 90–92 °C; IR (neat,
cm–1): 1723 (C=O), 1681 (C=O). 1H NMR (300 MHz, CDCl3, δ): 3.86 (s, 3H), 3.89 (s, 3H), 6.72
(d, 1H, J = 2.4 Hz), 6.93 (dd, 1H, J = 8.7, 2.4 Hz), 7.06 (d, 1H, J = 15.8 Hz), 7.12 (d, 1H, J =
15.8 Hz), 7.83 (d, 1H, J = 8.7 Hz), 9.93 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 52.7, 56.1,
108.8, 112.7, 121.5, 132.3, 133.7, 135.7, 152.6, 163.1, 165.1, 165.3, 187.3. HRMS-ESI (m/z)
calcd for C13H12O6 [M]+ 264.0628, found 264.0627; MS (EI, 70 eV): m/z (%) = 264 (1) [M+], 232
(9), 151 (19), 113 (29), 40 (100).
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2-Formyl-4-methoxyphenyl methyl fumarate (2e). Obtained according GP1 from 2-
hydroxy-5-methoxybenzaldehyde (1e, 400 mg, 2.63 mmol), (E)-4-methoxy-4-oxobut-2-enoic
acid chloride ((E)-8, 430 mg, 2.89 mmol) and NEt3 (426 mg, 0.59 mL, 4.21 mmol). Purification
by column chromatography on silica gel (cyclohexane:EtOAc 5:1). After recrystallization from
EtOH compound 2e was obtained as a light yellow solid (560 mg, 2.12 mmol, 81%). Rf (SiO2,
cyclohexane:EtOAc= 3:1)= 0.29; Mp 76–78 °C; IR (neat, cm–1): 1726 (C=O), 1693 (C=O). 1H
NMR (300 MHz, CDCl3, δ): 3.86 (s, 3H), 3.87 (s, 3H), 7.06 (d, 1H, J = 15.8 Hz), 7.12 (d, 1H, J
= 15.8 Hz), 7.13–7.21 (m, 2H), 7.36–7.38 (m, 1H), 10.07 (s, 1H). 13C{1H} NMR (75 MHz,
CDCl3, δ): 52.7, 56.0, 113.4, 122.1, 124.3, 128.4, 132.3, 135.7, 145.1, 158.0, 163.7, 165.1,
188.0. HRMS-ESI (m/z) calcd for C13H12O6Na [M+Na]+ 287.0526, found 287.0526; MS (EI, 70
eV): m/z (%) = 264 (8) [M+], 152 (37), 113 (100), 85 (13), 54 (20), 40 (32).
2-Formyl-5-methylphenyl methyl fumarate (2f). Obtained according GP1 from 2-
hydroxy-4-methylbenzaldehyde (1f, 400 mg, 2.94 mmol), (E)-4-methoxy-4-oxobut-2-enoic acid
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chloride ((E)-8, 480 mg, 3.23 mmol) and NEt3 (476 mg, 0.66 mL, 4.70 mmol). Purification by
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column chromatography on silica gel (cyclohexane:EtOAc 5:1) gave 2f as a yellow oil (2f, 625
mg, 2.52 mmol, 86%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.34; IR (neat, cm–1): 1726 (C=O),
1692 (C=O). 1H NMR (300 MHz, CDCl3, δ): 2.44 (s, 3H), 3.86 (s, 3H), 7.02–7.04 (m, 1H), 7.06
(d, 1H, J = 15.8 Hz), 7.12 (d, 1H, J = 15.8 Hz), 7.21–7.26 (m, 1H), 7.75–7.82 (m, 1H), 10.02 (s,
1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 21.9, 52.6, 123.8, 125.6, 127.9, 131.8, 132.4, 135.6,
147.3, 150.8, 163.3, 165.1, 188.2. HRMS-ESI (m/z) calcd for C13H13O5 [M+H]+ 249.0758,
found 249.0760. MS (EI, 70 eV): m/z (%) = 216 (17), 135 (21), 113 (54), 40 (100).
2-Formyl-4-methylphenyl methyl fumarate (2g). Obtained according GP1 from 4-methyl-
2-hydroxybenzaldehyde (1g, 500 mg, 3.67 mmol), (E)-4-methoxy-4-oxobut-2-enoic acid
chloride ((E)-8, 818 mg, 5.51 mmol) and NEt3 (594 mg, 0.82 mL, 5.87 mmol). Purification by
column chromatography on silica gel (cyclohexane:EtOAc 3:1) gave 2g as a yellow oil (875
mg, 3.52 mmol, 96%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.42; IR (neat, cm–1): 1724 (C=O),
1684 (C=O). 1H NMR (300 MHz, CDCl3, δ): 2.43 (s, 3H), 3.85 (s, 3H), 7.06 (d, 1H, J = 15.8
Hz), 7.11 (d, 1H, J = 15.8 Hz), 7.12 (d, 1H, J = 8.2 Hz), 7.43–7.48 (m, 1H), 7.68–7.70 (m, 1H),
10.05 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 20.9, 52.7, 123.1, 127.5, 131.8, 132.4, 135.6,
136.1, 137.0, 148.9, 163.4, 165.1, 188.7. Anal. calcd for C13H12O5: C, 62.90; H, 4.87. Found:
C, 62.91; H, 4.97. MS (EI, 70 eV): m/z (%) = 248 (1) [M+], 216 (13), 135 (26), 113 (100), 85
(17), 59 (17), 44 (11).
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4-(tert-Butyl)-2-formylphenyl methyl fumarate (2h). Obtained according GP1 from 5-tert-
butyl-2-hydroxybenzaldehyde (1h, 450 mg, 2.52 mmol), (E)-4-methoxy-4-oxobut-2-enoic acid
chloride ((E)-8, 561 mg, 3.78 mmol) and NEt3 (581 mg, 0.63 mL, 4.54 mmol). Purification by
column chromatography on silica gel (cyclohexane:EtOAc 20:1) gave 2h as a yellow oil (661
mg, 2.46 mmol, 90%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.45; IR (neat, cm–1): 1729 (C=O),
1691 (C=O). 1H NMR (300 MHz, CDCl3, δ): 1.36 (s, 9H), 3.86 (s, 3H), 7.07 (d, 1H, J = 15.8
Hz), 7.13 (d, 1H, J = 15.8 Hz), 7.16 (d, 1H, J = 8.6 Hz), 7.68 (dd, 1H, J = 8.6, 2.6 Hz), 7.90 (d,
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1H, J = 2.6 Hz), 10.09 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 31.3, 34.9, 52.7, 122.8,
127.3, 128.3, 132.4, 132.8, 135.6, 148.8, 150.3, 163.5, 165.1, 188.9. Anal. calcd for C16H18O5:
C, 66.20; H, 6.25. Found: C, 66.33; H, 6.18; MS (EI, 70 eV): m/z (%) = 290 (7) [M+], 258 (9),
177 (18), 163 (25), 113 (95), 85 (11), 40 (100).
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5-(Diethylamino)-2-formylphenyl methyl fumarate (2i). Obtained according GP1 from 4-
diethylamino-2-hydroxybenzaldehyde (1i. 500 mg, 2.59 mmol), (E)-4-methoxy-4-oxobut-2-
enoic acid chloride ((E)-8, 576 mg, 3.88 mmol) and NEt3 (459 mg, 0.58 mL, 4.14 mmol).
Purification by column chromatography on silica gel (cyclohexane:EtOAc 3:1) gave 2i as a
green oil (580 mg, 1.90 mmol, 73%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.21; IR (neat, cm–
1): 1762 (C=O), 1711 (C=O). 1H NMR (300 MHz, CDCl3, δ): 1.21 (t, 6H, J = 7.2 Hz), 3.42 (q,
4H, J = 7.2 Hz), 3.85 (s, 3H), 6.31 (d, 1H, J = 2.5 Hz), 6.57 (dd, 1H, J = 8.9, 2.5 Hz), 7.06 (d,
1H, J = 15.8 Hz), 7.12 (d, 1H, J = 15.8 Hz), 7.66 (d, 1H, J = 8.9 Hz), 9.73 (s, 1H). 13C{1H}
NMR (75 MHz, CDCl3, δ): 12.6, 45.0, 52.6, 104.3, 108.9, 116.0, 132.9, 134.3, 135.1, 153.1,
153.2, 163.4, 165.3, 186.4. Anal. calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C,
62.94; H, 6.28; N, 4.73. MS (EI, 70 eV): m/z (%) = 305 (24) [M+], 290 (52), 281 (24), 193 (16),
178 (76), 150 (13), 113 (12), 73 (21), 44 (100).
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2-Formylnaphthalen-1-yl methyl fumarate (2j). Obtained according GP1 from 1-hydroxy-
2-naphthylaldehyde (1j, 400 mg, 2.32 mmol), (E)-4-methoxy-4-oxobut-2-enoic acid chloride
((E)-8, 520 mg, 3.48 mmol) and NEt3 (376 mg, 0.52 mL, 3.71 mmol). Purification by column
chromatography on silica gel (cyclohexane:EtOAc 20:1). After recrystallization from EtOH
compound 2j was obtained as a colorless solid (400 mg, 1.41 mmol, 61%). Rf (SiO2,
cyclohexane:EtOAc= 3:1)= 0.37; Mp 113–115 °C; IR (neat, cm–1): 1719 (C=O), 1675 (C=O).
1H NMR (300 MHz, CDCl3, δ): 3.90 (s, 3H), 7.22 (d, 1H, J = 15.8 Hz), 7.30 (d, 1H, J = 15.8
Hz), 7.50–7.71 (m, 2H), 7.85–7.97 (m, 4H), 10.25 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ):
52.8, 122.6, 124.1, 124.3, 126.7, 127.2, 127.9, 128.5, 129.8, 131.8, 136.4, 137.6, 149.6,
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163.4, 165.0, 188.4. Anal. calcd for C16H12O5: C, 67.60; H, 4.26. Found: C, 67.55; H, 4.04; MS
(EI, 70 eV): m/z (%) = 284 (2) [M+], 172 (13), 113 (57), 40 (100).
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5-Chloro-2-formylphenyl methyl fumarate (2k). Obtained according GP1 from 4-chloro-
2-hydroxybenzaldehyde (1k, 400 mg, 2.55 mmol), (E)-4-methoxy-4-oxobut-2-enoic acid
chloride ((E)-8, 568 mg, 3.83 mmol) and NEt3 (476 mg, 0.57 mL, 4.08 mmol). Purification by
column chromatography on silica gel (cyclohexane:EtOAc 5:1) gave 2k as a colorless solid (,
474 mg, 1.91 mmol, 69%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.42; Mp 91–93 °C; IR (neat,
cm–1): 1715 (C=O), 1695 (C=O). 1H NMR (300 MHz, CDCl3, δ): 3.87 (s, 3H), 7.07–7.11 (m,
2H), 7.30 (d, 1H, J = 1.9 Hz), 7.43 (dd, 1H J = 8.3, 1.9 Hz), 7.85 (d, 1H, J=8.3 Hz), 10.05 (s,
1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 52.8, 124.0, 126.5, 127.5, 131.8, 132.4, 136.3, 141.4,
151.3, 162.8, 164.9, 187.3. Anal. calcd for C12H9ClO5: C, 53.65; H, 3.38. Found: C, 54.10; H,
3.01; MS (EI, 70 eV): m/z (%) = 191 (4), 119 (39), 44 (100).
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4-Chloro-2-formylphenyl methyl fumarate (2l). Obtained according GP1 from 5-chloro-2-
hydroxybenzaldehyde (1l, 500 mg, 3.19 mmol), (E)-4-methoxy-4-oxobut-2-enoic acid chloride
((E)-8, 712 mg, 4.79 mmol) and NEt3 (581 mg, 0.80 mL, 5.74 mmol). Purification by column
chromatography on silica gel (cyclohexane:EtOAc 5:1) was followed by recrystallization from
EtOH to afford 2l as a colorless solid (551 mg, 2.06 mmol, 64%). Rf (SiO2,
cyclohexane:EtOAc= 3:1)= 0.37; Mp 79–81 °C IR (neat, cm–1): 1720 (C=O), 1682 (C=O). 1H
NMR (300 MHz, CDCl3, δ): 3.86 (s, 3H), 7.07–7.12 (m, 2H), 7.22 (d, 1H, J = 8.7 Hz), 7.61 (dd,
1H, J = 8.7, 2.6 Hz), 7.87 (d, 1H, J = 2.6 Hz), 10.05 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ):
52.8, 124.9, 128.9, 130.8, 131.8, 132.9, 135.3, 136.2, 149.5, 163.0, 165.0, 187.0. Anal. calcd
for C12H9ClO5: C, 53.65; H, 3.38. Found: C, 53.51; H, 3.42. ; MS (EI, 70 eV): m/z (%) = 268 (1)
[M+], 155 (16), 113 (100), 85 (18), 44 (42).
2-Formyl-4-(methoxycarbonyl)phenyl methyl fumarate (2m). Obtained according GP1
from methyl-3-formyl-4-hydroxybenzoate (1m, 400 mg, 2.22 mmol), (E)-4-methoxy-4-oxobut-2-
enoic acid chloride ((E)-8, 494 mg, 3.33 mmol) and NEt3 (0.359 g, 0.50 mL, 3.55 mmol) as a
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light brown solid (2m, 646 mg, 2.21 mmol, 99%). Mp 118–120 °C; IR (neat, cm–1): 1719
(C=O), 1686 (C=O). 1H NMR (300 MHz, CDCl3, δ): 3.86 (s, 3H), 3.96 (s, 3H), 7.05–7.16 (m,
2H), 7.35 (d, 1H, J = 8.5 Hz), 8.32 (dd, 1H, J = 8.5, 2.2 Hz), 8.57 (d, 1H, J = 2.2 Hz), 10.11 (s,
1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 52.7, 52.8, 123.8, 127.9, 129.2, 131.9, 133.5, 136.2,
136.4, 153.9, 162.7, 165.0, 165.3, 187.8. Anal. calcd for C14H12O7: C, 57.54; H, 4.14. Found:
C, 57.55; H, 4.07. MS (EI, 70 eV): m/z (%) = 260 (15), 180 (25), 149 (34), 113 (100), 85 (18),
59 (13), 44 (91).
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General procedure 2 (GP2) for the synthesis of benzoxepinones 3ab,d–m.
Fumarate derivative 2a-m (1 equiv) was dissolved in anhydrous toluene (2 mL·mmol–1). 3-
Methyl-1-phenyl-2-phospholen 1-oxide (5, 0.05 equiv.), benzoic acid (0.05 equiv) and
(MeO)3SiH (3 equiv) were added under argon. The mixture was heated to 100 °C and stirred
for 16 h. After cooling to 23 °C all volatiles were removed. The product was purified by column
chromatography on silica gel (cyclohexane:EtOAc).
Methyl 2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3a).35 Obtained according to
GP2 from 2a (300 mg, 1.28 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 12 mg, 0.064
mmol), benzoic acid (8 mg, 0.06 mmol) and (MeO)3SiH (469 mg, 0.48 mL, 3.74 mmol) as a
colorless solid (101 mg, 0.463 mmol, 36%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.34; Mp 91–
93 °C; 1H NMR (400 MHz, CDCl3, δ): 3.44 (s, 2H), 3.88 (s, 3H), 7.26–7.31 (m, 2H), 7.41–7.51
(m, 2H), 7.87 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3, δ): 33.4, 52.9, 121.6, 125.0, 125.2,
125.8, 131.1, 131.5, 137.8, 150.9, 165.1, 167.8; MS (EI, 70 eV): m/z (%) = 218 (100) [M+], 186
(44), 175 (42), 158 (26), 147 (34), 131 (87), 115 (17), 102 (35), 77 (49), 63 (15), 51 (20).
Methyl 9-methoxy-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3b). Obtained
according GP2 from 2b (160 mg, 0.606 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 6
mg, 0.03 mmol), benzoic acid (4 mg, 0.03 mmol) and (MeO)3SiH (222 mg, 0.23 mL, 1.82
mmol) as a colorless solid (0.044 g, 0.178 mmol, 29%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.21; Mp 103–105 °C; IR (neat, cm–1): 1761 (C=O), 1702 (C=O). 1H NMR (300 MHz, CDCl3,
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δ): 3.44 (s, 2H), 3.87 (s, 3H), 3.91 (s, 3H), 6.96–7.00 (m, 1H), 7.02–7.07 (m, 1H), 7.18–7.24
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(m, 1H), 7.86 (s. 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 33.6, 52.9, 56.3, 113.4, 121.9, 125.1,
125.3, 125.5, 127.0, 137.8, 150.9, 165.1, 167.8. HRMS-ESI (m/z) calcd for C13H12O5Na
[M+Na]+ 271.0577, found 271.0579; MS (EI, 70 eV): m/z (%) = 248 (100) [M+], 233 (35), 216
(22), 205 (22), 188 (23), 161 (55), 146 (15), 118 (27), 89 (19), 40 (78).
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Methyl 8-methoxy-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3d). Obtained
according to GP2 from 2d (200 mg, 0.757 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5,
7 mg, 0.04 mmol), benzoic acid (5 mg, 0.04 mmol) and (MeO)3SiH (278 mg, 0.29 mL, 2.27
mmol) as a colorless solid (83 mg, 334 mmol, 44%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.27;
Mp 121–123 °C; IR (neat, cm–1): 1749 (C=O), 1699 (C=O). 1H NMR (400 MHz, CDCl3, δ): 3.43
(s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.78 (d, 1H, J = 2.5 Hz), 6.85 (dd, 1H, J = 8.7, 2.5 Hz), 7.32
(d, 1H, J = 8.7 Hz), 7.82 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, δ): 33.4, 52.7, 55.9, 105.8,
112.7, 118.5, 122.3, 132.1, 137.9, 152.2, 162.3, 165.4, 167.3. Anal. calcd for C13H12O5: C,
62.90; H, 4.87. Found: C, 62.86; H, 4.50; MS (EI, 70 eV): m/z (%) = 248 (100) [M+], 217 (23),
205 (87), 189 (28), 161 (66), 146 (12), 118 (31), 89 (21), 40 (38).
Methyl 7-methoxy-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3e). Obtained
according GP2 from 2e (300 mg, 1.14 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 11
mg, 0.06 mmol), benzoic acid (7 mg, 0.06 mmol) and (MeO)3SiH (416 mg, 0.43 mL, 3.41
mmol) as a colorless solid (98 mg, 0.40 mmol, 35%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.29; Mp 85–87 °C; IR (neat, cm–1): 1766 (C=O), 1708 (C=O). 1H NMR (300 MHz, CDCl3, δ):
3.43 (s, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.85 (d, 1H, J = 3.1 Hz), 7.01 (dd, 1H, J = 9.0, 3.1 Hz),
7.20 (d, 1H, J = 9.20 Hz), 7.82 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 33.3, 52.9, 55.9,
113.8, 118.1, 122.7, 125.3, 126.5, 137.7, 145.1, 156.3, 165.1, 168.2. HRMS-ESI (m/z) calcd
for C13H12O5Na [M+Na]+ 271.0577, found 271.0579; MS (EI, 70 eV): m/z (%) = 248 (44) [M+],
216 (90), 205 (63), 189 (20), 161 (100), 146 (12), 118 (46), 89 (29), 63 (15), 40 (43).
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The Journal of Organic Chemistry
Methyl 8-methyl-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3f). Obtained
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according GP2 from 2f (300 mg, 1.21 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 12
mg, 0.06 mmol), benzoic acid (7 mg, 0.06 mmol) and (MeO)3SiH (444 mg, 0.46 mL, 3.63
mmol) as a colorless solid (101 mg, 435 mmol, 36%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.32; Mp 130–132 °C; IR (neat, cm–1): 1758 (C=O), 1699 (C=O). 1H NMR (400 MHz, CDCl3,
δ): 2.42 (s, 3H), 3.42 (s, 2H), 3.87 (s, 3H), 7.07–7.11 (m, 2H), 7.28–7.31 (m, 1H), 7.84 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3, δ): 21.5, 33.4, 52.8, 121.8, 123.0, 124.0, 126.3, 130.9, 138.0,
142.6, 150.8, 165.3, 167.7. Anal. calcd for C13H12O4: C, 67.23; H, 5.21. Found: C, 67.43; H,
4.95; MS (EI, 70 eV): m/z (%) = 232 (100) [M+], 201 (28), 189 (36), 173 (22), 161 (12), 145
(65), 128 (11), 115 (44), 91 (13), 40 (82).
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Methyl 7-methyl-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3g). Obtained
according GP2 from 2g (300 mg, 1.21 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 12
mg, 0.06 mmol), benzoic acid (7 mg, 0.06 mmol) and (MeO)3SiH (444 mg, 0.46 mL, 3.63
mmol) as a colorless solid (112 mg, 482 mmol, 40%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.39; Mp 108–110 °C; IR (neat, cm–1): 1756 (C=O), 1712 (C=O). 1H NMR (300 MHz, CDCl3,
δ): 2.38 (s, 3H), 3.42 (s, 2H), 3.87 (s, 3H), 7.16 (d, 1H, J = 8.5 Hz), 7.19–7.21 (m, 1H), 7.25–
7.29 (m, 1H), 7.82 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 20.7, 33.4, 52.8, 121.3, 124.8,
125.4, 131.0, 132.4, 135.0, 138.1, 149.0, 165.2, 168.0. Anal. calcd for C13H12O4: C, 67.23; H,
5.21. Found: C, 67.51; H, 5.08; MS (EI, 70 eV): m/z (%) = 232 (86) [M+], 200 (87), 189 (53),
173 (34), 161 (22), 145 (100), 128 (11), 115 (79), 91 (29), 77 (15), 63 (15), 51 (14).
Methyl 7-(tert-butyl)-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3h). Obtained
according GP2 from 2h (300 mg, 1.03 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 10
mg, 0.05 mmol), benzoic acid (6 mg, 0.05 mmol) and (MeO)3SiH (378 mg, 0.39 mL, 3.09
mmol) as a colorless solid (96 mg, 0.35 mmol, 34%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.45; Mp 78–80 °C; IR (neat, cm–1): 1762 (C=O), 1711 (C=O). 1H NMR (300 MHz, CDCl3, δ):
1.34 (s, 9H), 3.44 (s, 2H), 3.88 (s, 3H), 7.20 (d, 1H, J = 8.6 Hz), 7.38 (d, 1H, J = 2.5 Hz), 7.50
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(dd, 1H, J = 8.6, 2.5 Hz), 7.88 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 31.4, 33.4, 34.6,
52.8, 121.1, 124.6, 125.1, 127.6, 129.0, 138.4, 148.3, 148.9, 165.3, 168.1. Anal. calcd for
C16H18O4: C, 70.06; H, 6.61. Found: C, 70.22; H, 6.47; MS (EI, 70 eV): m/z (%) = 274 (55)
[M+], 259 (63), 242 (87), 231 (100), 199 (30), 187 (16), 171 (26), 157 (21), 128 (30), 115 (21),
77 (12).
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N,N-Diethyl-4-(methoxycarbonyl)-2-oxo-2,3-dihydrobenzo[b]oxepin-8-aminium chloride
(3i). Obtained according GP2 from 2i (300 mg, 0.983 mmol), 3-methyl-1-phenyl-2-phospholen
1-oxide (5, 9 mg, 0.05 mmol), benzoic acid (6 mg, 0.05 mmol) and (MeO)3SiH (360 mg, 0.38
mL, 2.95 mmol) as a yellow oil (98 mg, 0.34 mmol). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.37.
The crude was dissolved in Et2O (1.5 mL) and 2M HCl solution in Et2O (0.20 mL, 0.406 mmol)
was added. Precipitates were collected by filtration yielding 3i as a colorless solid (85 mg, 294
mmol, 27%). Mp 161–163 °C; IR (neat, cm–1): 1763 (C=O), 1703 (C=O). 1H NMR (300 MHz,
CDCl3, δ): 1.28 (t, 6H, J = 7.2 Hz), 3.47 (s, 2H), 3.52 (q, 4H, J = 7.2 Hz), 3.88 (s, 3H), 7.45–
7.50 (m, 1H), 7.54 (d, 1H, J=8.5 Hz), 7.67–7.75 (m, 1H), 7.85 (s, 1H). 13C{1H} NMR (75 MHz,
CDCl3, δ): 10.8, 33.5, 52.3, 53.0, 100.1, 104.6, 113.8, 118.9, 125.6, 132.9, 136.4, 151.6,
164.8, 166.3. HRMS-ESI (m/z) calcd for C16H20NO4 [M]+ 290.1397, found 290.1394. MS (EI,
70 eV): m/z (%) = 289 (60), 274 (81), 246 (100), 207 (66), 186 (13), 158 (41), 133 (9), 73 (13),
44 (74).
Methyl 2-oxo-2,3-dihydronaphtho[1,2-b]oxepine-4-carboxylate (3j). Obtained according
GP2 from 3j (300 mg, 1.06 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 10 mg, 0.05
mmol), benzoic acid (6 mg, 0.05 mmol) and (MeO)3SiH (389 mg, 0.40 mL, 3.18 mmol) as a
yellow solid (122 mg, 0.455 mmol, 43%). Rf (SiO2, cyclohexane:EtOAc= 3:1)= 0.39; Mp 156–
158 °C; IR (neat, cm–1): 1756 (C=O), 1692 (C=O). 1H NMR (300 MHz, CDCl3, δ): 3.49 (s, 2H),
3.91 (s, 3H), 7.45 (d, 1H, J = 8.5 Hz), 7.59–7.66 (m, 2H), 7.71 (d, 1H, J = 8.5 Hz), 7.84–7.91
(m, 1H), 7.99 (s, 1H), 8.36–8.43 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ): 34.0, 52.9, 121.3,
123.0, 125.0, 125.1, 126.4, 126.5, 127.5, 127.8, 128.4, 135.0, 138.1, 147.0, 165.1, 167.5.
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The Journal of Organic Chemistry
HRMS-ESI (m/z) calcd for C16H12O4Na [M+Na]+ 291.0628, found 291.0628; MS (EI, 70 eV):
m/z (%) = 268 (84) [M+], 236 (31), 225 (10), 209 (45), 181 (100), 152 (71), 127 (11), 91 (13),
76 (14), 40 (80).
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Methyl 8-chloro-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3k). Obtained
according GP2 from 2k (300 mg, 1.12 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5, 11
mg, 0.056 mmol), benzoic acid (7 mg, 0.056 mmol) and (MeO)3SiH (411 mg, 0.43 mL, 3.36
mmol) as a colorless solid (91 mg, 0.36 mmol, 32%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.32; Mp 116–118 °C; IR (neat, cm–1): 1767 (C=O), 1703 (C=O). 1H NMR (400 MHz, CDCl3,
δ): 3.44 (s, 2H), 3.88 (s, 3H), 7.26–7.29 (m, 1H), 7.29–7.31 (m, 1H), 7.35–7.38 (m, 1H), 7.83
(s, 1H). 13C{1H} NMR (100 MHz, CDCl3, δ): 33.4, 53.0, 121.9, 124.3, 125.2, 125.7, 131.9,
136.9, 137.1, 151.0, 164.9, 166.8. Anal. calcd for C12H9ClO4: C, 57.05; H, 3.59. Found: C,
57.09; H, 3.61; MS (EI, 70 eV): m/z (%) = 252 (19) [M+], 220 (13), 209 (10), 193 (6), 165 (19),
102 (8), 75 (6), 40 (100).
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Methyl 7-chloro-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3l). Obtained
according to GP2 from 2l (300 mg, 1.12 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5,
11 mg, 0.056 mmol), benzoic acid (7 mg, 0.06 mmol) and (MeO)3SiH (411 mg, 0.43 mL, 3.36
mmol) as a colorless solid (118 mg, 0.467 mmol, 42%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.37; Mp 110–112 °C; IR (neat, cm–1): 1768 (C=O), 1706 (C=O). 1H NMR (300 MHz, CDCl3,
δ): 3.44 (s, 2H), 3.89 (s, 3H), 7.20–7.25 (m, 1H), 7.39–7.45 (m, 2H), 7.79 (s, 1H). 13C{1H}
NMR (75 MHz, CDCl3, δ): 33.4, 53.0, 123.1, 126.2, 127.1, 130.3, 130.6, 131.4, 136.5, 149.3,
164.8, 167.1. HRMS-ESI (m/z) calcd for C12H10ClO4 [M+H]+ 253.0262, found 253.0262; MS
(EI, 70 eV): m/z (%) = 252 (14) [M+], 220 (25), 209 (12), 193 (7), 180 (6), 165 (21), 102 (12),
40 (100).
Dimethyl 2-oxo-2,3-dihydrobenzo[b]oxepine-4,7-dicarboxylate (3m). Obtained
according to GP2 from 2m (300 mg, 1.03 mmol), 3-methyl-1-phenyl-2-phospholen 1-oxide (5,
10 mg, 0.05 mmol), benzoic acid (6 mg, 0.05 mmol) and (MeO)3SiH (378 mg, 0.39 mL, 3.09
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mmol) as a colorless solid (87 mg, 0.315 mmol, 31%). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.24; Mp 134–136 °C; IR (neat, cm–1): 1774 (C=O), 1721 (C=O), 1705 (C=O). 1H NMR (300
MHz, CDCl3, δ): 3.46 (s, 2H), 3.89 (s, 3H), 3.94 (s, 3H), 7.33 (d, 1H, J = 8.5 Hz), 7.90 (s, 1H),
8.10-8.16 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 33.5, 52.7, 53.0, 122.0, 125.6, 125.8,
127.3, 132.4, 133.1, 137.1, 153.7, 164.8, 165.6, 166.6. Anal. calcd for C14H12O6: C, 60.87; H,
4.38. Found: C, 61.06; H, 4.08; MS (EI, 70 eV): m/z (%) = 276 (63) [M+], 244 (100), 233 (41),
216 (62), 205 (21), 189 (83), 157 (18), 130 (47), 102 (29), 76 (21), 59 (22), 44 (30).
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Methyl 2-(2-oxo-2H-chromen-3-yl)acetate (4).43 To a solution of compound 2a (500 mg,
2.13 mmol) in dry toluene (3 mL) PBu3 (432 mg, 2.13 mmol, 0.53 mL) was added. The solution
was stirred at room temperature under argon for 22 h. Volatiles were evaporated. The crude
was purified by column chromatography on silica gel (cyclohexane:EtOAc 20:1) yielded
coumarin 4 as a white solid (91 mg, 0.417 mmol, 20 %). Rf (SiO2, cyclohexane:EtOAc= 3:1)=
0.22; 1H NMR (400 MHz, CDCl3, δ): 3.61 (s, 2H), 3.75 (s, 3H), 7.26–7.31 (m, 1H), 7.32–7.36
(m, 1H), 7.46–7.54 (m, 2H, 7.69 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, δ): 35.9, 52.5, 116.7,
119.2, 122.6, 124.6, 127.8, 131.5, 141.7, 153.6, 161.4, 170.6.
Synthesis of compounds for Control Experiments (Scheme 3).
Synthesis of 2-Formylphenyl methyl maleate (Z-2a).42
(Z)-4-Methoxy-4-oxobut-2-enoic acid chloride ((Z)-8). To a solution of (Z)-4-methoxy-4-
oxobut-2-enoic acid ((Z)-7, 1.00 g, 7.69 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added DMF
(0.10 mL). The mixture was cooled to 0 °C and thionyl chloride (1.08 g, 0.66 mL, 9.11 mmol,
1.2 equiv) was added dropwise. The resulting mixture was refluxed for 10 min. The solvent
was distilled off and the obtained product (Z)-8 was used without further purification
2-Formylphenyl methyl maleate (Z-2a).42 Obtained according to GP1 from aldehyde 1a
(909 mg, 0.80 mL, 7.44 mmol, 1 equiv), acid chloride ((Z)-8, 1.14 g, 7.69 mmol, 1.0 equiv) and
NEt3 (1.24 g, 1.70 mL, 12.3 mmol, 1.6 equiv). Purification by column chromatography on silica
gel (cyclohexane:EtOAc= 20:1) gave Z-2a as a yellow oil (408 mg, 1.64 mmol, 21%). Rf (SiO2,
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cyclohexane:EtOAc= 5:1)= 0.35; 1H NMR (300 MHz, CDCl3, δ): 3.81 (s, 3H), 6.44 (d, J = 12.0
Hz, 1H), 6.58 (d, J= 12.0 Hz, 1H), 7.32–7.47 (m, 2H), 7.62–7.72 (m, 1H), 7.88–7.96 (m, 1H),
10.2 (s, 1H) ppm.
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(1.00 equiv, 1.00 g, 10.2 mmol) was melted in a Schlenk flask at 70 °C under argon. MeOH
(1.00 equiv, 326 mg, 0.413 mL, 10.2 mmol) was added and the mixture was allowed to stir for
16 h at 23 °C. The reaction mixture was heated to 80 °C and AlCl3 (0.04 equiv, 54.4 mg,
0.408 mmol) was added. After 10 min most of the mixture solidified and was heated for
additional 2 h. The colorless solid was then cooled down to 23 °C. 1 M HCl (25 mL) was added
and the resulting mixture was extracted with EtOAc (340 mL). The organic phase was
washed with water (40 mL) and saturated NaCl solution (40 mL) and dried with Na2SO4. After
removal of all volatiles in vacuo the crude product was purified by column chromatography on
silica gel (cyclohexane:EtOAc 5:1 + 1% HOAc). Fractions of different E/Z ratios were collected
and recrystallized from water to yield (E)-4-methoxy-4-oxobut-2-enoic-2,3-d2 acid (15) as
colorless crystals (60%, 808 mg, 6.12 mmol, E/Z >99:1). Rf (SiO2, cyclohexane:EtOAc:HOAc=
1:2:0.01) = 0.28; 1H NMR (300 MHz, CDCl3, δ): 3.83 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3, δ): 52.5, 165, 170 ppm. Other signals could not be identified; IR (ATR): ṽ= 2960 (br),
2647 (br), 2543 (br), 2280 (s), 1716 (s), 1672 (s), 1611 (m), 1437 (m), 1423 (m), 1283 (s),
1248 (s), 1058 (w), 1030(m), 911.7 (s), 856.6 (w), 786.7 (s), 722.8 (m), 652.9 (w), 642.8 (m),
536.9 (w), 403.8 (m) cm–1; MS (EI, 70 eV)): m/z (%):132 (0.9) [M+], 115 (5), 101 (100), 87 (60),
45 (86); HRMS (EI): m/z calcd for C5H4D2O4 [M]+ 132.0392, found: 132.0389.
Acid 15 (1.10 g, 8.33 mmol, 1.0 equiv) was dissolved in CH2Cl2 (30 mL). After DMF
(0.15 mL) was added the mixture was cooled to 0 °C and thionyl chloride (1.15 g, 0.70 mL,
9.66 mmol, 1.2 equiv) was added dropwise. The resulting mixture was refluxed for 3 h. The
solvent was distilled off and the obtained acid chloride 16 was used without further purification.
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2-Formylphenyl methyl fumarate-d2 (2a-D2). Obtained according GP1 from aldehyde 1a
(909 mg, 0.80 mL, 7.44 mmol, 1 equiv), acid chloride 16 (1.25 g, 8.33 mmol, 1.1 equiv) and
NEt3 (1.24 g, 1.70 mL, 12.3 mmol, 1.7 equiv). Purification by column chromatography on silica
gel (cyclohexane:EtOAc= 20:1) gave the product 2a-D2 as a yellow oil (1.23 g, 5.21 mmol,
70%). Rf (SiO2, cyclohexane:EtOAc= 5:1)= 0.41; IR (neat, cm–1): 1724 (C=O), 1695 (C=O). 1H
NMR (300 MHz, CDCl3, δ): 3.82 (s, 3H), 7.19–7.23 (m, 1H), 7.39–7.44 (m, 1H), 7.60–7.66 (m,
1H), 7.85–7.90 (m, 1H), 10.1 (s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3, δ): 52.4, 123.1,
126.7, 127.6, 131.4, 135.3, 150.6, 162.9, 164.8, 188.3 ppm. Other signals could not be
identified; MS (EI, 70 eV)): m/z (%):236 (0.9) [M+], 149 (7), 121 (35), 115 (100); HRMS-ESI
(m/z) calcd for C12H8D2O5 [M]+ 236.0648 found: 236.0649.
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Synthesis of 1-(2-formylphenyl) 4-methyl 2-methylfumarate (11).
(E)-4-methoxy-2-methyl-4-oxobut-2-enoic acid chloride (10). Trimethyl
phosphonoacetate (3.00 g, 16.5 mmol, 1.0 equiv), DBU (3.67 g, 3.60 mL, 24.1 mmol, 1.5
equiv) and LiCl (1.20 g, 28.3 mmol, 1.7 equiv) were dissolved in anhydrous DMSO (45 mL)
and stirred under argon at room temperature for 15 min. Subsequently, sodium pyruvate (1.80
g, 16.4 mmol, 1.0 equiv) was added portion wise to the solution. The resulting mixture was
heated to 100 °C under an argon atmosphere for 16 h. The solution was allowed to cool to
room temperature, quenched with 20 mL of 1 M HCl and extracted with EtOAc (3  40 mL).
The organic phase was dried with Na2SO4, all volatiles were removed in vacuo. After
purification by column chromatography on silica gel (cyclohexane:EtOAc:AcOH= 5:1:0.01).
The resulting mixture of endo and exo-alkene product (mesaconic acid and itaconic acids,
respectively) was recrystallized from pentane to yield (E)-4-methoxy-2-methyl-4-oxobut-2-
enoic acid (9) as colorless crystals (838 mg, 5.81 mmol, 35%). Rf (SiO2,
cyclohexane:EtOAc:HOAc= 1:2:0.01) = 0.77; 1H NMR (300 MHz, CDCl3, δ): 2.25 (d, J= 1.6
Hz, 3H), 3.75 (s, 3H), 6.86 (m, 1H), 12.0 (br, 1H) ppm.
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To a solution of the acid 9 (440 mg, 3.06 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added
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DMF (0.10 mL). The mixture was cooled to 0 °C and thionyl chloride (575 mg, 0.35 mL, 4.83
mmol, 1.6 equiv) was added dropwise. The resulting mixture was refluxed for 3 h. The solvent
was distilled off and the obtained product 10 was used without further purification.
1-(2-Formylphenyl) 4-methyl 2-methylfumarate (11). Obtained according to the GP1
from aldehyde 1a (454 mg, 0.40 mL, 3.72 mmol, 1.2 equiv), crude acid chloride 10 (498 mg,
3.06 mmol, 1.0 equiv) and NEt3 (802 mg, 1.10 mL, 7.96 mmol, 2.6 equiv). Purification by
column chromatography on silica gel (cyclohexane:EtOAc= 20:1) gave the product 11 as a
yellow oil (320 mg, 1.30 mmol, 42%). Rf (SiO2, cyclohexane:EtOAc= 5:1)= 0.41; IR (neat, cm–
1): 1720 (C=O), 1694 (C=O). 1H NMR (300 MHz, CDCl3, δ): 2.39 (d, J= 1.6 Hz, CH3, 3H), 3.75
(s, OCH3, 3H), 7.00 (q, J= 1.5 Hz, 1H), 7.15–7.19 (m, 1H), 7.35–7.39 (m, 1H), 7.57–7.63 (m,
1H), 7.82–7.86 (m, 1H), 10.0 (s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3, δ): 14.2, 51.6,
123.1, 126., 127.7, 128.2, 131.5, 135.3, 151.0, 165.3, 165.7, 188.3 ppm; MS (EI, 70 eV)): m/z
(%):248 (0.6) [M+], 217 (6), 161 (5), 145 (3), 127 (100), 121 (35), 99 (66); HRMS-ESI (m/z)
calcd for C13H12O5 [M]+ 248.0679 found: 248.0680.
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Synthesis of 4-(2-formylphenyl) 1-methyl 2-methylfumarate (14)
(E)-4-methoxy-3-methyl-4-oxobut-2-enoic acid chloride (13). Methyl pyruvate (512 mg,
5.02 mmol, 1 equiv) was dissolved in CHCl3 (10 mL) and tert-butyl 2-(triphenyl-γ5-
phosphaneylidene)acetate (2.61 g, 6.93 mmol, 1.4 equiv) was added. The reaction mixture
was heated to reflux overnight under Ar, then filtered through silica, (CH2Cl2 as eluent) and
then concentrated in vacuo. The residue was dissolved in TFA/ CH2Cl2 (1:2, 5 mL) and stirred
at 23 °C for 24 h. Afterwards, all volatiles were removed and the crude product was purified by
column chromatography on silica gel (cyclohexane:EtOAc= 5:1 with 1% AcOH) to yield E-4-
methoxy-3-methyl-4-oxobut-2-enoic acid (12) as a colorless solid (550 mg, 3.82 mmol, 76%).
Rf (SiO2, cyclohexane:EtOAc:HOAc= 1:1:0.01) = 0.67; 1H NMR (300 MHz, CDCl3, δ): 2.32 (d,
J= 1.6 Hz, 3H), 3.82 (s, 3H), 6.80 (q, J= 1.6 Hz, 1H), 11.7 (br, 1H) ppm.
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To a solution of acid 12 (315 mg, 2.19 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added
DMF (0.10 mL). The mixture was cooled to 0 °C and thionyl chloride (312 mg, 0.19 mL, 2.62
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mmol, 1.2 equiv) was added dropwise. The resulting mixture was refluxed for 3 h. The solvent
was distilled off and the obtained product 13 was used without further purification.
4-(2-Formylphenyl) 1-methyl 2-methylfumarate (14). To a solution of potassium 2-
formylphenolate (1.05 g, 6.57 mmol, 3.0 equiv; prepared from KOH and aldehyde 1a in MeOH)
in DCM (25 mL) was dropwise added a solution of crude acid chloride (13) in CH2Cl2 (25 mL)
at 0 °C and stirred for 15 min at 0 °C. The reaction was then allowed to warm to room
temperature and stirred for 90 min. The mixture was quenched with H2O (2  2.5 mL·mmol–1)
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and washed with saturated aqueous KHCO3 solution (2  2.5 mL·mmol–1). The organic layer
was dried over Na2SO4, and the volatiles were removed under vacuum. Purification by column
chromatography on silica gel (cyclohexane:EtOAc= 20:1) gave the product 14 as a yellow oil
(90 mg, 0.36 mmol, 17%). Rf (SiO2, cyclohexane:EtOAc= 5:1)= 0.41; IR (neat, cm–1): 1717
(C=O), 1694 (C=O). 1H NMR (300 MHz, CDCl3, δ): 2.38 (d, J= 1.6 Hz, 3H), 3.86 (s, 3H), 7.00
(q, J= 1.5 Hz, 1H), 7.20–7.25 (m, 1H), 7.39–7.46 (m, 1H), 7.62–7.69 (m, 1H), 7.88–7.93 (m,
1H), 10.1 (s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3, δ): 14.6, 52.8, 123.1, 124.9, 126.6,
127.9, 131.0, 135.3, 147.2, 151.1, 163.9, 167.1, 188.5 ppm; MS (EI, 70 eV)): m/z (%):248 (0.5)
[M+], 216 (3), 161 (4), 127 (100), 121 (14), 99 (18), 39 (81); HRMS-ESI (m/z) calcd for
C13H12O5 [M]+ 248.0679 found: 248.0682.
Associated Content
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.XXXXXX.
Details of the control experiments and metabolic activity tests, 1H and 13C NMR spectra (PDF);
X-ray crystallographic data for benzoxepinone 3a (CIF).
AUTHOR INFORMATION
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Corresponding Author
*E-mail: thomas.werner@catalysis.de
ORCID
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Thomas Werner: 0000-0001-9025-3244
Aiga Grandane: 0000-0002-9563-131X
Edgars Suna: 0000-0002-3078-0576
Notes
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The authors declare no competing financial interest.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
ACKNOWLEDGMENT
We gratefully acknowledge European Regional Development Fund (ERDF, project No.
1.1.1.2/VIAA/1/16/235) for funding. This research project is part of the Leibniz Science
Campus Phosphorus Research Rostock and is co-funded by the funding line strategic
networks of the Leibniz Association.
REFERENCES
1.
Derivate. Liebigs Ann. Chem. 1953, 580, 44–57.
2. Wittig, G.; Schöllkopf, U., Über Triphenyl-phosphin-methylene als olefinbildende
Reagenzien. Chem. Ber. 1954, 87, 1318–1330.
Wittig, G.; Geissler, G., Zur Reaktionsweise des Pentaphenyl-phosphors und einiger
3.
Edmonds, M.; Abell, A., Modern Carbony Olefination. Wiley-VCH: Weinheim, 2004; p
1–17.
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4.
Edmonds, M.; Abell, A., Organophosphorus Reagents. Oxford University Press: Oxford,
1
2
3
2004; p 99–127.
4
5
6
7
5.
6.
Kolodiazhnyi, O., Phosphorus Ylides. Wiley-VCH: Weinheim, 2007; p 359–538.
van Kalkeren, H. A.; Blom, A. L.; Rutjes, F. P. J. T.; Huijbregts, M. A. J., On the
8
9
usefulness of life cycle assessment in early chemical methodology development: the case of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
organophosphorus-catalyzed Appel and Wittig reactions. Green Chem. 2013, 15, 1255–1263.
7.
Bypass Phosphine Oxide Waste. ChemSusChem 2013, 6, 1615–1624.
8. O'Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter, A. L.; Kunkel, S. R.;
van Kalkeren, H. A.; vanꢀDelft, F. L.; Rutjes, F. P. J. T., Organophosphorus Catalysis to
Przeworski, K. C.; Chass, G. A., Recycling the Waste: The Development of a Catalytic Wittig
Reaction. Angew. Chem. 2009, 121, 6968–6971.
9.
P(III)/P(V) redox cycling. Pure Appl. Chem. 2018, DOI: 10.1515/pac-2018-0920.
10. Tsai, Y.-L.; Lin, W., Synthesis of Multifunctional Alkenes from Substituted Acrylates and
Longwitz, L.; Werner, T., Recent advances in catalytic Wittig-type reactions based on
Aldehydes via Phosphine-Catalyzed Wittig Reaction. Asian J. Org. Chem. 2015, 4, 1040–
1043.
11.
Wang, L.; Sun, M.; Ding, M.-W., Catalytic Intramolecular Wittig Reaction Based on a
Phosphine/Phosphine Oxide Catalytic Cycle for the Synthesis of Heterocycles. Eur. J. Org.
Chem. 2017, 2017, 2568–2578.
12.
Lee, C.-J.; Chang, T.-H.; Yu, J.-K.; Madhusudhan Reddy, G.; Hsiao, M.-Y.; Lin, W.,
Synthesis of Functionalized Furans via Chemoselective Reduction/Wittig Reaction Using
Catalytic Triethylamine and Phosphine. Org. Lett. 2016, 18, 3758–3761.
13.
Schirmer, M.-L.; Adomeit, S.; Werner, T., First Base-Free Catalytic Wittig Reaction.
Org. Lett. 2015, 17, 3078–3081.
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Schirmer, M.-L.; Adomeit, S.; Spannenberg, A.; Werner, T., Novel Base-Free Catalytic
Wittig Reaction for the Synthesis of Highly Functionalized Alkenes. Chem. Eur. J. 2016, 22,
2458-2465.
14.
1
2
3
4
5
6
7
8
15.
Saleh, N.; Voituriez, A., Synthesis of 9H-Pyrrolo[1,2-a]indole and 3H-Pyrrolizine
9
Derivatives via a Phosphine-Catalyzed Umpolung Addition/Intramolecular Wittig Reaction. J.
Org. Chem. 2016, 81, 4371–4377.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16.
Gruijters, B. W. T.; van Veldhuizen, A.; Weijers, C. A. G. M.; Wijnberg, J. B. P. A., Total
Synthesis and Bioactivity of Some Naturally Occurring Pterulones. J. Nat. Prod. 2002, 65,
558–561.
17.
Huang, S.-T.; Kuo, H.-S.; Chen, C.-T., Total synthesis of NADH:ubiquinone
oxidoreductase (complex I) antagonist pterulone and its analogue. Tetrahedron Lett. 2001, 42,
7473–7475.
18.
pterulone B and related analogues. Org. Biomol. Chem. 2003, 1, 4209–4219.
19. Kahnberg, P.; Lee, C. W.; Grubbs, R. H.; Sterner, O., Alternative routes to pterulone.
Tetrahedron 2002, 58, 5203–5208.
20. Izquierdo, J.; Orue, A.; Scheidt, K. A., A Dual Lewis Base Activation Strategy for
Lemaire, P.; Balme, G.; Desbordes, P.; Vors, J.-P., Efficient syntheses of pterulone,
Enantioselective Carbene-Catalyzed Annulations. J. Am. Chem. Soc. 2013, 135, 10634–
10637.
21.
Ghosh, S.; Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V., Synthesis of heliannuols
A and K, allelochemicals from cultivar sunflowers and the marine metabolite helianane,
unusual sesquiterpenes containing a benzoxocane ring system. Tetrahedron 2007, 63, 644–
651.
22.
Biswas, B.; Sen, P. K.; Venkateswaran, R. V., The synthesis of heliannuol C, an
allelochemical from Helianthus annuus. Tetrahedron Lett. 2006, 47, 4019–4021.
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