RhIII-Catalyzed Regioselective Synthesis of Phthalides with Water as the Solvent

Article abstract of DOI:10.1002/ejoc.201601320

Under rhodium(III)-catalyzed conditions, a broad range of benzoic acids reacted with acrylates successfully to provide phthalides through the direct functionalization of a C–H bond followed by β-hydride elimination and intramolecular Michael addition. The reaction provides an alternative strategy for the construction of diverse and useful phthalide derivatives from readily available starting materials. In most cases, high regioselectivity was obtained, and this is the first report of the rhodium-catalyzed synthesis of phthalides in water.

Full text of DOI:10.1002/ejoc.201601320

A Journal of
Accepted Article
Title: RhIII-Catalyzed Regioselective Synthesis of Phthalides Using
Water as the Solvent
Authors: You-Quan Zhu, Jun-Xian Li, Ting-Feng Han, Jing-Li He, and
Kun Zhu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601320
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601320
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10.1002/ejoc.201601320
European Journal of Organic Chemistry
RhIII-Catalyzed Regioselective Synthesis of Phthalides Using
Water as the Solvent
You-Quan Zhu,*[a] Jun-Xian Li,[a] Ting-Feng Han,[a] Jing-Li He[a] and Kun Zhu[a]
R2O
O
Previous reports
Abstract: Under rhodium (III)-catalyzed conditions, a broad range of
benzoic acids reacted with acrylates successfully to provide
phthalides via direct functionalization of C-H bond followed by β-
hydride elimination and intramolecular Michael addition. The reaction
provides an alternative strategy for the construction of diverse and
useful phthalide derivatives from readily available starting materials.
In most cases, high regioselective was obtained and this is the first
report of rhodium-catalyzed synthesis of phthalides in water.
O
H
O
[Cp*RhCl2]2
O2 / DCE
O
OH
O
R1
R2
+
R1
O
(a)
R1
O
+
O
O
O
O
OR2
OR2
R2O
O
O
H
O
O
[Cp*RhCl2
]
2
OH
O
R1
R2
+
R1
O
(b)
R1
O
+
Cu(II) / DMF
O
O
O
OR2
OR2
O
O
Introduction
R1
R2
[(COD)RhCl]2
AgOTf/Cu(II) / PhCl
O
OH
OH
R1
+
+
(c)
O
O
O
H
O
H
Phthalides are versatile building blocks and pervasive motifs in
many bioactive natural products that show a broad range of
important bioactivities, such as antibacterial, anti-HIV, antifungal,
R2
O
This work
R1
R1
O
[Cp*RhCl2
]
2
O
R2
antibiotic,
antitumor
and immunosuppressive
activity.1
(d)
O
NaClO2 / HOAc / H2O
OR2
Consequently, a number of synthetic strategies have been
developed for their construction, involving the use of ortho-
substituted benzaldehydes(1),2 ortho-substituted cinnamate
Scheme 1. Rh(III)‐catalyzed approaches to synthesize phthalides
.
3
(2),2e, 2f, 2g, 2-hydroxy-2-phenylacetic acid (3)4 and others (4)5
cyclization (Scheme 1a).7a Similarly, Zhao and Su described a
Rh-catalyzed C-H olefination of benzoic acids, which also
generated the mixed products (Scheme 1b).7b In 2016, Li’s
group reported the synthesis of phthalides from benzoic acids
(Fig. 1).
Traditional approaches to phthalides were usually carried out
under harsh conditions or using complicated substitutes. In the
past decade, due to the high atom- and step-economy ,
transition metal-catalyzed C-H functionalization has emerged as
an efficient protocol for the synthesis of phthalides, and many
elegant reactions have been developed with the readily available
benzoic acids in the presence of oxidant.6,7 However, most of
these reactions used Ru salt as the catalyst,6 and other
transition-metal catalyst such as Rh salt usually led to low
regioselectivity of C-H functionalization or limited substrate
scope.7 For examples, Satoh and Miura discovered a Rh-Cu-
catalyzed reaction of benzoic acids with acrylates, which gave 7-
vinylphthalide derivatives via divinylation and subsequent
and
conjugated
alkenes
via
Rh-catalyzed
tandem
dehydrogenative coupling and Michael addition. Despite high
regioselectivity was obtained, only α,β-unsaturated ketones were
applied into this reaction, and other conjugated alkenes as α,β-
unsaturated esters did not undergo this reaction well (Scheme
1c).7c Therefore, more effective synthetic protocols to phthalides
via Rh-catalyzed C-H functionalization with wide substrates
scope are highly desired.
In the past decade, Rh(III) catalysis has shown high
functional group tolerance and unique reactivity and selectivity,
due to its unique properties in mediating C–H activation that is
compatible with subsequent functionalization reactions. This
method has proved powerful in delivering molecular complexity,
especially in the synthesis of a variety of useful heterocycles.8
Motivated by these and in continuation of our interest in Rh-
catalyzed heterocycle building,9 herein, we report an efficient
approach to synthesize phthalides via oxidative coupling of
benzoic acids with unsaturated esters under mild conditions
using sodium chlorite as the oxidant (Scheme 1d). Notably,
different from existing examples of Rh-catalyzed synthesis of
phthalides in which organic solvents are generally used, our
protocol is more eco-friendly by carrying out the reaction in
water.
O
CO2R1
H
R
R
1
2
R = CHO,CO2R1, CO2H,
R = CHO, CO2H,
CN, Br.
CH=CHCO2R2.
O
OH
R1
CO2H
R
H
3
4
R = CO2R1, H; R1 = phenyl,
alkyl and heterocycles
Figure 1． The Structures of Compounds 1-4
Results and Discussion
We started our study by examining the model reaction of para-
fluorobenzoic acid (1a) and methyl acrylate (2a) in the presence
of sodium chlorite as the oxidant (Table 1). Initially, the model
reaction was conducted at 100 oC in water using [Cp*RhCl2]2 as
[a]
You-Quan, Zhu
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071, China
E-mail: zyq8165@nankai.edu.cn
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10.1002/ejoc.201601320
European Journal of Organic Chemistry
Table 2. Scope of isobenzofuran-1(3H)-ones substituted at the C-3 position a
the catalyst. The desired product (3a) was generated in 51%
yield (Table 1, entry 1). When the catalyst was replaced by
RhCl3, Pd(OAc)2, Cp*Rh(MeCN)3(SbF6)2, [Ru(p-cymene)Cl2]2
and [Rh(OAc)2]2, respectively, no desired product was detected
(Table 1, entries 2-6). When the reaction was carried out in other
solvents such as dioxane, N,N-dimethylformamide (DMF),
dichloroethane (DCE), dimethyl sulfoxide (DMSO) and
acetonitrile, 3a also was not generated (Table 1, entries 7-11).
This was attributed to the fact that water can dissolve sodium
chlorite better and help chlorous acid (a stronger oxidant) be
formed. However, when the temperature was elevated to 150 oC,
the yield was decreased to 25% (Table 1, entry 12), presumably
because the decomposition of 2a might result in the insufficient
transformation of 1a to the desired product (3a). The best result
(85%) was obtained when the temperature was dropped to 120
oC (Table 1, entry 13), thereby suggesting that the optimal
O
O
R1
O
[Cp*RhCl2]2 / H2O
NaClO2 / HOAc
O
OH
R1
R2
+
O
O
H
120 o
C
2
R2
O
1
3
O
O
O
O
O
F3C
O
O
O
F
O2N
O
O
H3C
O
O
O
O
3a 80%
3b 75%
3c 49%
O
3d 47%
O
CO2CH3
O
O
O
O
Cl
O
O
O
Cl
H3CO
H3CO
O
O
O
O
H3CO
3fb
81% (3fa : 3fb :3fc = 8:1:0.5)b
O
O
3fa
O
O
3e 75%
o
3fc
temperature was about 120 C. However, a little of hydrolysis
O
O
O
F
O
O
F
O
product (CO2CH3 to CO2H) of 3a was detected by GCMS.
Further decreasing the amount of sodium chlorite, acetic acid or
using other acids (such as pivalic acid and trifluoroacetic acid)
led to low yield, which indicating that the nature of acid additives
O
O
O
O
O
O
F3C
O
O
O
O
O
F
O
3k 68%
3g 30%
3h 43%
3i 70%
3j 65%
O
O
O
O
O
O
O
O
O
Table 1. Effect of Catalyst, Solvent, Temperature and Acid a
O
O
F
O
H3CO
O
O
O
O
O
3m 71%
3l 81%
3o 80%
3n 65%
O
O
O
O
O
D
Catalyst / H2O
NaClO2 / HOAc
O
O
O
OH
O
O
+
D
F
O
O
O
O
O
O
F
H
D
H3C
O
Cl
O2N
O
O
O
1a
2a
O
3a
D
3p 60%
O
O
3r 38%
3q 45%
3s 55%
O
O
Catalyst
Solvent
Temp
(oC)
Acid
Yield
(%) b
aReaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), [Cp*RhCl2]2 (5 mol%), acetic
acid (0.2 mmol), sodium chlorite(0.6 mmol), H2O (0.5 mL), 24 h; the reaction
vessels were closed and the reaction atmosphere was air. Yield of purified
product is reported. b the ratio was determined by 1H NMR analysis of the
crude reaction mixture using mesitylene as internal standard.
Entry
[Cp*RhCl2]2
RhCl3,
100
100
HOAc
HOAc
1
2
3
4
5
H2O
H2O
51
0
100
100
100
100
HOAc
HOAc
HOAc
HOAc
Pd(OAc)2
H2O
H2O
H2O
H2O
0
was crucial to the reaction outcome (Table 1, entries 14-17).
Under the optimum reaction conditions above (Table 1, entry
13), the substrate scope of benzoic acids was investigated. As
shown in Table 2, benzoic acids with electron-donating groups
(methyl, methoxyl) or weak electron-withdrawing groups (fluoro
and chloro) showed efficiently reactivity, producing the desired
products in good yields (3a, 3b, 3e, 3l, 3o). However, when the
benzoic acid was substituted by a nitro or trifluoromethyl group,
the yields of corresponding products were decreased
Rh(MeCN)3(SbF6)2
[Ru(p-cymene)Cl2]2
[Rh(OAc)2]2
0
0
6
7
8
9
0
0
0
0
100
100
HOAc
HOAc
[Cp*RhCl2]2
[Cp*RhCl2]2
dioxane
DMF
100
HOAc
[Cp*RhCl2]2
DCE
100
100
HOAc
HOAc
10
11
[Cp*RhCl2]2
[Cp*RhCl2]2
DMSO
CH3CN
0
0
significantly, along with large amount of unreacted benzoic acids.
HOAc
HOAc
HOAc
[Cp*RhCl2]2
[Cp*RhCl2]2
150
120
12
13
H2O
H2O
25
85
D
O
D
D
CO2H
D
CO2H
+
O
[Cp*RhCl2]2 / H2O
O
+
NaClO2 / HOAc
120 oC
O
O
(0.1mmol)
14
[Cp*RhCl2]2
[Cp*RhCl2]2
H2O
H2O
120
39
D
-1j
2a
0.6 mmol
1j
0.1 mmol
O
[D5]
0.1 mmol
+
pivalic acid
15
16
17
120
120
120
45
31
D
D
O
D
D
[Cp*RhCl2]2
[Cp*RhCl2]2
H2O
H2O
CF3CO2H
HOAc
O
58 c
O
aReaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), catalyst (5 mol%), acid (0.2
O
mmol), sodium chlorite (0.6 mmol), solvent (0.5 mL), 24 h; the reaction vessels
b
Scheme 2. Hydrogen-deuterium exchange experiments.
were closed and the reaction atmosphere was air. the yield was determined
1
by H NMR analysis of the crude reaction mixture using mesitylene as internal
standard. c sodium chlorite (0.4 mmol).
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10.1002/ejoc.201601320
European Journal of Organic Chemistry
[Cp*RhCl2]2
[Cp*RhCl2]2 and sodium chlorite as the catalyst and the oxidant,
respectively. The reactions provided target products in good
yields, while no extra additive were required. This easy
approach affords an alternative strategy for the construction of
diverse and useful phthalide derivatives.
HOAc
NaClO2
O
O
Cp*RhCl2
R
NaOAc
3j
Michael addition
CO2H
CO2H
Experimental Section
1j
R
Solvents and reagents were purchased from Sigma-Aldrich and were
used without further purification unless otherwise specified. 1H and 13C
NMR spectra were recorded on Bruker 400 MHz, or 500 MHz
spectrometers; internal reference of δ = 7.28 or 77.0 CHCl3 as standard.
HRMS was conducted using electro-spraying ionization (ESI), and was
performed by McGill University on a Thermo-Scientific Exactive Orbitrap.
Sodium adducts [M + Na+] were used for empirical formula confirmation.
D
Rh
AcO
OAc
C-H activation
bata-H
elimination
HOAc + N
aClO2
Rh OAc
O
Na
O
Na
O
O
Rh
OAc
General Synthetic Procedure for Compounds 3a – 3r
A
R
An reaction vessel was charged with [Cp*RhCl2]2 (6.18 mg, 5 mol%, 0.01
mmol), NaClO2(54 mg, 0.6 mmol), substituted benzoic acids (0.2 mmol),
CH3CO2H (0.2 mmol), acrylate (0.6 mmol), and H2O (0.5 mL). The
C
migratory
insertion
R
R
Rh
O
o
Na
reaction vessels were closed (air) and the mixture was stirred at 120 C
O
(oil bath temperature) for 24 h. After this time, the resulting mixture was
cooled down to room temperature, extracted with ethyl acetate (10 mL)
for three times. The organic phase was dried with dry Na2SO4, filtered,
and then concentrated under vacuum. The residue was purified by
preparative TLC (eluent: hexane/ethyl acetate = 10 : 1) to afford the
corresponding product.
B
Scheme 3. Proposed catalytic cycle for rhodium oxidase C-H alkenylation.
R
= CO2CH3 or CO2C2H5
This is probably due to the more difficult process of C-H
activation (3c, 3d, 3h, 3r). When 4-methoxybenzoic acid was
used as reactant, three products (3fa, 3fb and 3fc) were
obtained, which maybe derived from the chlorination of anisic
acid by sodium chlorite. Compared with previous reports, 6,7 the
divinyllation of this reaction was decreased significantly,
presumably because of the specific oxidizing ability of sodium
chlorite in acidic solution.
O
R1
[Cp*RhCl2]2 (5 mol%)
CO2R2
NaClO2/CH3CO2H/H2O R1
O
CO2H
+
OR2
120 oC, 24 h
H
3
1
2
O
Methyl 2-(6-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3a)
White solid, mp 119.8-121.5 oC; yield 80%; 1H NMR (400 MHz, CDCl3) δ
8.12 - 8.17, 7.89 - 7.95 (m, 1H), 7.10 - 7.35 (m, 2H), 5.86 (t, J = 6.4Hz,
1H), 3.79 (s, 3H), 2.83 - 3.06 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
169.53, 168.59, 167.89, 165.34, 151.56, 151.46, 132.87, 132.77, 128.30,
128.19, 122.03, 122.01, 117.95, 117.71, 115.81, 115.59, 109.92, 109.67,
76.19, 76.17, 52.31, 39.05. 19F NMR (377 MHz, CDCl3) δ -102.04, -
104.37. HRMS (ESI) m/z calcd for C11H9FO4 [M + Na+] 247.0377, found
247.0386.
Methyl 2-(6-methyl-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
(3b) White solid, mp 87.8-88.8 oC; yield 75%; 1H NMR (400 MHz, CDCl3)
δ 7.80 (d, J = 7.6Hz, 1H), 7.35 - 7.39 (m, 1H), 7.28 - 7.31 (m, 1H), 5.85 (t,
J = 6.4Hz, 1H), 3.79 (s, 3H), 2.83-2.97 (m, 2H), 2.51 (s, 3H). 13C NMR
(126 MHz, CDCl3) δ 169.86, 169.82, 149.26, 145.62, 130.74, 125.63,
123.35, 122.35, 76.64, 52.22, 39.44, 22.13. HRMS (ESI) m/z calcd for
C12H12O4 [M + Na+] 243.0628, found 243.0633.
According to the reported method,7c an intermolecular
competition reaction between 1j and [D ]-1j for C-H alkenylation
5
was performed and the kH/D value was 2.9 (Scheme 2); this
suggests that the ortho-C-H bond cleavage is likely the rate-
limiting step in this transformation.
7
Based on our experiment and the reported literature,6,
a
plausible mechanism was proposed (Scheme 3). The first step is
the generation of an Rh benzoate and forms rhodacycle
intermediate
A through electrophilic substitution of ortho-
rhodation. Then, the coordination of the olefin substrate to the
Rh center forms complex B. Finally, complex B undergoes
migration/insertion, β-hydride elimination and intramolecular
Michael addition to yield the final product 3j.
Methyl
2-(3-oxo-5-(trifluoromethyl)-1,3-dihydroisobenzofuran-1-yl)
acetate (3c) Colorless liquid; yield 49%; 1H NMR (400 MHz, CDCl3) δ
7.60-8.41 (m, 3H), 5.97 (t, J = 6.4Hz, 1H), 3.80 (s, 3H), 2.88 - 3.10 (m,
2H). 13C NMR (126 MHz, CDCl3) δ 169.39, 168.24, 151.83, 133.35,
132.78, 132.51, 131.19, 131.17, 130.26, 129.97, 129.25, 126.95, 124.35,
123.29, 123.26, 123.23, 122.18, 76.90, 52.38, 38.85. 19F NMR (471 MHz,
CDCl3) δ -62.58, -62.88. HRMS (ESI) m/z calcd for C12H9F3O4 [M + Na+]
297.0345, found 297.0354.
Conclusions
In summary, we have developed a convenient cascade Rh(III)-
catalyzed C-H activation and annulation reactions in water in the
presence of non-transition-metal oxidant for the synthesis of
phthalides. The protocol employs readily available substituted
benzoic acids and acrylates as the starting materials,
Methyl 2-(6-nitro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3d)
White solid, mp 121.4-122.2 oC; yield 47%; 1H NMR (400 MHz, CDCl3) δ
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10.1002/ejoc.201601320
European Journal of Organic Chemistry
8.42 - 8.47 (m, 2H), 8.12 (d, J = 8.0Hz, 1H), 5.99 (t, J = 6.4Hz, 1H), 3.80
(s, 3H), 2.95 - 3.16 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 169.12,
167.42, 151.77, 149.71, 131.11, 127.16, 125.20, 118.19, 77.27, 77.01,
76.76, 52.47, 38.55. HRMS (ESI) m/z calcd for C11H9NO6 [M + Na+]
274.0322, found 274.0327.
Methyl 2-(6-chloro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
(3e)7b White solid, mp 116.6-117.4 oC; yield 75%; 1H NMR (400 MHz,
CDCl3) δ 7.86 (dd, J = 1.6Hz, 1H), 7.53 - 7.57 (m, 2H), 5.86 (t, J = 6.8Hz,
1H), 3.79 (s, 3H), 2.84 - 3.05 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
169.48, 168.62, 150.33, 141.07, 130.39, 127.02, 124.47, 122.77, 76.28,
52.32, 39.00.
= 6.8Hz, 1H), 4.23 (t, J = 7.2Hz, 2H), 2.85 - 2.99 (m, 2H), 1.29 (q, J =
7.2Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.87, 169.23, 148.80,
134.27, 129.55, 125.99, 125.85, 122.08, 77.00, 61.28, 39.58, 14.12.
Ethyl 2-(4,6-dimethyl-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
(3m) 6c liquid; yield 71%; 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 7.07
(s, 1H), 5.77 (t, J = 6.4Hz, 1H), 4.23 (t, J = 7.2Hz, 2H), 2.85 (d, J = 6.4Hz,
2H), 2.65 (s, 3H), 2.44 (s, 3H), 1.29 (t, J = 7.2Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 170.09, 169.46, 149.85, 145.16, 139.50, 132.21, 120.92,
119.69, 75.80, 61.20, 39.86, 21.92, 17.25, 14.14. HRMS (ESI) m/z calcd
for C14H16O4 [M + Na+] 271.0941, found 271.0949.
Ethyl 2-(6-methoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
5c
Methyl 2-(6-methoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
(3n)
White solid, mp 56.5-56.7 oC; yield 65%; 1H NMR (400 MHz,
7b
(3fa)
White solid, mp 98.5-99.7 oC; yield 68%. 1H NMR (400 MHz,
CDCl3) δ 7.82 (d, J = 8.4Hz, 1H), 7.06 (dd, J = 2.0Hz, 1H), 6.95 (d, J =
2.0Hz, 1H), 5.81 (t, J = 7.2Hz, 1H), 4.24 (q, J = 6.8Hz, 2H), 3.91 (s, 3H),
2.81 - 2.98 (m, 2H), 1.30 (t, J = 7.2Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
169.63, 169.38, 164.84, 151.62, 127.34, 118.16, 116.75, 106.27, 76.30,
61.28, 55.88, 39.66, 14.15. HRMS (ESI) m/z calcd for C12H2O5 [M + Na+]
259.0577, found 259.0577.
Ethyl 2-(6-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3o)
White solid, mp 113-115 oC; yield 80%; 1H NMR (500 MHz, CDCl3) δ
7.90 - 7.94 (m, 1H), 7.22 - 7.29 (m, 2H), 5.85 (t, J = 7.0Hz, 1H), 4.24 (q, J
= 7.5Hz, 2H), 2.80 - 3.05 (m, 2H), 1.29 (t, J = 7.5Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 169.05, 168.65, 167.62, 165.58, 151.65, 151.57, 128.23,
128.15, 122.07, 122.05, 117.88, 117.69, 109.90, 109.71, 76.28, 76.26,
61.41, 39.24, 14.11. 19F NMR (471 MHz, CDCl3) δ -101.85. HRMS (ESI)
m/z calcd for C12H11FO4 [M + Na+] 261.0534, found 261.0539.
CDCl3) δ 7.82 (d, J = 8.4Hz, 1H), 7.06 (dd, J = 2.0Hz, 1H), 6.95 (d, J =
2.0Hz, 1H), 5.81 (t, J = 6.8Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 2.83 - 2.97
(m, 2H). 13C NMR (101 MHz, CDCl3) δ 169.83, 169.53, 164.86, 151.51,
127.38, 118.11, 116.72, 106.31, 76.21, 55.88, 52.20, 39.46.
Methyl 2-(6-methoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
(3fb) White solid, mp 112.5-113.7 oC; yield 9%. 1H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 8.4Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 5.86 - 5.91 (m,
1H), 4.04 (s, 3H), 3.75 (s, 3H), 3.47 (dd, J = 2.8 Hz, 1H), 2.75 (t, J =
8.8Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 169.41, 168.57, 159.91,
147.27, 125.69, 119.98, 116.25, 113.37, 76.16, 56.98, 52.24, 36.96.
HRMS (ESI) m/z calcd for C12H11ClO5 [M + Na+] 293.0187, found
293.0189.
Methyl 2-(5,7-difluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
(3g) White solid, mp 65.6-66.7 oC; yield 30%; 1H NMR (500 MHz, CDCl3)
δ 7.46 (dd, J = 1.5Hz, 1H), 7.13 - 7.20 (m, 1H), 5.97 (dd, J = 1.5Hz, 1H),
3.76 (s, 3H), 3.20 (dd, J = 3.2Hz, 1H), 2.84 (q, J = 6.4Hz, 1H). 13C NMR
(126 MHz, CDCl3) δ 168.84, 167.34, 162.93, 157.65, 155.63, 130.40,
130.15, 110.10, 109.92, 109.88, 109.70, 109.00, 108.97, 108.81, 108.78,
52.33, 37.84, 29.71. 19F NMR (471 MHz, CDCl3) δ -105.46, -114.48.
HRMS (ESI) m/z calcd for C11H8F2O4 [M + Na+] 265.0283, found
265.0291.
Ethyl 2-(6-methyl-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3p)
5c
1
White solid, mp 98-98.5 oC; yield 60%; H NMR (400 MHz, CDCl3) δ
7.80 (d, J = 7.8Hz, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.30 (d, J = 0.4Hz, 1H),
5.85 (t, J = 6.8Hz, 1H), 4.24 (q, J = 6.8Hz, 2H), 2.80 - 2.95 (m, 2H), 2.51
(s, 3H), 1.30(t, J = 7.2Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.91,
169.34, 149.35, 145.56, 130.68, 125.59, 123.41, 122.37, 76.72, 61.25,
39.65, 22.11, 14.13.
Ethyl 2-(6-chloro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3q)
10
Methyl
2-(6-trifluoromethyl-3-oxo-1,3-dihydroisobenzofuran-1-yl)
White solid, mp 124.3-126.1 oC; yield 45%; 1H NMR (500 MHz, CDCl3)
acetate (3h) White solid, mp 44-45 oC; yield 43%; 1H NMR (400 MHz,
CDCl3) δ 8.07 (d, J = 8.0Hz, 1H), 7.82 - 7.89 (m, 1H), 5.96 (t, J = 6.8Hz,
1H), 3.80 (s, 3H), 2.90 - 3.10(m, 2H). 13C NMR (126 MHz, CDCl3) δ
169.37, 168.28, 149.09, 136.28, 129.23, 126.99, 126.96, 126.63, 122.16,
119.80, 119.76, 76.88, 52.39, 38.90. 19F NMR (471 MHz, CDCl3) δ -
62.57. HMRS (ESI) m/z calcd for C12H9F3O4 [M + Na+] 297.0345, found
297.0356.
Methyl 2-(4-fluoro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3i)
White solid, mp 87.4-88.3 oC; yield 70%; 1H NMR (400 MHz, CDCl3) δ
7.66 - 7.74 (m, 1H), 7.18 - 7.33 (m, 2H), 5.90 (t, J = 6.8Hz, 1H), 3.79 (s,
3H), 2.87 - 3.03 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 169.46, 165.81,
165.78, 160.74, 158.64, 151.28, 151.27, 136.94, 136.88, 118.05, 118.02,
116.74, 116.59, 113.90, 113.79, 76.53, 52.31, 39.22. 19F NMR (377 MHz,
CDCl3) δ -113.36. HRMS (ESI) m/z calcd for C11H9FO4 [M + Na+]
247.0377, found 247.0380.
δ 7.86 (d, J = 8.5Hz, 1H), 7.54 - 7.57 (m, 2H), 5.86 (t, J = 6.5Hz, 1H),
4.25 (q, J = 7.0Hz, 2H), 2.84 - 3.03 (m, 2H), 1.31 (t, J = 7.0Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 169.02, 168.71, 150.43, 141.04, 130.35,
127.00, 124.52, 122.80, 76.37, 61.45, 39.23, 14.12.
Ethyl 2-(6-nitro-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3r)
White solid, mp 116.8-117.6 oC; yield 38%; 1H NMR (400 MHz, CDCl3) δ
8.43 - 8.47(m, 2H), 8.12 (dd, J = 0.8Hz, 1H), 5.99 (t, J = 6.4Hz, 1H), 4.26
(q, J = 7.2Hz, 2H), 2.85 - 3.25 (m, 2H), 1.31 (t, J = 7.2Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ 168.63, 167.47, 151.76, 149.82, 131.14, 127.12,
125.15, 118.21, 76.83, 61.66, 38.80, 14.11. HMRS (ESI) m/z calcd for
C
12H11NO6 [M + Na+] 288.0479, found 288.0481.
Procedures of deuteration experiments 7b
A reaction vessel was charged with [Cp*RhCl2]2 (6.18 mg, 5 mol %, 0.01
mmol), methyl acrylate (0.5 mmol), benzoic acid (0.1 mmol), d5-benzoic
acid (0.1 mmol), acetic acid (0.2 mmol), sodium chlorite (0.6 mmol), H2O
(0.5 mL). The reaction mixture was slowly heated to 120 oC and stirred
for 7 h. Upon completion, the reaction mixture was diluted with 10mL
ethyl acetate, filtered through a pad of silica gel, followed by washing the
pad of the silica gel with the ethyl acetate (20 mL).The filtrate was
concentrated under reduced pressure. The residue was then purified by
TLC to provide the corresponding product 3. The isolated products were
analyzed by 1H NMR, the KIE value was average of three runs.
Methyl 2-(3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3j) 7b Liquid;
yield 65%; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.6Hz, 1H), 7.71 (td,
J = 1.2Hz and 7.6Hz, 1H), 7.58 (t, J =7.2Hz, 1H), 7.52 (dd, J = 0.8Hz,
1H), 5.91 (t, J = 6.8Hz, 1H), 3.79 (s, 1H), 2.86 - 3.00 (m, 2H). 13C NMR
(126 MHz, CDCl3) δ 169.83, 169.73, 148.70, 134.32, 129.61, 125.92,
125.90, 122.07, 76.93, 52.24, 39.39.
Methyl 2-(4-methyl-3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate
7b
(3k)
White solid, mp 89.0-90.2 oC; yield 68%; 1H NMR (500 MHz,
CDCl3) δ 7.55 (t, J = 7.5Hz, 1H), 7.27 - 7.33 (m, 2H), 5.84 (t, J = 6.5Hz,
1H), 3.79 (s, 3H), 2.89 (d, J = 6.5Hz, 2H), 2.71 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 170.01, 169.85, 149.19, 140.00, 134.00, 131.19, 123.36,
119.24, 76.01, 52.21, 39.64, 17.36.
2f
Ethyl 2-(3-oxo-1,3-dihydroisobenzofuran-1-yl) acetate (3l)
White
Acknowledgements
o
1
solid, mp 56.0-58.0 C; yield 81%; H NMR (400 MHz, CDCl3) δ 7.93 (d,
J = 7.6Hz, 1H), 7.71 (t, J = 7.6Hz, 1H), 7.56 (td, J = 7.6Hz, 2H), 5.91 (t, J
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10.1002/ejoc.201601320
European Journal of Organic Chemistry
Sudalai, Org. Biomol. Chem., 2012, 10, 3655; c) X. Wu, P. Nilsson,
M. Larhed, J. Org. Chem., 2005, 70, 346.
We are grateful for the support from the National Natural
Science Foundation of China (No. 21072108 and 21372134)
and thank Prof. Chao-Jun Li (McGill University) for providing the
lab and facility for the starting of the research.
[4]
[5]
L. Chen, H. Li, F. Yu, L. Wang, Chem. Commun., 2014, 50, 14866.
a) C.-H. Yeh, Y.-C. Lin, S. Mannathan, K. Hung, C.-H. Cheng, Adv.
Synth. Catal., 2014, 356, 831; b) A. Dragan, D. H. Jones, A. R.
Kennedy, N. C. O. Tomkinson, Org. Lett. 2016, 18, 3086; c) N. K.
Mishra, J. Park, M. Choi, S. Sharma, H. Jo, T. Jeong, S. Han, S.
Kim, I. S. Kim, Eur. J. Org. Chem. 2016, 3076.
Keywords: benzoic acid • methyl acrylate • sodium chlorite •
phthalides • transition metal-catalyzed C-H functionaliza-tion
[6]
a) A. Bechtoldt, C. Tirler, K. Raghuvanshi, S. Warratz, C. Kornhaa, L.
Ackermann, Angew. Chem. Int. Ed. 2016, 55, 264; b) S. Warratz, C.
Kornhaass, A. Cajaraville, B. Niepӧter, D. Stalke, L. Ackermann,
Angew. Chem. Int. Ed., 2015, 54, 5513; c) H. Zhao, T. Zhang, T.
Yan, M. Cai, J. Org. Chem. 2015, 80, 8849; d) L. Ackermann, J.
Pospech, Org. Lett., 2011, 13, 4153; e) H. Miura, K. Tsutsui, K.
____________
[1]
a) R. Karmakar, P. Pahari and D. Mal, Chem. Rev., 2014, 114,
6213; b) G. Strobel, E. Ford, J. Worapong, J. K. Harper, A. M. Arif,
D. M. Grant, P. C. W. Fung and R. M. W. Chau, Phytochemistry,
2002, 60, 179; c) A. Arnone, G. Assante, G. Nasini, S. Strada and A.
Vercesi, J. Nat. Prod., 2002, 65, 48; d) T. H. Chou, I. S. Chen, T. L.
Hwang, T. C. Wang, T. H. Lee, L. Y. Cheng, Y. C. Chang, J. Y. Cho
and J. J. Chen, J. Nat. Prod., 2008, 71, 1692; e) L. P. L. Logrado, C.
O. Santos, L. A. S. Romeiro, A. M. Costa, J. R. O. Ferreira, B. C.
Cavalcanti, O. M. de Moraes, L. V. Costa-Lotufo, C. Pessoa and M.
L. dos Santos, Eur. J. Med. Chem., 2010, 45, 3480.
Wada, T. Shishido, Chem. Commun., 2015, 51, 1654; f) P.
Gandeepan, P. Rajamalli, C.-H. Cheng, Chem. Eur. J., 2015, 21,
9198; g) M. Miura, T. Tsuda, T. Satoh, S. Pivsa, M. Nomura, J. Org.
Chem., 1998, 63, 5211; h) X. Shi, C.-J. Li, Adv. Synth. Catal., 2012
354, 2933.
,
[7]
[8]
a) K. Ueura, T. Satoh, M. Miura, Org. Lett. 2007, 9, 1407; b) Q. Jiang, C.
Zhu, H. Zhao, W. Su, Chem. Asian J. 2016, 11, 356. c) A. Renzetti, H.
Nakazawa, C.-J. Li, RSC Adv. 2016, 6, 40626.
[2]
a) D. M. Antonia, C. Gianluca, M. Vijaykumar, D. C. Paolo, F.
Rosanna, M. Antonio, Tetrahedron, 2012, 68, 6146; b) T. Matsuda,
a) H. Wang, N. Schroeder,F. Glorius, Angew. Chem. Int. Ed. 2013, 52,
5386; b) B.-J. Li, H.-Y. Wang, Q.-L. Zhu, Z.-J. Shi, Angew. Chem. Int.
Ed., 2012, 51, 3948; c) Y.-F. Wang, K. K. Toh, J.-Y. Lee, S. Chiba,
Angew. Chem. Int. Ed., 2011, 50, 5927; d) G. Zhang, L. Yang, Y. Wang,
Y. Xie, H. Huang, J. Am. Chem. Soc., 2013,135, 8850.
K. Suzuki, S. Abe, H. Kirikae, N. Okada, Tetrahedron, 2015
,
71, 9264; c) N. S. Jaiprakash, A. M. K. A. Siddique, B. S. Devanand,
Chin. Chem. Lettt, 2011, 22, 163; d) S. C. Shen, X.-W. Sun, G. Lin,
Synthesis, 2013, 45, 1181; e) S. W. Youn, H. S. Song, J. H. Park,
Org. Lett. 2014, 16, 1028; f) S. W. Youn, H. S. Song, J. H. Park, Org.
Biomol. Chem., 2014, 12, 2388; g) N. Yasmina, J. K. Ray, RSC
Adv., 2013, 3, 25631.
[9]
Y.-Q. Zhu, Y. Liu, H. N. Wang, W. B. Liu, C.-J. Li, Org. Chem. Front.
2016, 3, 971.
[10]
A. Allahdad, D. W. Knight, J. Chem. Soc., Perkin Transactions 1,
[3]
a) E. T. Penha, J. A. Forni, A. F. P. Biajoli, C. R. D. Correia,
Tetrahedron Lett., 2011, 52, 6342; b) R. S. Reddy, I. N. C. Kiran, A.
1982, 1855.
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10.1002/ejoc.201601320
European Journal of Organic Chemistry
Entry for the Table of Contents
Layout 2:
FULL PAPER
Heterocycle synthesis
You-Quan Zhu,*[a] Jun-Xian Li,[a] Ting-
Feng Han,[a] Jing-Li He[a] and Kun Zhu [a]
Page No. – Page No.
RhIII-Catalyzed regioselective
Synthesis of Phthalides Using Water
as the Solvent
A convenient cascade Rh(III)-catalyzed C-H activation and annulation reactions in
water in the presence of non-transition-metal oxidant has been developed for the
synthesis of phthalides.
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