Acid-base-sensitive allylic oxidation of 2-allylbenzoic acids to form phthalides

Article abstract of DOI:10.1039/d0ob00303d

Allylic oxidation of 2-allylbenzoic acids to phthalides, instead of Wacker-type isocoumarins, was achieved with 1,2-bis(phenylsulfinyl)ethane palladium(ii) acetate (White catalyst) and oxygen in DMSO. The selective formation of 3-ethylidenephthalides or 3-vinylphthalides was controlled by the addition of acids or bases, and the reaction conditions were applied to substituted 2-allylbenzoic acids to generate corresponding phthalides selectively. Mechanistic studies, including the corresponding reaction of (E)-2-(1-propenyl)benzoic acid to 3-methylisocoumarin, isomerization reaction of 3-vinylphthalide to 3-ethylidenephthalide, and the kinetic isotope effect using 2-(1,1-d₂-allyl)benzoic acid, revealed the competition between Wacker-type oxidation and allylic C-H cleavage, which is the key step to generating phthalides. A natural product, 3-ethyl-6-hydroxyphthalide, was prepared by this method.

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DOI: 10.1039/D0OB00303D
ARTICLE
Acid-base-sensitive allylic oxidation of 2-allylbenzoic acids to form
phthalides†
Le Thi Ngoc Chuc, Thi Anh Hong Nguyen and Duen-Ren Hou*
Received 00th January 20xx,
Accepted 00th January 20xx
Allylic oxidation of 2-allylbenzoic acids to phthalides, instead of Wacker-type isocoumarins, was achieved with 1,2-
bis(phenylsulfinyl)ethane palladium(II) acetate (White catalyst) and oxygen in DMSO. The selective formation of 3-
ethylidenephthalides or 3-vinylphthalides was controlled by the addition of acids or bases, and the reaction conditions were
applied to substituted 2-allylbenzoic acids to generate correspodning phthalides selectively. Mechanistic studies, including
the corresponding reaction of (E)-2-(1-propenyl)benzoic acid to 3-methylisocoumarin, isomerization reaction of 3-
vinylphthalide to 3-ethylidenephthalide, and the kinetic isotope effect using 2-(1,1-d2-allyl)benzoic acid, revealed the
DOI: 10.1039/x0xx00000x
competition between Wacker-type oxidation and allylic C-H cleavage, which is the key step to generating phthalides.
natural product, 3-ethyl-6-hydroxyphthalide, was prepared by this method.
A
Many elegant methods have been developed to prepare
phthalides.33-41 In this regard, Hegedus’ and Larock’s groups
reported the formation of 3-methylisocoumarin (2) and 3-
ethylidenephthalide (3) from 2-allylbenzoic acid (1) by
palladium(II) catalysts and oxygen (eqs 1 and 2).42, 43 This direct
oxidative lactonization of 2-allylbenzoic acid is attractive
because it is commercially available or conveniently prepared
Introduction
The framework of isobenzofuran-1(3H)-one, also known as
phthalide, is widely found in natural products,1-7,8-11
pharmaceutical compounds,12-14 and synthetic building blocks
(Figure 1).15-22 In 2018, more than fifteen new natural products
containing the phthalide moiety have been reported,1, 7, 23-27
and the number of naturally occurring phthalides isolated from
various plants, bacteria, and fungi has exceeded two hundred.28,
29 Because of the pervasiveness and broad biological activities
of phthalides and their function as synthetic precursors, the
preparation of phthalides has attracted much attention from
organic chemists.28, 30-32
by the one-pot sequence of magnesiation and allylation of 2-
45
iodobenzoic acid.44,
However, the formation of 3-
vinylphthalide by this approach has not been achieved; instead,
3-vinylphthalides were produced by the intramolecular
condensation of the corresponding allylic alcohols (eq 3).46
Stoltz’s and Sasai’s groups prepared substituted 3-
vinylphthalide and γ-lactones by the oxidative cyclization of 2-
(2-butenyl)benzoic acid and 4-alkenoic acids, respectively (eq
4).47, 48 Breder’s group recently reported that a catalytic amount
of diphenyldiselenide and N-fluorobenzenesulfonimide (NFSI)
as the oxidant converted 2-allylbenzoic acids to the
corresponding lactones (eq 5).49 However, this reaction is
limited to olefins conjugated with an aromatic ring. Li’s group
also reported a copper-catalysed, aerobic lactonization of
alkenoic acids (eq 6) recently.50-52
OH
O
O
O
O
HO
O
O
O
O
n-C4H9
Et
n-C3H7
n
-C H
8
17
butylphthalide
(treatment of
(S)-3-ethyl-6-hydroxy-
phthalide, isolated from
Cochliobolus lunatus
paecilocin A
(antibacterial)
(Z)-3-butylidenephthalide
(insecticidal)
ischemic stroke)
OMe
O
O
O
OH
O
HO
HN
The recent development of allylic C-H activation, especially by
using 1,2-bis(phenylsulfinyl)ethane palladium(II) acetate (White
catalyst), has become a powerful tool for furnishing allyl
amides, esters, lactones, carbamates, imidazolidinones, and
oxazolidinones inter- or intramolecularly.53-64 We surmised that
the challenge in preparing 3-vinylphthalides from 2-allylbenzoic
acids could be met by using this palladium catalyst (eq 7).
O
O
C13H27
X
C3H7
X=OH, H or X=O
cytotoxic
senkyunolide B
(antidiabetic)
harmandianamine A
(antibacterial)
Figure 1 Selected phthalide derivatives having biological activity
O
Hegedus
CO2H
PdCl2(CH3CN)2 (1 equiv), air
Na2CO3, THF, 25 °C, 3 h, 86%
O
(eq 1)
Department of Chemistry, National Central University, No. 300 Jhong-Da Road,
Jhong-li, Taoyuan, Taiwan 32001.
1
2
†Electronic Supplementary Information (ESI) available: [1H and 13C{1H} NMR spectra
for compounds 2-4, 3a-3h, 4d,
6 and all the new compounds]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
O
Larock
Results and discussion
View Article Online
CO2H
Our results for preparing lactones utiliziDnOgIa: 1ll0y.1li0c3C9/-DH0OclBe0a0v3a0g3eD,
i.e., 3-ethylidenephthalide (3) or 3-vinylphthalide (4) from 2-
allylbenzoic acid (1), are summarized in Table 1. The initial
experiments using White catalyst, p-benzoquinone (BQ) and the
Pd(OAc)2 (5 mol%), O2, NaOAc
DMSO, 80 °C, 72 h, 71%
(eq 2)
O
3
1
Aponick
O
reported reaction conditions (SI Table
1 in Supporting
PdCl2(CH3CN)2 (10 mol%)
CO2H
Information) were not satisfactory,53, 55-58, 65 as isocoumarin 2,
derived from Wacker-type oxidation, was the major product.
Utilizing DMSO, acetic acid, or their 1:1 mixture, solvents often
applied in allylic C-H cleavages, also gave isocoumarin 2 as the
major product (entries 1–3). Although White catalyst is known
for promoting allylic oxidation rather than Wacker-type
reactions, these results indicate that the reported conditions
are not effective for suppressing Wacker oxidation and
activating the allylic/benzylic C-H bond of 1. However, we
noticed that the addition of sodium azide, a reagent often
applied to attack the intermediate palladium allyl complex,66
afforded a 74% yield of 3-ethylidenephthalide (3) mainly as the
Z diastereomer (entry 4), and a similar yield (72%) was obtained
when benzoquinone was replaced with oxygen (entry 5). Simply
adding sodium hydroxide solution (1 N) to the reaction mixture
further improved the yield of 3 to 87% (entry 6), suggesting that
the reaction pathway could be altered by base. This finding
prompted us to further study the effect of acid and base on the
reaction. As the pH values of the reaction media decreased by
adding different buffered solutions (pH 9.8–4.7), the yields of 3
also decreased (entries 7–9). We were glad to find that the
desired 3-vinylphthalide (4) was produced in high yields when
hydrochloric acid (1 N) or acetic acid was applied (entries 10 and
11). To our knowledge, the direct allylic oxidation of
O
R
R
or PPh3PAuCl/AgOTf (5 mol%)
CH2OH
(eq 3)
4, R = H
Stoltz and Sasai
O
CO2H
Pd(II), ligands, O2 or BQ
O
(eq 4)
R1
R1 = Me, H
O
R1
Breder
CO2H
O
(eq 5)
Ar
(PhSe)2 (10 mol%)
Ar
NFSI, toluene
Li
O
CO2H
Cu(II), O2, KI or
R
(eq 6)
R
O
Cu(II), O2, KI, HNR'2
R1
R1
O
I or NR'2
This work
O
O
O
CO2H
(PhSCH2)2
O
Pd(OAc)2
(PhSCH2)2
Pd(OAc)2
X
O
X
X
(eq 7)
O2, acid
O2, base
Table 1 Reaction Conditions for the Oxidation of 2-Allylbenzoic acids (1)
O
O
O
O
CO2H
(PhSCH2)2
Pd(OAc)2
O
O
O
3
1
2
4
Entry a
1
Yield (%)b
reagents
Solvent
DMSO
Time (h)
24
2
80
3 (E:Z)c
4
Recovered 1
White catalyst, BQ
2
3
White catalyst, BQ
White catalyst, BQ
AcOH
DMSO/AcOH
(1:1)
24
24
75
95
8
4
5
6
7
8
White catalyst, BQ, NaN3 (1.5 equiv)
White catalyst, O2, NaN3 (1.5 equiv)
White catalyst, O2, NaOH(aq) (1 N, 50 μL, 0.5 equiv)
White catalyst, O2, Na2HPO4(aq) (pH 9.8, 2 M, 100 μL)
White catalyst, O2, phosphate buffer (pH 7.0, 2 M, 100 μL)
White catalyst, O2, KH2PO4(aq) (pH 4.7, 2 M, 100 μL)
White catalyst, d O2, HCl(aq) (1 N, 50 μL, 0.5 equiv)
White catalyst, d O2, AcOH (1.5 equiv)
Pd(OAc)2, O2, NaOH(aq) (1 N, 50 μL, 0.5 equiv)
Pd(OAc)2, O2, HCl(aq) (1 N, 50 μL, 0.5 equiv)
PdCl2, O2, HCl(aq) (1 N, 50 μL, 0.5 equiv)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
24
24
12
12
12
12
24
24
12
24
24
74 (1:8)c
72 (1:9)c
87 (1:14)c
85 (1:10)c
50 (1:5)c
29 (1:10)c
15
39
9
71
60
10
11
12
13
14
5
3
14
11
47
92
94
82 (1:10)c
29
53
a2-Allylbenzoic acid (1.0 mmol), Pd catalyst (5 mol%), solvent (1.0 mL), benzoquinone (BQ, 2.0 mmol) or O2 (1 atm) at 100 °C. bIsolated yields. cE- to Z-ratio based on
1H NMR analysis. d10 mol%.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0OB00303D
ARTICLE
2-allylbenzoic acid to give 3-vinylphthalide with high purity is Table 2 Selective Formation of Phthalides
O
O
achieved for the first time. Replacing White catalyst with
palladium acetate, the basic condition provided fewer 3,
6
CO2H
5
condition A or B
X
O
X
X
O
accompanied with byproduct 2 (entry 12 versus 6). Comparing
with Larock’s condition to generate 3 (eq 2), the White catalyst
and basic condition reported in entry 6 has the advantages of a
shorter reaction time and a better yield. Under the acidic
condition, the reaction of Pd(OAc)2 also provided an inferior
result (entry 13 versus 11). Palladium(II) chloride gave nearly 1:1
4
3
3a-3j
4a-4j
1a-1j
Entry
X, reactant
Conditiona
Product
Yield
E:Zc
(%)b
63
65
65
86
26
56
65
85
71
42
86
1
2
3
4
5
6
7
8
9
4-F, 1a
4-F, 1a
4-Cl, 1b
4-Cl, 1b
5-Cl, 1c
A
B
A
B
A
B
A
B
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3f
1:15
-
1:10
-
1:5.4
-
1:3
-
1:4.5
-
ratio of 4 and 2 under the same acidic conditions (1 N HCl(aq)
,
entry 14). These results suggest that benzoquinone is not
required to produce phthalides 3 and 4; rather their ratio is
affected by the acidity of the environment and White catalyst is
a better choice for activation/oxidation of the allylic C-H bond.
The optimized conditions were applied to convert various 2-
allylbenzoic acids to the corresponding phthalide derivatives
using White catalyst. The starting 2-allylbenzoic acids 1a–1j
were prepared according to eq 8.45 The standard conditions we
used for preparing the 3-ethylidenephthalide 3, i.e., White
catalyst (5 mol%), oxygen gas (1 atm), in DMSO (0.1 M) with 0.5
equivalent of sodium hydroxide (Condition A), provided the
corresponding phthalides 3a–3h and 3j, with the Z-
diastereomer predominating. On the other hand, replacing the
base with hydrochloric acid (Condition B) gave the 3-
vinylphthalides 4a–4h and 4j as the major product (Table 2).
5-Cl, 1c
5-Br, 1d
5-Br, 1d
5-OMe, 1e
5-OMe, 1e
4,5-(OMe)2,
1f
A
B
Ad
10
11
1:14
12
4,5-(OMe)2,
1f
B
4f
63
-
13
14
15
16
17
18
19
20
5-Me, 1g
5-Me, 1g
6-Me, 1h
6-Me, 1h
5-CN, 1i
5-CN, 1i
5-OH, 1j
5-OH, 1j
A
B
Ad
B
A
B
A
B
3g
4g
3h
4h
5i
75
25
69
20
93e
95f
80
50
1:16
-
1:6.3
-
-
-
-
1:4.8
-
1) i-PrMgCl, CuCN, LiCl
-40 °C,1 h, then allyl bromide
CO2CH3
I
CO2H
3j
4j
X
(eq 8)
X
2) LiOH, then H3O+
aA: Substituted benzoic acid 1 (0.1 mmol), White catalyst (5 mol%), O2 (1 atm),
NaOH(aq) (1 N, 50 μL) in DMSO (1 mL), 100 °C, 12 h; B: Substituted benzoic acid
1 (0.1 mmol), White catalyst (10 mol%), O2 (1 atm), HCl(aq) (1 N, 50 μL) in DMSO
(1 mL), 100 °C, 24 h. bIsolated yields. cE- to Z-ratio based on 1H NMR analysis.
dNaN3 (0.15 mmol) instead of NaOH(aq)
propenyl)benzoic acid (5i) produced. fStarting material 1i recovered.
In general, the reactions carried out under Condition A were
completed in 12 and provided better yields of 3-
h
,
24 h. e(E)-5-Cyano-2-(1-
ethylidenephthalides than those under Condition B to yield 3-
vinylphthalides. All the halogenated substrates (1a–1d)
provided the corresponding phthalides with yields up to 86%
(entries 1–8). The reactions of 4- or 5-methoxy-substituted
benzoic acids 1e and 1f also went smoothly in good yields
(entries 9–12), although addition of sodium azide provided a
better yield (86%) for the formation of 3f (entry 11). The
corresponding reactions of the methyl-substituted 2-
allylbenzoic acids 1g and 1h were more challenging. 3-
Ethylidenephthalides 3g and 3h were prepared in good yields
using Condition A (entries 13 and 15), but Condition B produced
low yields of the 3-vinylphthalides 4g and 4h, and the phthalides
were contaminated with Wacker-type products (entries 14 and
16). The 5-cyano-substituted benzoic acid 1i gave only the
isomerized, (E)-5-cyano-2-(1-propenyl)benzoic acid (5i) under
Condition A (entry 17), suggesting that the electron-
withdrawing 5-cyano group not only facilitates the
isomerization but suppresses further oxidation of the olefin.
We also found that 1i was stable under Condition B (entry 18).
The reactions of 5-hydroxyl-substituted benzoic acid 1j
provided slightly better yields of 3j and 4j, comparing with its 5-
methoxy counterpart 1e (entries 19 and 20). Hydrogenation of
3j achieved the racemic synthesis of 3-ethyl-6-hydroxyphthalide
(6, eq 9), a natural product recently discovered.7
O
O
HO
HO
H2, Pd/C
(eq 9)
O
O
CH3OH, 92%
6
3j
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DOI: 10.1039/D0OB00303D
Mechanistic insights were obtained from the following C-H activation efficiently.53-56, 59 However, this effect should not
reactions (eqs 10–13). We found that 3-vinylphthalide (4) were be critical for the reaction of 1, as the functionalization step now
rapidly converted to 3-ethylidenephthalide (3) under the basic is an intramolecular, kinetically favored 5-exo-tect process to
condition and White catalyst (25 °C, 5 min, eq 10). In the form intermediates B and D.68, 69 The fact that isocoumarin 2
absence of White catalyst, 3-vinylphthalide (4) was stable in the was always generated in the reactions using benzoquinone
basic reaction media, indicating that the isomerization of 4 to 3 (entries 1–3, Table 1 and SI Table 1) suggests that its presence
requires palladium (eq 11). No trace of thermodynamically may also increase the reaction rate of the Wacker-type
stable isocoumarin 2 was found in these isomerization studies,67 oxidation. Under basic conditions, the resulting carboxylate-
which suggests that the formation of phthalides and palladium complex allows facile allylic C-H oxidation; however,
isocoumarins are two independent processes, viz., allylic C-H the basic environment also promotes migration of the terminal
oxidation and Wacker-type oxidation, respectively. When (E)-2- double bond to give product 3 as seen in eq 10. On the other
(1-propenyl)benzoic acid (5)42 was subjected to the allylic C-H hand, the acidic condition not only slows down all the reactions
oxidation, both Conditions A and B yielded only isocoumarin 2 but makes the allylic C-H cleavage/functionalization a dominant
(eqs 12 and 13). These results also indicate that phthalides 3 and pathway to give 4.
4 are only derived from 2-allylbenzoic acids (1) through allylic C- To better understand the reaction mechanism, 2-(1,1-
H cleavage, which competes with the processes of Wacker d2allyl)benzoic acid (1-D2, 98% CD2) was prepared (SI Scheme 1
oxidation/isomerization leading to isocoumarin 2.
in Supporting Information). Under the basic condition, two
parallel, oxidative lactonizations of 1 and 1-D2 were performed
to determine the kinetic isotope effect (Scheme 2). As
O
O
White catalyst (5 mol%)
1 N NaOH(aq)
(eq 10)
O
O
1
monitored by in situ H NMR, a substantial KIE was observed
DMSO, O2, 25 °C, 5 min, >95%
using the initial rates method for each reaction at the onset of
product formation (kH/kD = 4.3−4.4, see Supporting Information
for details). The KIE value is consistent with primary isotope
effects70 and indicates that the cleavage of the allylic C-H bond
should be the rate-determining step.71, 72 We also observed that
the methyl group of 3-D derived from 1-D2 contained only 10%
deuterium according to 1H NMR analysis. The loss of deuterium
can be attributed to the extensive exchange between Pd-D and
protons of the reaction media during the isomerization step B
to afford 3 (Scheme 1).
We also measured the reaction rate of 1 under the acidic
condition, which was only 15% of the reaction rate of 1 under
the basic condition (see Supporting Information). In addition,
the reaction of 1-D2 in the acidic media provided Wacker-type
product 2-D as the major product (67% yield) with traces of
phthalide 4-D (7% yield, eq 14). This result indicates that the
competing Wacker-type oxidation seems less influenced by the
acidic media and results in the isocoumarin 2-D being the major
product. The slow and negligible formation of 4-D makes the
measurement of this KIE unlikely. However, the remaining
deuterium of 1-D2 was well retained (>95%) in the two products
2-D and 4-D, which is in agreement with the speculation that
isomerization and hydrogen exchange, catalyzed by palladium-
hydride species generated from allylic C-H activations,73, 74 are
prevalent under basic conditions, but very limited under acidic
conditions.
4
3
O
O2, 1 N NaOH(aq)
4
(eq 11)
O
(99%, recovered)
DMSO, 100 °C, 12 h
4
O
COOH
White catalyst (5 mol%)
O
1 N NaOH(aq)
(eq 12)
DMSO, O2,100 °C, 12 h, 91%
5
2
O
White catalyst (10 mol%)
1 N HCl(aq)
COOH
O
(eq 13)
DMSO, O2,100 °C, 24 h, 90%
2
5
Based on our experimental results, a reaction mechanism for
the formation of phthalides can be proposed (Scheme 1).
Previous studies using White catalyst and benzoquinone
indicated that the quinone facilitates the functionalization of -
allylpalladium intermediates with incoming nucleophiles such
as acetate, carboxylates and carbamates, etc. to achieve allylic
4 | J. Name., 2012, 00, 1-3
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ARTICLE
O
HO
O
O2, H3O+
CO2H
PdLn
O
O2/BQ, Pd-catalyzed
White catalyst
Wacker oxidation/isomerization
allylic C-H cleavage
C
1
2
O2, OH-
slow
White catalyst
allylic C-H cleavage
OH
O
O
PdLn
O
O
O
O
PdLn
OH-, Pd cat.
isomerization
D
O
fast
PdLn, H3O+
O
PdLn
OH-, H2O, PdLn
3
B
A
O
4
Scheme 1 Proposed reaction mechanism
O
indicator; purification by chromatography was conducted using
silica gel (230–400 mesh). Chemical shifts for 1H-NMR and
13C{1H} NMR spectra are reported in δ units (parts per million)
with reference to residual solvent peaks. All spectra were
obtained at 25 °C. The multiplicities are abbreviated as follows:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd
= doublet of doublets, td = triplet of doublets. High-resolution
mass spectrometry (HRMS) data were recorded on a JMS-700
quadrupole mass spectrometer. 1,2-Bis(phenylsulfinyl)ethane
palladium(II) acetate (White catalyst)55 and 2-allylbenzoic acids
1, 1a, 1b, 1d, 1e, 1f, 1g, 1h and 1i45 were prepared according to
the literature.
COOH
White catalyst (5 mol%), O2 (1 atm)
O
NaOH (1 N, 0.5 equiv), DMSO-d6, 100 °C
1
3
CH3
kH
O
COOH
White catalyst (5 mol%), O2 (1 atm)
O
NaOH (1 N, 0.5 equiv), DMSO-d6, 100 °C
C
D2
kD
CH2D
(10%)
3-D
1-D2
kH/kD = 4.3-4.4
Scheme 2 Kinetic Isotope Effect of the Oxidative Lactonization
2-Allyl-5-chlorobenzoic Acid (1c)
i-PrMgCl (1 M in THF, 10 mL, 10.0 mmol) was added dropwise
to a solution of methyl 5-chloro-2-iodobenzoate75, 76 (1.0 g, 3.37
mmol) and THF (34 mL) at -40 °C. The reaction mixture was
added with a solution of CuCN·2LiCl in THF (0.34 M in THF, 10
mL, 3.37 mmol), stirred for 30 min at -40 °C, added with a
solution of allyl bromide (1.1 mL, 13.50 mmol) and stirred for
another 1 h at -40 °C. The reaction mixture was allowed to warm
to room temperature overnight, quenched with sat. NH4Cl(aq)
(25 mL), and extracted with ethyl acetate (45 mL × 3). The
combined organic layers were washed with sat. NaCl(aq) (25 mL),
dried over Na2SO4, filtered and concentrated. The crude product
was re-dissolved in THF (24 mL), methanol (6 mL) and water (6
mL), added with lithium hydroxide monohydrate (0.71 g, 16.8
mmol) and stirred at rt for 16 h. The reaction mixture was
concentrated, washed with diethyl ether (15 mL × 2), acidified
O
O
COOH
White catalyst (10 mol%), O2
O
(eq 14)
O
+
HCl(aq), DMSO, 100 °C, 24 h
2-D, 67%
C
D (> 95%)
4-D, 7%
D2
D (> 95%)
1-D2
Experimental
General experimental details
Dichloromethane and dimethyl sulfoxide (DMSO) were dried
over calcium hydride and distilled prior to use. Tetrahydrofuran
and diethyl ether were dried over sodium, monitored with
benzophenone ketyl radicals and distilled prior to use. DMF was
dried over molecular sieves (3 Å). TLC was conducted using pre-
coated silica gel 60 F254 plates containing a fluorescent
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Organic & Biomolecular Chemistry
Page 6 of 11
ARTICLE
Journal Name
with HCl(aq) (2 N, 5 mL) and extracted with diethyl ether (15 mL HRMS (ESI) calcd for [M + H]+ (C11H10NO2) 188V.0ie7w1A1rt,iclefoOunlninde
DOI: 10.1039/D0OB00303D
× 3). The combined organic layers were washed with sat. NaCl(aq) 188.0704.
(15 mL), dried over Na2SO4, filtered and concentrated. The crude 3-Methylisocoumarin (2)
product was further purified by column chromatography (SiO2, A reaction mixture of 2-allylbenzoic acid (1, 16.2 mg, 99.9 µmol),
ethyl acetate/hexanes,1:3; Rf 0.50) to give 1c (517.0 mg, 2.63 White cat (5.0 mg, 10 µmol) and p-benzoquinone (22.0 mg, 201
mmol, 78% over two steps) as a white amorphous solid. Mp: µmol) in DMSO (1 mL) was stirred at 100 °C (oil bath) for 24 h,
54.5–56.0 °C; 1H NMR (CDCl3, 300 MHz) δ 3.77 (d, J = 6.5 Hz, 2H), added with water (1 mL) and extracted with diethyl ether (2 mL
4.99–5.07 (m, 2H), 5.94–6.02 (m, 1H), 7.25 (d, J = 8.3 Hz, 1H), × 3). The combined organic layers were dried over Na2SO4,
7.44 (dd, J = 2.5 Hz, 8.3 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H); 13C{1H} filtered, and concentrated. The crude product was purified by
NMR (CDCl3, 75 MHz) δ 37.8, 116.2, 129.5, 131.4, 132.1, 132.5, column chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf
133.0, 136.6, 141.2, 171.9; HRMS (ESI) calcd for [M + H]+ 0.50) to give 2 (12.8 mg, 0.08 mmol, 80%) as a white solid. 1H
(C10H10ClO2) 197.0369, found 197.0393.
NMR (CDCl3, 500 MHz) δ 2.25 (s, 3H), 6.23 (s, 1H), 7.30 (d, J =
7.9 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 8.21
(d, J = 7.5 Hz,1 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 19.6, 103.5,
2-Allyl-5-cyanobenzoic acid (1i)
A solution of methyl 2-amino-5-cyanobenzoate77 (2.6 g, 14.7 119.9, 124.8, 127.5, 129.4, 134.7, 137.6, 154.5, 162.9. The NMR
mmol) in water (24 mL) was added HCl(aq) (0.7 M, 21 mL, 14.7 spectroscopic data were consistent with the literature.78
mmol), sodium nitrite (1.2 g, 17.7 mmol) in water (5.5 mL)
slowly at 0 °C. The resulting solution was stirred for 30 min and (Z)-3-Ethylidenephthalide (3)
added with a solution of potassium iodide (4.90 g, 29.5 mmol) A solution of 2-allylbenzoic acid (1, 16.2 mg, 99.9 µmol), White
in water (12.4 mL). The reaction mixture was heated at 30 °C (oil cat (2.5 mg, 5 µmol) and DMSO (1 mL) was added with NaOH(aq)
bath) for 16 h, quenched with a sat. Na2S2O3(aq) (65 mL) and (1 N, 50 µL, 50 µmol). The reaction mixture was stirred at 100
extracted with ethyl acetate (70 mL × 3). The combined organic °C (oil bath) for 12 h under an atmosphere of oxygen, added
layers were dried over NaSO4, filtered and concentrated. The with water (1 mL) and extracted with diethyl ether (2 mL × 3).
crude product was further purified by column chromatography The combined organic layers were dried over Na2SO4, filtered
(SiO2, ethyl acetate/hexanes, 1:10; Rf 0.50) to give methyl 5- and concentrated. The crude product was purified by column
cyano-2-iodobenzoate (2.4 g, 8.36 mmol, 57%) as a colourless chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf 0.55) to
liquid. 1H NMR (CDCl3, 500 MHz) δ 3.94 (s, 3H), 7.35 (dd, J = 2.0 give 3 (14 mg, 0.087 mmol, 87%) as a colourless liquid. 1H NMR
Hz, 8.3 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H); (CDCl3, 500 MHz) δ 1.97 (d, J = 7.5 Hz, 3H), 5.61 (q, J = 7.0 Hz,
13C{1H} NMR (CDCl3, 125 MHz) δ 53.0, 100.3, 112.4, 117.2, 1H), 7.44–7.47 (m, 1H), 7.57–7.64 (m, 2H), 7.82 (d, J = 7.5 Hz,
133.9, 134.6, 136.1, 142.5, 165.0; HRMS (ESI) calcd for [M + H]+ 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 11.1, 104.1, 119.4, 124.3,
(C9H7INO2) 287.9521, found 287.9506.
125.1, 129.2, 134.1, 139.4, 146.3, 167.0. The NMR spectroscopic
i-PrMgCl (1 M in THF, 10 mL, 10.0 mmol) was added dropwise data were consistent with the literature.79
to a solution of 5-cyano-2-iodobenzoate (0.50 g, 1.74 mmol)
and THF (17 mL) at -40 °C. The reaction mixture was added with 3-Vinylphthalide (4)
a solution of CuCN·2LiCl in THF (0.34 M in THF, 5.1 mL, 1.74 A solution of 2-allylbenzoic acid (1, 16.2 mg, 99.9 µmol), White
mmol), stirred for 30 min at -40 °C, added with a solution of allyl catalyst (5.0 mg, 10 µmol) and DMSO (1 mL) was added with
bromide (0.45 mL, 5.22 mmol) and stirred for another 1 h at -40 HCl(aq) (1 N, 50 µL, 50 µmol). The reaction mixture was stirred at
°C. The reaction mixture was warmed to room temperature 100 °C (oil bath) for 24 h under an atmosphere of oxygen, added
overnight, quenched with sat. NH4Cl(aq) (12 mL), and extracted with water (1 mL) and extracted with diethyl ether (2 mL × 3).
with ethyl acetate (15 mL × 3). The combined organic layers The combined organic layers were dried over Na2SO4, filtered,
were washed with sat. NaCl(aq) (12 mL), dried over Na2SO4, and concentrated. The crude product was purified by column
filtered and concentrated. The crude product was re-dissolved chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf 0.45) to
in THF (8 mL), methanol (1 mL) and water (1 mL), added with give 4 (14 mg, 0.092 mmol, 92%) as a colourless liquid. 1H NMR
lithium hydroxide monohydrate (0.37 g, 8.5 mmol) and stirred (CDCl3, 500 MHz) δ 5.37–5.41 (m, 1H), 5.56-5.61 (m, 1H), 5.80–
at rt for 16 h. The reaction mixture was concentrated, washed 5.87 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.65
with diethyl ether (2 mL), acidified with HCl(aq) (2 N, 0.5 mL) and (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13C{1H} NMR (CDCl3,
extracted with diethyl ether (5 mL × 3). The combined organic 125 MHz) δ 82.0, 119.9, 122.4, 125.7, 129.3, 130.2, 133.3, 134.1,
layers were washed with sat. NaCl(aq) (5 mL), dried over Na2SO4, 148.5, 170.2. The NMR spectroscopic data were consistent with
filtered and concentrated. The crude product was further the literature.80
purified by column chromatography (SiO2, ethyl
acetate/hexanes,1:3; Rf 0.35) to give 1i (227.0 mg, 1.21 mmol, (Z)-3-Ethylidene-5-fluoroisobenzofuran-1(3H)-one (3a)
70% over two steps) as a colourless liquid. 1H NMR (CDCl3, 500 The procedure to prepare 3 was followed. Starting with 1a (19.6
MHz) δ 3.58 (d, J =6.5 Hz, 2H), 5.02–5.11 (m, 2H), 5.92–6.00 (m, mg, 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), and White cat
1H), 7.43 (d, J = 8.0 Hz, 1H), 7.73 (dd, J = 1.5 Hz, 8.0 Hz, 1H), 7.83 (2.5 mg, 5 µmol) in DMSO (1 mL), compound 3a (11.2 mg, 0.063
(d, J = 2.0 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 38.4, 110.6, mmol, 63%) was produced after column chromatography (SiO2,
117.2, 117.7, 129.3, 132.1, 135.3, 135.4, 135.7, 148.0, 170.8; ethyl acetate/hexanes, 1:20; Rf 0.50) as a colourless liquid. 1H
NMR (CDCl3, 500 MHz) δ 1.99 (d, J = 7.5 Hz, 3H), 5.61 (q, J = 7.0
6 | J. Name., 2012, 00, 1-3
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Hz, 1H), 7.14–7.21 (m, 1H), 7.22–7.25 (m, 1H), 7.84 (q, J = 4.5 6-Chloro-3-vinylisobenzofuran-1(3H)-one (4c)
ARTICLE
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Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 11.3, 105.6, 106.3 (d, The procedure to prepare 4 was followed. Starting with 1c (19.7
DOI: 10.1039/D0OB00303D
2JC-F = 24.8 Hz), 117.7 (d, 2JC-F = 24.3 Hz), 120.6, 127.7 (d, 3JC-F
=
mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), and White cat (5.0
10.3 Hz), 142.0 (d, 3JC-F = 11.3 Hz), 145.5, 166.7 (d, 1JC-F = 253.3 mg, 10 µmol) in DMSO (1 mL), compound 4c (10.9 mg, 0.056
Hz), 165.9. The NMR spectroscopic data were consistent with mmol, 56%) was produced after column chromatography (SiO2,
the literature.81
ethyl acetate/hexanes, 1:20; Rf 0.45) as a colourless liquid. 1H
NMR (CDCl3, 500 MHz) δ 5.39 (m, 1H), 5.55 (m, 1H), 5.76–5.83
(m, 2H), 7.39 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.61 (dd, J = 1.4 Hz,
5-Fluoro-3-vinylisobenzofuran-1(3H)-one (4a)
The procedure to prepare 4 was followed. Starting with 1a (19.6 8.0 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H); 13C{1H} NMR (CDCl3, 125
mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), and White cat (5.0 MHz) δ 29.6, 81.8,120.3, 123.7, 125.6, 132.8, 134.4, 135.8,
mg, 10 µmol) in DMSO (1 mL), compound 4a (11.5 mg, 0.065 146.6, 168.6; HRMS (ESI) calcd for [M + H]+ (C10H8ClO2)
mmol, 65%) was produced after column chromatography (SiO2, 195.0213, found 195.0205.
ethyl acetate/hexanes, 1:20; Rf 0.45) as a colourless liquid. 1H
NMR (CDCl3, 300 MHz) δ 5.39 (d, J = 15.3 Hz, 1H), 5.62 (d, J = (Z)-6-Bromo-3-ethylideneisobenzofuran-1(3H)-one (3d). The
20.0 Hz, 1H), 5.75–5.87 (m, 2H), 7.39 (s, 1H), 7.18 (dd, J = 7.5 Hz, procedure to prepare 3 was followed. Starting with 1d (24.0 mg,
J = 8.1 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H); 13C{1H} NMR (CDCl3, 75 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), and White cat (2.5
MHz) δ 81.3, 109.8 (d, 2JC-F = 24.2 Hz), 117.7 (d, 2JC-F = 23.9 Hz), mg, 5 µmol) in DMSO (1 mL), and compound 3d (15.5 mg, 0.065
120.5, 121.7, 128.1 (d, 3JC-F = 10.1 Hz), 132.7, 151.3 (d, 3JC-F = 9.6 mmol, 65%) was produced after column chromatography (SiO2,
Hz), 166.6 (d, 1JC-F = 255.0 Hz), 169.0; HRMS (ESI) calcd for [M + ethyl acetate/hexanes, 1:20; Rf 0.50) as a colourless liquid. 1H
H] + (C10H8FO2) 179.0508, found 179.0502.
NMR (CDCl3, 300 MHz) δ 1.98 (d, J = 7.2 Hz, 3H), 5.63 (q, J = 7.2
Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.73 (dd, J = 1.8 Hz, J = 8.4 Hz,
1H), 7.99 (d, J = 1.5 Hz, 1H); 13C{1H} NMR (CDCl3, 75 MHz) δ 11.3,
(Z)-5-Chloro-3-ethylideneisobenzofuran-1(3H)-one (3b)
The procedure to prepare 3 was followed. Starting with 1b (19.7 105.3, 120.8, 120.9, 123.1, 126.1, 128.1, 137.3, 137.4, 138.1,
mg, 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), and White cat 145.7, 165.5. The NMR spectroscopic data were consistent with
(2.5 mg, 5 µmol) in DMSO (1 mL), compound 3b (12.6 mg, 0.065 the literature.82
mmol, 65%) as a colourless liquid was produced after column
chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf 0.50). 1H 6-Bromo-3-vinylisobenzofuran-1(3H)-one (4d)
NMR (CDCl3, 300 MHz) δ 1.99 (d, J = 7.3 Hz, 3H), 5.63 (q, J = 7.2 The procedure to prepare 4 was followed. Starting with 1d (24.0
Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.78 (d, J = 8.1 Hz, mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), and White cat (5.0
1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 11.3, 105.7, 119.7, 122.8, mg, 10 µmol) in DMSO (1 mL), compound 4d (20.3 mg, 0.085
126.5, 129.9, 140.9, 141.0, 145.3, 166.0. The NMR spectroscopic mmol, 85%) was produced after column chromatography (SiO2,
data were consistent with the literature.81
ethyl acetate/hexanes, 1:20; Rf 0.45) as a colourless liquid. 1H
NMR (CDCl3, 500 MHz) δ 5.40 (d, J = 9.2 Hz, 1H), 5.60 (d, J = 16.5
Hz, 1H), 5.75–5.83 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 7.76 (dd, J =
5-Chloro-3-vinylisobenzofuran-1(3H)-one (4b)
The procedure to prepare 4 was followed. Starting with 1b (19.7 1.7 Hz, J = 8.1 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H); 13C{1H} NMR
mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), and White cat (5.0 (CDCl3, 125 MHz) δ 81.8, 120.4, 123.4, 124.0, 127.7, 128.7,
mg, 10 µmol) in DMSO (1 mL), compound 4b (16.7 mg, 0.086 132.7, 137.2, 147.1, 168.5; HRMS (ESI) calcd for [M + H]+
mmol, 86%) was produced after column chromatography (SiO2, (C10H8BrO2) 238.9707, found 238.9690. The NMR spectroscopic
ethyl acetate/hexanes, 1:20; Rf 0.45) as a colourless liquid. 1H data were consistent with the literature.46
NMR (CDCl3, 300 MHz) δ 5.41 (m, 1H), 5.57 (m, 1H), 5.75–5.86
(m, 2H), 7.39 (s, 1H), 7.48 (dd, J = 1.2 Hz, J = 8.1 Hz, 1H), 7.80 (d, (Z)-3-Ethylidene-6-methoxyisobenzofuran-1(3H)-one (3e)
J = 8.1 Hz, 1H);13C{1H} NMR (CDCl3, 75 MHz) δ 81.4, 120.6, 122.9, The procedure to prepare 3 was followed. Starting with 1e (19.0
126.9, 128.0, 130.2, 132.7, 140.9, 150.1, 169.0; HRMS (ESI) calcd mg, 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), and White cat
for [M + H]+ (C10H8ClO2) 195.0213, found 195.0202.
(2.5 mg, 5 µmol) in DMSO (1 mL), compound 3e (13.5 mg, 0.071
mmol, 71%) as a colourless liquid was produced after column
chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf 0.50). 1H
(Z)-6-Chloro-3-ethylideneisobenzofuran-1(3H)-one (3c)
The procedure to prepare 3 was followed. Starting with 1c (19.7 NMR (CDCl3, 300 MHz) δ 1.96 (d, J = 7.2 Hz, 3H), 3.85 (s, 3H),
mg, 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), and White cat 5.46 (q, J = 7.2 Hz, 1H), 7.19–7.27 (m, 2H), 7.47 (d, J = 8.4 Hz,
(2.5 mg, 5 µmol) in DMSO (1 mL), compound 3c (5 mg, 0.026 1H); 13C{1H} NMR (CDCl3, 75 MHz) δ 11.1, 55.8, 102.4, 106.3,
mmol, 26%) was produced after column chromatography (SiO2, 120.7, 123.7, 125.8, 132.7, 146.1, 160.8, 167.2. The NMR
ethyl acetate/hexanes, 1:20; Rf 0.50) as a colourless liquid. 1H spectroscopic data were consistent with the literature.83
NMR (CDCl3, 300 MHz) δ 2.03 (d, J = 7.2 Hz, 3H), 5.63 (q, J = 7.5 6-Methoxy-3-vinylisobenzofuran-1(3H)-one (4e)
Hz, 1H), 7.27 (m, 2H), 7.87 (d, J = 0.6 Hz, 1H); 13C{1H} NMR The procedure to prepare 4 was followed. Starting with 1e (19.0
(CDCl3, 75 MHz) δ 11.3, 105.2, 120.7, 125.1, 125.9, 134.6, 135.4, mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), and White cat (5.0
137.7, 145.6, 165.6; HRMS (ESI) calcd for [M+H]+ (C10H8ClO2) mg, 10 µmol) in DMSO (1 mL), compound 4e (7.9 mg, 0.042
195.0213, found 195.0204.
mmol, 42%) was produced after column chromatography (SiO2,
ethyl acetate/hexanes, 1:20; Rf 0.45) as a colourless liquid. 1H
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NMR (CDCl3, 500 MHz) δ 3.85 (s, 3H), 5.35 (d, J = 8.4 Hz, 1H), The procedure to prepare 3 was followed. StartingVwieiwthAr1tichle(O1n7lin.6e
DOI: 10.1039/D0OB00303D
5.38 (d, J = 8.4 Hz, 1H), 5.57–5.86 (m, 2H), 7.19–7.31 (m, 3H). mg, 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), and White cat
13C{1H} NMR (CDCl3, 125 MHz) δ 11.1, 55.8, 102.4, 106.3, 120.7, (2.5 mg, 5 µmol) in DMSO (1 mL), compound 3h (12.0 mg, 0.069
123.7, 125.8, 132.7, 146.1, 160.8, 167.2; HRMS (ESI) calcd for mmol, 69%) as a colourless liquid was produced after column
[M + H]+ (C11H11O3) 191.0708, found 191.0700.
chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf 0.50). 1H
NMR (CDCl3, 500 MHz) δ 1.97 (d, J = 7.5 Hz, 3H), 2.65 (s, 3H),
5.57 (q, J = 7.0 Hz, 1H), 7.20 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.0
(Z)-3-Ethylidene-5,6-dimethoxyisobenzofuran-1(3H)-one (3f)
The procedure to prepare 3 was followed. Starting with 1f (19.0 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ
mg, 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), White cat (2.5 11.1, 17.4, 103.2, 116.8, 122.1, 130.8, 133.9, 139.2, 139.9,
mg, 5 µmol) in DMSO (1 mL), compound 3f (18.9 mg, 0.086 146.1, 167.3. The NMR spectroscopic data were consistent with
mmol, 86%) was produced after column chromatography (SiO2, the literature.81
1
ethyl acetate/hexanes, 1:20; Rf 0.50) as a colourless liquid. H
NMR (CDCl3, 500 MHz) δ 1.96 (d, J = 7.3 Hz, 3H), 3.91(s, 3H), 3.96 7-Methyl-3-vinylisobenzofuran-1(3H)-one (4h)
(s, 3H), 5.47 (q, J = 7.0 Hz, 1H), 6.95 (s, 1H), 6.21 (s, 1H); 13C{1H} The procedure to prepare 4 was followed. Starting with 1h (17.6
NMR (CDCl3, 125 MHz) δ 11.2, 56.3, 56.4, 100.5, 102.5, 105.2, mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), and White cat (5.0
116.9, 134.2, 146.2, 151.1, 155.1, 167.3. The NMR spectroscopic mg, 10 µmol) in DMSO (1 mL), compound racemic 4h (3.4 mg,
data were consistent with the literature.84
0.02 mmol, 20%) was produced after column chromatography
(SiO2, ethyl acetate/hexanes, 1:20; Rf 0.45) as a colourless
liquid. 1H NMR (CDCl3, 500 MHz) δ 2.67 (s, 3H), 5.35 (d, J = 10.0
5,6-Dimethoxy-3-vinylisobenzofuran-1(3H)-one (4f)
The general procedure for the lactonization was followed. Hz, 1H), 5.55 (d, J = 15.9 Hz, 1H), 5.72 (d, J = 7.3 Hz, 1H), 5.78–
Starting with 1f (19 mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), 5.85 (m, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H). 7.49
and White cat (5.0 mg, 10 µmol) in DMSO (1 mL), compound 4f (t, J = 7.5 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 17.2, 81.0,
(13.8 mg, 0.063 mmol, 63%) as a colourless liquid was purified 119.4, 119.7, 123.1, 130.9, 133.7, 133.8, 139.8, 149.0, 170.4;
by column chromatography (C18-reversed phase silica gel, HRMS (ESI) calcd for [M + H]+ (C11H11O2) 175.0759, found
H2O/MeOH, 1:3; Rf 0.42). 1H NMR (CDCl3, 500 MHz) 3.92 (s, 3H), 175.0752.
3.94 (s, 3H), 5.38 (d, J = 7.5 Hz, 1H), 5.56 (d, J = 17.0 Hz, 1H), 5.68
(d, J = 7.8 Hz, 1H), 5.75 (m, 1H), 6.76 (s, 1H), 7.27 (s, 1H). 13C{1H} (E)-5-Cyano-2-(1-propen-yl)benzoic acid (5i)
NMR (CDCl3, 125 MHz) δ 56.3, 56.4, 81.5, 103.7, 106.1, 117.6, A solution of 1i (19.0 mg, 100.0 µmol), White cat (2.5 mg, 5
119.8, 133.8, 143.1, 150.7, 155.0, 170.4. HRMS (ESI) calcd for [M µmol) and DMSO (1 mL) was added with NaOH(aq) (1 N, 50 µL,
+ H]+ (C12H13O4) 221.0814, found 221.0801.
50 µmol). The reaction mixture was stirred at 100 °C (oil bath)
for 12 h under an atmosphere of oxygen, added with water (1
mL) and extracted with diethyl ether (2 mL × 3). The combined
(Z)-3-Ethylidene-6-methylisobenzofuran-1(3H)-one (3g)
The procedure to prepare 3 was followed. Starting with 1g (17.6 organic layers were dried over Na2SO4, filtered and
mg, 0.10 mmol), NaOH(aq) (1 N, 50 µL, 50 µmol), and White cat concentrated. The crude product was purified by column
(2.5 mg, 5 µmol) in DMSO (1 mL), compound 3g (13.0 mg, 0.075 chromatography (SiO2, ethyl acetate/hexanes, 1:3; Rf 0.50) to
1
mmol, 75%) as a colourless liquid was produced after column give 5i (14.9 mg, 0.093 mmol, 93%) as a colourless liquid. H
chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf 0.50). 1H NMR (CDCl3, 500 MHz) δ 1.95 (dd, J = 2.0 Hz, J = 7.0 Hz, 3H), 6.29
NMR (CDCl3, 300 MHz) δ 1.96 (d, J = 7.5 Hz, 3H), 2.44 (s, 3H), (tq, J = 7.0 Hz, J = 13.5 Hz, 1H), 7.26 (d, J = 14.5 Hz, 1H), 7.64 (d,
5.53 (q, J = 7.2 Hz, 1H), 7.43–7.50 (m, 2H), 7.64 (s, 1H); 13C{1H} J = 8.0 Hz, 1H), 7.70 (dd, J = 1.5 Hz, J = 8.5 Hz, 1H), 8.27 (d, J =
NMR (CDCl3, 75 MHz) δ 11.2, 21.4, 103.1, 119.2, 124.2, 125.0, 2.0 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 19.0, 110.3, 117.8,
135.5, 137.2, 139.8, 146.4, 167.3. The NMR spectroscopic data 127.3, 128.1, 128.4, 133.3, 135.3, 135.4, 144.7, 170.9; HRMS
were consistent with the literature.81
(ESI) calcd for [M + H]+ (C11H10NO2) 188.0711, found 188.0708.
6-Methyl-3-vinylisobenzofuran-1(3H)-one (4g)
(Z)-3-Ethylidene-6-hydroxyisobenzofuran-1(3H)-one (3j)
The procedure to prepare 4 was followed. Starting with 1g (17.6 The procedure to prepare 3 was followed. Starting with 1j (50.0
mg, 0.10 mmol), HCl(aq) (1 N, 50 µL, 50 µmol), and White cat (5.0 mg, 0.28 mmol), NaOH(aq) (1 N, 140 µL, 140 µmol) and White cat
mg, 10 µmol) in DMSO (1 mL), compound 4g (4.3 mg, 0.025 (7.1 mg, 14.0 µmol) in DMSO (2.8 mL), compound 3j (39.4 mg,
mmol, 25%) was produced after column chromatography (SiO2, 0.22 mmol, 80%) was prepared after column chromatography
ethyl acetate/hexanes, 1:20; Rf 0.45) as a colourless liquid. 1H (SiO2, ethyl acetate/hexanes, 1:3; Rf 0.60) as a colourless liquid.
NMR (CDCl3, 300 MHz) δ 2.44 (s, 3H), 5.35 (d, J = 9.9 Hz, 1H), 1H NMR (CDCl3/ (CD3)2CO, 6:1 (v/v), 300 MHz) δ 1.87 (d, J = 7.3
5.53 (d, J = 16.4 Hz, 1H), 5.74-5.87 (m, 2H), 7.26 (d, J = 7.7 Hz, Hz, 3H), 5.38 (q, J = 7.3 Hz, 1H), 7.12-7.19 (m, 2H), 7.41 (d, J =
1H), 7.45 (d, J = 7.5 Hz, 1H). 7.67 (s, 1H); 13C{1H} NMR (CDCl3, 75 8.4 Hz, 1H). 13C{1H} NMR (CDCl3/(CD3)2CO, 6:1 (v/v), 75 MHz) δ
MHz) δ 21.2, 81.9, 119.6, 122.1, 125.6, 133.6, 135.3, 139.7, 10.4, 100.7, 109.2, 120.5, 122.8, 125.3, 131.1, 145.9, 158.1,
142.1, 145.9, 170.4; HRMS (ESI) calcd for [M + H]+ (C11H11O2) 166.6. HRMS (ESI) calcd for [M + H]+ (C10H9O3) 177.0552, found
175.0759, found 175.0752.
177.0554.
(Z)-3-Ethylidene-7-methylisobenzofuran-1(3H)-one (3h)
6-Hydroxy-3-vinylisobenzofuran-1(3H)-one (4j)
8 | J. Name., 2012, 00, 1-3
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The general procedure to prepare 4 was followed. Starting with 130.4, 131.6, 131.8, 140.0, 168.0; HRMS (ESI) calcd for [M + H]+
View Article Online
DOI: 10.1039/D0OB00303D
1j (50 mg, 0.28 mmol), HCl(aq) (1 N, 140 µL, 140 µmol), and White (C9H8D3O2) 154.0947, found 154.0919.
catalyst (14.1 mg, 28 µmol) in DMSO (2.8 mL), compound
racemic 4j (24.5 mg, 0.14 mmol, 50%) was produced after Methyl 2-(bromomethyl-d2)benzoate (9)
column chromatography (SiO2, ethyl acetate/hexanes, 1:2; Rf N-Bromosuccinimide (384 mg, 2.14 mmol) was added to a
0.43) as a colourless liquid. 1H NMR (CDCl3 +(CD3)2CO, 6:1 (v/v), solution of 8 (300 mg, 1.94 mmol), benzoyl peroxide (480 mg,
300 MHz) δ 5.34-5.40 (m, 1H), 5.51-5.591 (m, 1H), 5.73-5.85 (m, 0.08 mmol) and benzene (4 mL). The reaction mixture was
2H), 7.19-7.26 (m, 2H), 7.51 (d, J = 1.5 Hz, 1H). 13C{1H} NMR heated in an oil bath to reflux for 48 h, added with sat.
(CDCl3 +(CD3)2CO, 6:1 (v/v), 75 MHz) δ 82.5, 110.9, 119.9, 123.1, NaHCO3(aq) (4 mL) and extracted with diethyl ether (8 mL × 3).
123.5, 126.8, 133.4, 140.5, 157.6, 171.2. HRMS (ESI) calcd for [M The combined organic layers were washed with sat. NaCl(aq) (25
+ H]+ (C10H8O3) 177.0552, found 177.0553.
mL), dried over Na2SO4, filtered, and concentrated. The crude
product was further purified by column chromatography (SiO2,
ethyl acetate/hexanes, 1:20; Rf 0.55) to give 9 (190 mg, 0.82
3-Ethyl-6-hydroxyphthalide (6)
A suspension of 3j (17.6 mg, 0.10 mmol) and palladium on mmol, 42%; 98.7% CD2Br) as a colourless liquid. 1H NMR (CDCl3,
activated charcoal (10%, 5.3 mg) in methanol (2 mL) was stirred 300 MHz) δ 3.91 (m, 3H), 4.91 (m, 0.027H), 7.32–7.37 (m, 1H),
under an atmosphere of hydrogen (500 psi) at 30 °C for 5 h and 7.41–7.51 (m, 2H), 7.93 (dd, J = 8.0 Hz, J = 0.9 Hz, 1H); 13C{1H}
then concentrated. The crude product was purified by column NMR (CDCl3, 75 MHz) δ 52.2, 128.4, 129.0, 131.2, 131.6, 132.4,
chromatography (ethyl acetate/hexanes, 1:2; Rf 0.45) to give 6 139.0, 166.9. HRMS (ESI) calcd for [M + H]+ (C9H8BrD2O2)
(16.3 mg, 0.092 mmol, 92%). 1H NMR (CDCl3/ (CD3)2CO, 6:1 (v/v), 230.9989, found 230.9953.
500 MHz) δ 0.91 (t, J = 7.3 Hz, 1H), 1.68-1.76 (m, 1H), 1.98-2.03
(m, 1H), 5.30-5.33 (m, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 2-(Allyl-1,1-d2)benzoic acid (1-D2)
8.2 Hz, 1H), 7.26 (s, 1H); 13C{1H} NMR (CDCl3/(CD3)2CO, 6:1 (v/v), Vinylmagnesium bromide (1 M in THF, 1.1 mL, 1.1 mmol) was
125 MHz) δ 8.7, 27.7, 82.8, 110.9, 122.7, 122.8, 127.4, 141.7, added dropwise to a solution of 9 (120 mg, 0.51 mmol), CuI
157.5, 171.5. The NMR spectroscopic data were consistent with (19.4 mg, 0.1 mmol), 2,2'-bipyridyl (15.6 mg, 0.1 mmol) and THF
the literature.7
(3.0 mL) at -60 °C. The reaction mixture was stirred at -60 °C for
1 h, another 12 h at rt, quenched with sat. NH4Cl(aq) (2 mL) and
The reaction scheme to prepare 1-D2 is shown in Supporting extracted with diethyl ether (3 mL × 3). The combined organic
Information (SI Scheme 1).
2-(Methyl-d3)benzoic acid (7)
layers were washed with sat. NaCl(aq) (10 mL), dried over
Na2SO4, filtered, and concentrated. Lithium hydroxide (107.0
n-BuLi (2.5 M in hexanes, 73.4 mL, 183.6 mmol) was added mg, 2.55 mmol) in THF/ MeOH/H2O (4: 1: 1, 5 mL) was added to
dropwise to a solution of 2-methylbenzoic acid (5.0 g, 36.72 the residue, and the solution was stirred at rt for 16 h, acidified
mmol), THF (250 mL), and hexamethylphosphoramide (HMPA; with HCl(aq) (1 N, 1.5 mL) and extracted with diethyl ether (3 mL
26 mL, 147 mmol) at -60 °C. The reaction mixture was stirred at × 3). The combined organic layers were washed with sat. NaCl(aq)
-60 °C for 1 h, added with D2O (6.6 mL, 367.2 mmol), diluted (10 mL), dried over Na2SO4, filtered, and concentrated. The
with HCl(aq) (5 N, 30 mL) and extracted with diethyl ether (50 mL crude product was purified by column chromatography (SiO2,
× 3). The combined organic layers were washed with sat. NaCl(aq) ethyl acetate/hexanes, 1:3; Rf 0.50) to give 1-D2 (39.4 mg, 0.24
1
(60 mL), dried over Na2SO4, filtered, and concentrated. The mmol, 47% two steps; 98% CD2) as a colorless solid. H NMR
deprotonation and deuteriation was repeated five times, and (CDCl3, 500 MHz) δ 5.01-5.04 (m, 2H), 5.99 (q, J = 10.8 Hz, 1H),
the crude product was further purified by column 7.28 (m, 2H), 7.46 (dt, J = 7.9 Hz, J =1.4 Hz, 1H), 8.03 (dd, J = 7.9
chromatography (SiO2, ethyl acetate/hexanes, 1:3; Rf 0.43) to Hz, J =1.4 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 115.7, 126.3,
give 7 (1.51 g, 10.86 mmol, 30% with 94% deuteriated methyl 128.2, 131.1, 131.6, 133.0, 137.2, 142.7, 172.7; HRMS (ESI) calcd
group). 1H NMR (CDCl3, 500 MHz) δ 7.25 (t, J = 7.8 Hz, 2H), 7.42 for [M + H]+ (C10H9D2O2) 165.0884, found 165.0887.
(t, J = 7.4 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (CDCl3,
125 MHz) δ 125.8, 128.3, 131.5, 131.9, 132.9, 141.2, 173.1; 3-Methyl-1H-isochromen-1-one-4-d
HRMS (EI+) calcd for [M]+ (C8H5D3O2) 139.0712, found 139.0713. vinylisobenzofuran-1(3H)-one-3-d (4-D)
(2-D)
and
3-
A solution of 1-D2 (16.4 mg, 010 mmol), White cat (5.0 mg, 10
µmol) and DMSO (1 mL) was added with HCl(aq) (1 N, 50 µL, 50
Methyl 2-(methyl-d3)benzoate (8)
Dimethyl sulfate (3.1 mL, 32.6 mmol) was added to a solution of µmol). The reaction mixture was stirred at 100 °C (oil bath) for
2-(methyl-d3)benzoic acid (7, 1.51 g, 10.86 mmol), potassium 12 h under an atmosphere of oxygen, added with water (1 mL)
carbonate (4.5 g, 32.6 mmol) and acetone (54 mL). The reaction and extracted with diethyl ether (2 mL × 3). The combined
mixture was stirred at rt for 8 h, filtered over a pad of celite and organic layers were dried over Na2SO4, filtered and
concentrated. The crude product was further purified by concentrated. The crude product was purified by column
column chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf chromatography to give a mixture of 2-D and 4-D (9:1, 12.0 mg,
0.50) to give 8 (1.36 g, 8.90 mmol, 82%) as a colourless liquid. 0.074 mmol, 74%) as a colourless liquid. HRMS (ESI) calcd for [M
1H NMR (CDCl3, 500 MHz) δ 3.86 (m, 3H), 7.20–7.23 (m, 2H), + H]+ (C10H8DO2) 162.0665, found 162.0659.
7.35–7.38 (dt, J = 7.8 Hz, J = 1.5 Hz, 1H), 7.88 (dd, J = 7.8 Hz, J =
1.5 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 51.7, 125.6, 129.5, (E)-3-(Ethylidene-2-d)isobenzofuran-1(3H)-one (3-D)
This journal is © The Royal Society of Chemistry 20xx
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6.
7.
W. Wei, W. Xu and X.-W. Yang, J. Asian Nat. Prod. Res.,
A solution of 1-D2 (16.4 mg, 010 mmol), White cat (2.5 mg, 5
µmol) and DMSO (1 mL) was added with sodium azide (10.0 mg,
0.15 mmol). The reaction mixture was stirred at 100 °C (oil bath)
for 12 h under an atmosphere of oxygen, added with water (1
mL) and extracted with diethyl ether (2 mL × 3). The combined
organic layers were dried over Na2SO4, filtered and
concentrated. The crude product was purified by column
chromatography (SiO2, ethyl acetate/hexanes, 1:20; Rf 0.55) to
give 3-D (10.0 mg , 0.062 mmol, 62%; 10% CH2D) as a colourless
liquid. HRMS (ESI) calcd for [M + H]+ (C10H8DO2) 162.0665, found
162.0649.
View Article Online
2017, 19, 704-711.
DOI: 10.1039/D0OB00303D
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Conclusions
We have developed a practical allylic oxidation of 2-allylbenzoic
acids to yield phthalides. Using White catalyst and
environmentally benign oxygen,85 the Wacker oxidation to form
isocoumarins is suppressed, and the selective formation of 3-
ethylidenephthalidesor 3-vinylphthalidesis achieved by
adjusting the acidity of the reaction media. A natural product is
prepared after hydrogenation of the generated 3-
ethylidenephthalide. The mechanistic study using 2-(1-
propenyl)benzoic acid and deuterated 2-allylbenzoic acid
reveals that the oxidative cleavage of allylic C-H bond to form
phthalides is competing with Wacker-type oxidation and is
sensitive to the reagents and the pH values of the reaction
media.
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Conflicts of interest
There are no conflicts to declare.
S. Kobayashi, H. Tamanoi, Y. Hasegawa, Y. Segawa and A.
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Acknowledgements
Financial support from the Ministry of Science and Technology
(MOST 104-2113-M-008-003 and MOST 105-2113-M-008-001),
Taiwan, is gratefully acknowledged. We thank Prof. John C.
Gilbert, Santa Clara University, for helpful comments. Thanks
are also due to the Institute of Chemistry, Academia Sinica and
the Valuable Instrument Center at National Central University,
Taiwan, for mass analysis.
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