Regio- and Stereoselective Synthesis of (Z)-3-Ylidenephthalides via H3PMo12O40-Catalyzed Cyclization of 2-Acylbenzoic Acids with Benzylic Alcohols

Article abstract of DOI:10.1002/cjoc.202100397

We report an exclusively tandem C—O and C—C bond forming beyond the esterification and cyclization reaction of 2-acylbenzoic acids with alcohols to regio- and stereoselective synthesis of the (Z)-3-ylidenephthalides. The reaction uses the nontoxic, inexpensive H₃PMo₁₂O₄₀ as catalyst and produces water as the sole by-product, making the reaction environmentally benign and sustainable. Moreover, this reaction features an eco-friendly reaction condition, facile scalability, and easy derivatization of the products to drugs and bioactive compounds. The mechanism studies and density functional theory calculations reveal that the appropriate acid catalyst is the key to the selectivity of this transformation.

Full text of DOI:10.1002/cjoc.202100397

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Regio- and Stereoselective Synthesis of (Z)-3-Ylidenephthalides via
H3PMo12O40-Catalyzed Cyclization of 2-Acylbenzoic Acids with Benzylic Alcohols
Authors: Guoping Yang, Ke Li, Xiaoling Lin, Yijin Li, Chengxing Cui, Shixiong Li,*
Yuanyuan Cheng,* and Yufeng Liu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100397.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202100397.
ISSN 1001-604X • CN 31-1547/O6
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Yang Guoping (Orcid ID: 0000-0002-4891-2290)
Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Regio- and Stereoselective Synthesis of (Z)-3-Ylidenephthalides
via H3PMo12O40-Catalyzed Cyclization of 2-Acylbenzoic Acids with
Benzylic Alcohols
Guoping Yang,a Ke Li,a Xiaoling Lin,a Yijin Li,a Chengxing Cui,c Shixiong Li,*,b Yuanyuan Cheng,*,a and Yufeng Liu*,a
a Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation, Jiangxi Province Key Laboratory of Synthetic Chemistry, East China
University of Technology, Nanchang, 330013, P. R. China
b School of Chemical Engineering and Resource Recycling, Wuzhou University, Wuzhou, 543002, P. R. China
c School of Chemical and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang, 453003, P. R. China
Keywords
Phosphomolybdic acid |Regio- and stereoselective | (Z)-3-ylidenephthalides | 2-Acylbenzoic acids | Benzylic alcohols
Main observation and conclusion
We report an exclusively tandem C−O and C−C bond forming beyond the esterification and cyclization reaction of 2-acylbenzoic acids
with alcohols to regio- and stereoselective synthesis the (Z)-3-ylidenephthalides. The reaction uses the nontoxic, inexpensive
H3PMo12O40 as catalyst and produces water as the sole by-product, making the reaction environmentally benign and sustainable.
Moreover, this reaction features an eco-friendly reaction conditions, facile scalability, and easy derivatization of the products to drugs
and bioactive compounds. The mechanism studies and DFT calculations reveal that the appropriate acid catalyst is the key to the
selectivity of this transformation.
Comprehensive Graphic Content
*E-mail: lsx1324@163.com; chengyyup@163.com; yfliu@ecut.edu.cn
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Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX©
2021
SIOC,
CAS,
Shanghai,
&
WILEY-VCH
GmbH
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First author et al.
Report
Environmentally benign and inexpensive polyoxometalates (POMs)
are demonstrated to be practical and selective catalysts for the
coupling and cyclization reaction.[10] In this protocol, we believe
that the benzylic alcohol is protonated by phosphomolybdic acid
(H3PMo12O40) to generate a stable benzyl cation,[11] which avoiding
the addition reaction with carbonyl group. Furthermore, the side
products such as phthalides or ester are hard to exist because of
the highly acidic of reaction condition.
Background and Originality Content
3-Ylidenephthalides and polyheterocycles containing
a
isobenzofuran-1(3H)-ones are common motifs in drugs, natural
products, wide-ranging biological activities and important
intermediates to further build other bioactive heterocyclic
compounds in orgnic synthesis.[1] For example, the Chinese angelica
ingredient
3-butylidenephthalide
exhibit
antidiabetic,
antispasmodic, anticoagulant, and antiproliferative activities.[1c]
Multiple methods to generate such structures have been
disclosed.[2] The main methods of intermolecular cyclization
methods include the modified Perkin or Julia reaction with phthalic
anhydride,[3] transition-metal-catalyzed cyclization of benzoic acid
derivatives with alkenes or alkynes and the CO insertion-annulation
reactions.[4] An alternative strategy is the intramolecular cyclization
reaction such as the cyclization of 2-allyl or 2-alkenyl benzoic acid
derivatives and the annulation of 2-alkynylbenzaldehydes.[5]
Although these methods provided various strategies for the
preparation of 3-ylidenephthalides, they still have limitations
including harsh reaction conditions, expensive catalysts, ligands
and side products.[6]
Results and Discussion
We initiated our studies using 2-acetylbenzoic acid (1a) and
diphenylmethanol (2a) as the model substrates to vary the reaction
parameters (Table 1). After the extensive screening (see Supporting
Information Tables S1-S6 for more details), we found that the
treatment of substrates in chlorobenzene (PhCl) at 80 oC for 3 h in
the presence of a catalytic amount of H3PMo12O40 resulted in the
formation of product 3a in 93% yield (Table 1, entry 3). The
structure of 3a was conformed by crystal and the Z-selectivity may
be due to the Z-configuration of product is more stable than its E-
configuration and steric hindrance effect. Decreased yields were
obtained with other Keggin-type POMs, e.g., H4SiW12O40 and
H3PW12O40 as the catalyst, which may be due to the softest
heteropoly anion of H3PMo12O40 can stabilize the reaction
intermediate (entries 1-3).[11] Other Bronsted acid like p-TSA did not
improve the yield compared to the POMs (entry 4). Two
representative Lewis acids, FeCl3 and Cu(OTf)2, were tested as
catalysts under the same conditions and did not form any desired
product (entries 5 and 6). No product was obtained in the absence
of catalyst (entry 7). Solvent screening results seem indicated that
nonpolar solvents are beneficial to give a better yield than polar
solvents (entries 8-13). Low temperature lead to a lower yield and
increasing temperature did not improve the yield (entry 14 and 15).
The cyclization of 2-acylbenzoic acids is a convenient method
for the direct and atom-economical synthesis of 3-
ylidenephthalides. Some catalytic systems have been developed in
this area such as SOCl2/CHCl3 system, TSTU/DIEA system and
AlCl3/CH3CN system.[7] However, the above methods need toxic or
expensive reagents and the intramolecular strategy result in the
limitation of products, only the monosubstituted of terminal
double bond products can be obtained (Scheme 1A). Meanwhile, 2-
acylbenzoic acids are recognized as the crucial substrates coupled
with nucleophile such as aniline or alcohol in the intramolecular
cyclization reaction, but the corresponding products were not 3-
ylidenephthalides.[8] It is well know that the electrophilic nature of
carbonyl group permits easily coupling with nucleophile, which
leads to the formation of other products. In principle, the reactions
between 2-acylbenzoic acids and alcohols take place at the
carbonyl site of ketone or carboxyl giving the 3-substituted
phthalides or 2-acylbenzoate product (Scheme 1B).[9] However, it’s
still a challenge that 2-acylbenzoic acids react with alcohols at the
α-carbon site of ketone to produce 3-ylidenephthalides. Herein, we
envision to fill this gap by reporting our new results on the direct
cyclization of 2-acylbenzoic acids with benzylic alcohols producing
3-ylidenephthalides (Scheme 1C).
Table 1 Optimization of reaction conditions.a
Ph
Ph
O
OH
Ph solvent, 3 h
catalyst
T,
+
O
Ph
OH
of
structure 3a
2047476
O
O
crystal
CCDC
1a
2a
3a
Entry
1
Catalyst (mol %)
H3PW12O40 (1.5)
H4SiW12O40 (1.5)
H3PMo12O40 (1.5)
p-TSA (10)
Solvent
T (oC)
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
Yield (%)b
PhCl
PhCl
71
72
93
46
0
2
Scheme 1 Varied reaction patterns between 2-acylbenzoic acid and alcohol
3
PhCl
intramolecular
of
acid to
of
synthesis
(A)
cyclizetion
2-acylbenzoic
3-ylidenephthalides
R
O
R
4
PhCl
Xue: TSTU, DIEA;
Wang: AlCl CH CN
,
3 3
(i)
(ii)
Takaishi: SOCl CHCl
O
5
FeCl3 (10)
PhCl
OH
O
,
(iii)
2
3
O
6
Cu(OTf)2 (10)
PhCl
0
and
conventional
reactive sites of
acid towards alcohol
2-acylbenzoic
(B)
unexplored
7
―
PhCl
0
R
O
8
H3PMo12O40 (1.5)
H3PMo12O40 (1.5)
H3PMo12O40 (1.5)
H3PMo12O40 (1.5)
H3PMo12O40 (1.5)
H3PMo12O40 (1.5)
H3PMo12O40 (1.5)
H3PMo12O40 (1.5)
H2O
11
67
69
61
19
49
83
93
R'
carbonyl of ketone
R
O
9
DCE
R'
known
O
R
O
α
-carbon
unkonwn
10
11
12
13
14
15
Toluene
Benzene
CH3CN
CH3NO2
PhCl
+
O
R' OH
O
OH
R
O
O
carbonyl of carboxylic
known
O
R'
O
work:
This
H3PMo12O40-catalyzed
to
of
synthesis 3-ylidenephthalides
(C)
cyclization
Ar1
R
O
PhCl
R
OH
Ar2
Ar2
a Reaction conditions: 2-acetylbenzoic acid (1a, 0.3 mmol), diphenylmetha-
nol (2a, 0.2 mmol), solvent (1.0 mL), catalysis for 3 h. b The yields determined
by GC with biphenyl as the internal standard.
+
H3PMo12O40
OH
Ar1
O
O
O
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Having identified optimized conditions for substrates 1a and 2a, were cyclized well to give the desired products 3t, 3u and 3v in good
we next explored the scope of this reaction. A range of benzylic
alcohol derivatives in the cyclization reaction with 2-acetylbenzoic
acid (1a) as the standard substrate was examined.[12] As shown in
Table 2, diphenylmethanols substituted with electron-donating
(Me, iPr, OMe) or electron-withdrawing groups (F, Cl, Br) smoothly
underwent cyclization to give the desired products 3b-3k. The
reactivity of this reaction was slightly influenced by the electronic
properties of the aryl rings. Diphenylmethanols with electron-
donating groups afforded lower yields of the corresponding
products (3b-3d) than those with electron-withdrawing groups (3f-
3i). Furthermore, diphenylmethanols bearing the same
substituents at different positions also had little influence on the
efficiency of this transformation. For example, the Me or Cl
substituent at ortho-position of phenyl rings gave lower yield than
meta-/para-position (3b/3c/3d or 3f/3g/3h). In the case of tertiary
alcohol, the corresponding product 3l was obtained in a yield of
65%. The substrate scope of 2-acetylbenzoic acids were also tested
with diphenylmethanol as substrates. 2-Acylbenzoic acids with
electron-donating and electron-withdrawing functional groups all
reacted smoothly with diphenylmethanols to generate the desired
products in good yields (3m-3s). To expand the substrate scope of
yields with different benzylic alcohols. It was noted that the 2-
phenylacetyl substrate underwent the cyclization process to
provide 3-ylidenephthalide 1’ rather than the expected product,
which may be due to the steric hindrance effect of the benzene ring
substituent in C=C bond. Unfortunately, simple alcohol and 2-(2-
methoxyacetyl)benzoic acid couldn’t convert to the desired prod-
ucts under the standard conditions (3w-3z).
After developing the methodology, we further demonstrated
its utility by the gram-scale synthesis and derivatization reactions.
The product 3a, 3f and 3t could be produced without modifying the
standard conditions in 85%, 82% and 60% yields on a 5 mmol scale,
respectively (Scheme 2A). The 3-ylidenephthalide skeletons of the
products offer handles for further derivatization. To illustrate this
point, the product 3a was treated with hydrazine and
ethylenediamine to give the phtalazinone 4 and imidazoisoindole 5
in excellent yields,[13] respectively, which exhibit antiviral and
antibacterial activities. Futhermore, product 3a could also be easily
transformed to the corresponding isoindolin-1-one 6 through a
amine substitution reaction (Scheme 2B).[14] The versatilities and
the rapidly preparation of these products revealed that our
stragety are highly useful and attractive in the synthetic and
this transformation, we examined the different 2-acyl-substitutents. medicinal chemistry.
2-Propionylbenzoic acid and 2-caproylbenzoic acid
Scheme 2 Gram-scale reactions and derivatization reactions
Table 2 Substrate scope.a, b
Gram-scale reactions
(A)
Ph
Ph
O
R1
OH
Ph
mol%
PhCl, 80 o 3 h
H3PMo12O40 1.5
,
+
O
R4
OH
O
Ph
OH
C,
R4
mol%
PhCl, 80 o 3 h
H3PMo12O40 1.5
,
R3
R2
R1
+
O
mmol)
O
OH
R3
O
C,
3a
1.326 g
, 85%,
mmol)
2a
1a
1a
(5
(7.5
(7.5
R2
O
1
Ph
O
2
3
O
OH
Br
mol%
PhCl, 80 o 3 h
H3PMo12O40 1.5
,
3a, R=H,
93%
Ph
+
+
R
O
O
OH
3b, R=4-Me,
3c, R=3-Me,
3d, R=2-Me,
3e, R=4-iPr,
89%
85%
81%
89%
C,
Cl
Cl
O
mmol)
3f
1.418
g
, 82%,
mmol)
2f
(5
Ph
Ph
O
Ph
Ph
3f, R=4-Cl, 91%
O
O
R=3-Cl,
3g,
3h, R=2-Cl,
90%
85%
OH
mol%
PhCl, 80 o 3 h
O
O
H3PMo12O40 1.5
,
of
structure 3i
crystal
CCDC 2047477
3i, 97%
O
OH
C,
Ph
Ph
F
OMe
O
mmol)
O
1.02 g
3t
, 60%,
mmol)
2a
(5
1t
(7.5
Ph
Ph
Ph
Ph
Derivatization reactions
Ph
(B)
O
O
O
O
O
Ph
Ph
F
OMe
O
87%
O
HO
O
3j,
Ph
NaOH
N2H4 H2SO4
reflux 3 h
Ph
Ph
NH2
3l,
3m,
3k,
65%
42%
88%
H2N
N
N
N
O
Ph
Ph
Ph
Ph
Ph
Ph
H
2O,
HN
O
Ph
5
4
3a
O
O
O
O
O
O
CuI, Cs2CO3
DMSO, 120 o
Cl
NH4OAc
O
O
O
C
3n,
84%
3o, 75%
81%
3r,
83%
3p,
Ph
Ph
Ph
Ph
Ph
NH
O
O
Br
Cl
O
O
O
6
of
structure
CCDC 2047478
3q
78%
crystal
3q,
3s,
75%
Ph
Ph
Ph
Ph
Cl
In order to have a deeper understanding on this transformation
Ph
and to get further insight into the mechanism, several control
experiments were conducted (Scheme 3). When the model
reaction was stopped at 5 min, ca. 10% compound INT4, 13%
compound BP1, 21% compound BP2, 52% compound BP3 and 8%
3a were detected by GC-MS. Upon further heating the reaction
mixture for 3 h, INT4, BP1, BP2, and BP3 disappeared, whereas the
yield of 3a was increased to 93% (Eq. (1) see Supporting
Information Figure S1 for more GC-MS details). Pure INT4 and BP3
were synthesized following the established procedure. Under the
standard reaction conditions, both INT4 and BP3 could be
converted to 3a in 92% and 89% yields, respectively (Eq. (2) and (3)).
O
O
O
O
O
O
Cl
O
O
3t,
3v,
1',
68%
66%
71%
Ph
3u,
73%
O
Ph
Ph
Ph
O
O
O
O
O
O
O
O
3w,
3x,
0%
0%
0%
3y,
3z, 0%
a Reaction conditions: 2-acylbenzoic acid (1, 0.3 mmol), diphenylmethanol
(2, 0.2 mmol), PhCl (1.0 mL), H3PMo12O40 (1.5 mol %), 80 oC for 3 h. b Isolated
yield.
Chin. J. Chem. 2021, 39, XXX－XXX
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First author et al.
Report
These results further proved that INT4 and BP3 would be the key
intermediates in this reaction. Furthermore, isolated compound
BP1 and BP2 were proven to reformed the substrates 1a and 2a
29.2 kcal mol-1 to form cyclic intermediate INT2. In this cyclization
process, nucleophilic attack of O3 atom and proton transfer from
O3 atom to O1 atom proceed in an asynchronous-concerted
and further converted to 3a under the standard reaction conditions, fashion. The subsequent dehydration process of INT2 readily
respectively (Eq. (4) see Supporting Information Figures S2 and S3
for more GC-MS details). The results indicated that the compounds
BP1 and BP2 were the by-products and reformed the substrates
through the reversible reactions.
proceeds thought TS2 to form INT3, which is nearly barrierless. Af-
ter deprotonation process of INT3, the experimental detected INT4
is formed from reactant 1a, which is an endergonic process by 4.8
kcal mol-1. Furthermore, another two pathways separately induced
by protonation on O1 and O2 atoms of reactant 1a, which also un-
dergo intramolecular cyclization reaction, dehydration and depro-
tonation processes successively, could be ruled out because of
much higher activation free energies (Figure S5). Next, the reaction
between reactant 2a and INT4 to form the final product 3a is theo-
retically studied (Figure 1B). After protonation process of reactant
2a, the generated INT5 immediately occurs dehydration process via
TS3 with a small activation free energy of 2.5 kcal mol-1 to form a
more stable carbocation intermediate INT6. Then, INT6 reacts with
INT4 through TS4 with an activation free energy of 12.8 kcal mol-1
to form INT7. Finally, deprotonation process of INT7 leads to the
final product 3a. The whole reaction producing 3a from 2a is an ex-
ergonic process by 5.9 kcal mol-1.
Scheme 3 Control experiments
O
O
Ph
OH
Ph
standard condition
+
+
O
O
(1)
Ph
OH
Ph
O
O
INT4
O
BP1
2a
1a
10%
0
13%
5 min
3 h
0
Ph
Ph
O
Ph
Ph
Ph
Ph
+
Ph
+
+
O
O
O
O
O
Ph
BP2
3a
BP3
52%
0
5 min
3 h
21%
0
8%
93%
Ph
O
(A)
H
OH
Ph
H
O
standard condition
+
O
Δ
GPhCl
O
O
H
(2)
Ph
Ph
H
O
mol-1
kcal
O
O
O
O
TS
67.1
3a, 92%
3a, 89%
INT4
2a
TS1
21.9
Ph
Ph
O
1a'
13.1
Ph
Ph
Ph
Ph
OH2
standard condition
+
O
O
O
(3)
(4)
OH
O
O
OH
O
O
INT4
4.8
H
O
O
O
1a
BP3
O
TS2
1.4
1a
0.0
Ph
Ph
Ph
OH
INT2
1.9
H
2O
INT3
O
O
H
H
1
O
Ph
Ph
OH2
standard
condition
standard
condition
O
-4.3
H
O
O
Ph
3
H
O
O
O
O
O
Ph
O
O
INT1
-7.3
O 2
O
O
O
3a, 72%
Ph
BP1
BP2
3a, 67%
O
Ph
Ph
(B)
To better understand the mechanism of this reaction, a density
functional theory (DFT) calculation was employed in the same
experimental conditions (solvent of chlorobenzene, temperature at
353.15 K, and pressure at 1.00 atm) using M06-2X functional. For
one of the reactants, its keto form (1a) is more stable, as
transformation from keto form to enol form (1a’) is an endergonic
process by 13.1 kcal mol-1, which goes through transition state (TS)
with a large activation free energy of 67.1 kcal mol-1 (Figure 1).
Therefore, the reaction is more likely to occur between reactants
1a and 2a, which is theoretically investigated here. In this reaction,
POMs provide an acidic environment similar to protonic acid, thus,
a simple H3O+-H2O model was used to estimate the Gibbs free
energy changes during protonation and deprotonation processes.
There are three potential sites for protonation of reactant 1a,
including carbonyl oxygen atom in ketone group (O1), carbonyl (O2)
and hydroxyl (O3) oxygen atoms in acid group. Theoretical
calculation results (Figure S4) show that regardless of the
conformation of reactant 1a, O1 atom is the most potential proto-
nation site, followed by O2 atom. Additionally, the protonation pro-
cess on O3 atom is endergonic by 13.8-19.4 kcal mol-1, which is un-
likely to occur. Different from reactant 1a, reactant 2a has only one
potential protonation site. Initially, reactants 1a and 2a are readily
protonated to form INT1 and INT5, which are exergonic processes
by 7.3 and 2.6 kcal mol-1, respectively.
O
Δ
GPhCl
mol-1
kcal
O
TS4
4.1
OH2
Ph
2a
Ph
0.0
OH
H
Ph
Ph
TS3
-0.1
INT5
-2.6
Ph
Ph
OH2
O
O
H
2O
3a
-5.9
Ph
Ph
INT4
Ph
Ph
INT6
-8.7
H
O
Ph
Ph
INT7
-11.7
O
Figure 1 Proposed reaction mechanism and predicted relative Gibbs free
energies based on DFT calculation. (A) the formation reaction of INT4 from
reactant 1a; (B) the reaction forming the final product 3a.
In the experiment, two major by-products BP2 and BP3 are
observed in the earlier stage of reaction and final product 3a is
formed with high yield in the later stage of reaction. To explain the
experimental observations, theoretical calculations of two side re-
actions forming major by-products BP2 and BP3 are performed
(Figure S6). INT6 from 2a reacting with INT4 and reactants 1a-1 and
2a to respectively form final product 3a and by-products BP2 and
BP3 are three competitive reactions. As discussed above, the
formation of INT4 needs to overcome a high activation free energy
of 29.2 kcal mol-1. What’s more, the activation free energy (12.8
kcal mol-1) of INT6 reacting with INT4 to form final product 3a is
higher than those (4.6 and 8.0 kcal mol-1) of two side reactions
forming by-products BP2 and BP3. Therefore, two side reactions
forming by-products BP2 and BP3 are dominant reactions in the
earlier stage of reaction. These two side reactions are reversible
reactions, as free energy changes are nearly unchanged from 2a to
BP2 (0.4 kcal mol-1) and BP3 (-0.5 kcal mol-1). The reaction forming
It was observed experimentally that the detected INT4 can
replace reactant 1a reacting with reactant 2a to form the final
product 3a and INT4 is able to be directly formed from reactant 1a.
Thus, the formation reaction of INT4 from reactant 1a is firstly
calculated in details (Figure 1A). After protonation process of
reactant 1a, the produced INT1 undergoes intramolecular
cyclization reaction through TS1 with an activation free energy of
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Running title
Chin. J. Chem.
final product 3a is exergonic reaction, as free energy change from
2a to 3a is -5.9 kcal mol-1. Therefore, reaction forming final product
3a is dominant reaction in the later stage of reaction. A summary
of proposed reaction mechanism and calculated free energies can
be seen in Figure S7. Furthermore, to explain the Z-selectivity of the
products, we have also calculated the Gibbs free energies of Z and
E configurations of product 3a, which shows the Gibbs free energy
of Z-configuration is 1.7 kcal mol-1 smaller than that of E-configura-
tion. That is to say, Z-configuration of product is more stable than
its E-configuration. Thus, energy stability is one driven force to ob-
tain Z-configuration of product. Besides the aspect of Gibbs free en-
ergy, we can also analyze from the aspect of geometry. According
to our reaction mechanism, INT6 electrophilic attacks INT4 with
planar structure from vertical direction to form INT7. Observing the
geometry of INT7 (Figure S8), dihedral angle ∠C1-C8-C9-C10 is
larger than 90° while dihedral angle ∠O1-C8-C9-C10 is smaller
than 90°, which shows that it tends to form product 3a with Z-con-
figuration after deprotonation process. Comparing the geometries
of Z and E configurations (Figure S9), the marked bond angles in Z-
configuration are smaller than the corresponding ones in E-config-
uration while the marked bond distance in Z-configuration is larger
than that in E-configuration, which shows that Z-configuration
should have smaller steric resistance than E-configuration. Thus,
steric hindrance effect is another driven force to obtain Z-configu-
ration of products. All calculated results are in good agreement
with the experimental observations.
Based on the above results and related literature studies, a
plausible mechanism is proposed in Scheme 4. It is believed that
the acid catalyst initially protonates the 1a to provide INT1, which
has a better nucleophilic site than 1a, thus enabling the subsequent
nucleophilic attack of carboxyl to afford INT2. Alternatively, INT1
could also experience nucleophilic attack of 2a followed by
deprotonation and dehydration to form by-product BP1. The
undesired by-product BP1 could reform INT1 and 2a through the
reversible reactions. After dehydration of INT2, the carbocation
species INT3 were generated, followed by the deprotonation to
form INT4. Meanwhile, under the promotion of heteropoly acid
H3PMo12O40, carbocation species INT6 would be generated directly
by protonation/dehydration of the alcohol 2a. Subsequently, INT6
electrophilic attack on INT4 to afford the carbocation species INT7,
which produce desired product 3a through the deprotonation pro-
cess. INT6 could also electrophilic attack on carboxyl of 1a leads to
the formation of the corresponding ester BP2, which would reform
INT6 and 1a under the acidic condition.
formation via environmentally benign catalyst H3PMo12O40-cata-
lyzed cyclization and coupling reaction to regio- and stereoselective
synthesis the (Z)-3-ylidenephthalides in good to excellent yields,
which also opens a new reaction space for the selective coupling of
carbonyls or carboxyl with alcohols. Overall, the reaction features
an eco-friendly reaction conditions, highly atom efficient, facile
scalability, and easy derivatization of the products to drugs and bi-
oactive compounds. Detailed mechanistic studies and DFT calcula-
tions reveal that the reaction involves the well-known esterification
and cyclization reactions, the corresponding by-product would re-
form the substrates to generate the desired product due to their
different stability in the acidic reaction conditions.
Experimental
Gneral procedure for the synthesis of products 3: In a reaction vial
of 4 mL, 2-acetylbenzoic acid (1, 0.3 mmol), diphenylmethanol (2,
0.2 mmol), H3PMo12O40 (1.5 mol%) and PhCl (1 mL) were added.
Then the reaction was carried out in screw cap vials with a Teflon
seal at 80 oC for 3 h. After cooling to room temperature, the mixture
was further purified by column chromatography (petroleum
ether/EtOAc) to afford the desired products.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
Acknowledgement
We thank Prof. Chang-wen Hu from Beijing Institute of Technol-
ogy for his guidance on the mechanism of polyoxometalates catal-
ysis. We thank Prof. Konstantin Chingin for helpful manuscript revi-
sions. We also thank the National Natural Science Foundation of
China (22001034, 21804019), the Open Fund of the Jiangxi Province
Key Laboratory of Synthetic Chemistry (JXSC202008), the Research
Found of East China University of Technology (No. DHBK2019265,
DHBK2019267, DHBK2019264) for financial support.
References
(a) Rukachaisirikul, V.; Rodglin, A.; Sukpondma, Y.; Phongpaichit, S.;
Batong J.; Sakayaroj, J. Phthalide and Isocoumarin Derivatives Pro-
duced by an Acremonium sp. Isolated from a Mangrove Rhizophora
Apiculata. J. Nat. Pro. 2012, 75, 853–858; (b) Ortar, G.; Moriello, A. S.;
Morera, E.; Nalli, M.; Di Marzo. V.; De Petrocellis L. 3-Ylidenephthalides
as a New Class of Transient Receptor Potential Channel TRPA1 and
TRPM8 Modulators. Bioorg. Med. Chem. Lett. 2013, 23, 5614–5618; (c)
Yang, H.; Hu, G.; Chen, J.; Wang, Y.; Wang, H. Synthesis, Resolution,
and Antiplatelet Activity of 3-Substituted 1(3H)-Isobenzofuranone.
Bioorg. Med. Chem. Lett. 2007, 17, 5210–5213; (d) Ge, Y.; Han, Z.;
Wang, Z.; Feng, C.; Zhao, Q.; Lin G.; Ding, K. Ir-SpinPHOX Catalyzed En-
antioselective Hydrogenation of 3-Ylidenephthalides. Angew. Chem.
Int. Ed. 2018, 57, 13140–13144; (e) Quéméner, A. S.; Maillasson, M.;
Arzel, L.; Sicard, B.; Vomiandry, R.; Mortier, E.; Dubreuil, D.; Jacques,
Y.; Lebreton J.; Mathé-Allainmat, M. Discovery of a Small-molecule In-
hibitor of Interleukin 15: Pharmacophore-based Virtual Screening and
Hit Optimization. J. Med. Chem. 2017, 60, 6249–6272.
(a) Lee, K. Y.; Kim J. M.; Kim, J. N. Facile Synthesis of 3-Alkylidene-3H-
isobenzofuranones from the Baylis-Hillman Reaction of 2-Carboxyben-
zaldehyde. Synlett. 2003, 2003, 0357–0360; (b) Shapiro, S. L.; Geiger K.;
Freedman, L. Indandione Anticoagulants. J. Org. Chem. 1960, 25,
1860–1865; (c) Zhu, T.; Mou, C.; Li, B.; Smetankova, M.; Song B.; Chi, Y.
N-heterocyclic Carbene-catalyzed δ-Carbon LUMO Activation of Un-
saturated Aldehydes. J. Am. Chem. Soc. 2015, 137, 5658–5661.
Scheme 4 Proposed mechanism
OH2
O
O
INT2
Ph
OH
O
Ph
Ph
OH
Ph
O
H
O
Ph
+
O
OH
Ph
O
O
O
O
2a
BP1
3a
INT1
INT3
H
H
H
H2O
+
Ph
Ph
O
O
O
H
+
O
Ph
Ph
O
Ph
Ph
OH
O
O
O
O
INT6
INT4
1a
INT7
BP2
Conclusions
In summary, we have developed a tandem C−O and C−C bond
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

First author et al.
Report
(a) Gabriel, S.; Michael, A. Ueber die Einwirkung von wasserentzi-
X. Li, G.; Zhang, X.; Feng, Z.; Jiang, J.; Yang, Y.; Zhang, P. Stereoselective
Synthesis of (Z)-3-Ylidenephthalides via AlCl3-Mediated Cyclization
with 2-Acylbenzoic acids. Tetrahedron Lett. 2020, 61, 151734.
(a) El-Harairy, A.; Lai, B.; Vaccaro, L.; Li, M.; Gu, Y. A Sulfone-Containing
Imidazolium-Based Brønsted Acid Ionic Liquid Catalyst Enables Replac-
ing Dipolar Aprotic Solvents with Butyl Acetate. Adv. Synth. Catal. 2019,
361, 3342–3350; (b) Lu, B.; Xie, Z.; Lu, J.; Liu, J.; Cui, S.; Ma, Y. Hu, X.;
Liu, Y.; Zhong, K. Highly Atom-Economic, Catalyst-Free, and Solvent-
Free Synthesis of Phthalazinones. ACS Sustain. Chem. Eng. 2018, 7,
134–138; (c) Liu, Y.; Majhi, P. K.; Song, R.; Mou, C.; Hao, L.; Chai, H.; Jin
Z.; Chi, Y. Carbene-Catalyzed Dynamic Kinetic Resolution and Asym-
metric Acylation of Hydroxyphthalides and Related Natural Products.
Angew. Chem. Int. Ed. 2020, 59, 3859–3863; (d) Xie, C.; Song, J.; Wu,
H.; Hu, Y.; Liu, H.; Zhang, Z.; Zhang, P.; Chen, B.; Han, B. Ambient Re-
ductive Amination of Levulinic Acid to Pyrrolidones over Pt Nanocata-
lysts on Porous TiO2 Nanosheets. J. Am. Chem. Soc. 2019, 141, 4002–
4009.
(a) Morgan, D. O.; Ollis W. D.; Stanforth, S. P. Preparation and Cycload-
dition Reactions of Novel Heterocyclic Mesomeric Betaines. Tetrahe-
dron. 2000, 56, 5523–5534; (b) Li, G.; Yin, D.; Liang, X. A Facile Synthe-
sis of 3-Substituted Phthalides. Synth. Commun. 2004, 34, 1183–1189.
(a) Yang, G.; Liu, Y.; Li, K.; Liu, W.; Yu, B.; Hu, C. H3PMo12O40-Catalyzed
Coupling of Diarylmethanols with Epoxides/diols/aldehydes toward
Polyaryl-substituted Aldehydes. Chin. Chem. Lett. 2020, 31, 3233–3236;
(b) Yang, G.; Wu, X.; Yu, B.; Hu, C. Ionic Liquid from Vitamin B1 Ana-
logue and Heteropolyacid: A Recyclable Heterogeneous Catalyst for
Dehydrative Coupling in Organic Carbonate. ACS Sustain. Chem. Eng.
2019, 7, 3727–3732; (c) Yang, G.; Shang, S.; Yu, B.; Hu, C. Ce (III)-Con-
taining Tungstotellurate (VI) with a Sandwich Structure: an Efficient
Lewis Acid-base Catalyst for the Condensation Cyclization of 1, 3-
Diketones with Hydrazines/hydrazides or Diamines. Inorg. Chem. Front.
2018, 5, 2472–2477.
Yang, G.; Zhang, N.; Ma, N.; Yu, B.; Hu, C. An Atom-Economical Route
to Substituted β-Arylethyl Ketones: Phosphomolybdic Acid-Catalyzed
Carbohydroxylation of Terminal Alkynes in Organic Carbonate. Adv.
Synth. Catal. 2017, 359, 926–932.
CCDC 2047476, 2047477 and 2047476 (3a, 3i and 3q) contains the sup-
plementary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Cen-
tre via www.ccdc.cam.ac.uk/data_request/cif
(a) Ibrahim, H. S.; Eldehna, W. M.; Abdel-Aziz, H. A.; Elaasser, M. M.;
Abdel-Aziz, M. M. Improvement of Antibacterial Activity of Some Sulfa
Drugs Through Linkage to Certain Phthalazin-1(2H)-one Scaffolds. Eur.
J. Med. Chem. 2014, 85, 480–486; (b) Zamilpa, A.; Herrera-Ruiz, M.; Del
Olmo, E.; López-Pérez, J. L.; Tortoriello, J.; San Feliciano, A. [1, 3] Di-
azaheterofused Isoindolol Derivatives Displaying Anxiolytic-like Effects
on Mice. Bioorg. Med. Chem. Lett. 2007, 17, 4016–4021.
Irudayanathan, F. M.; Noh, J.; Choi, J.; Lee, S. Copper-Catalyzed Selec-
tive Synthesis of Isoindolin-1-Ones and Isoquinolin-1-Ones from The
Three-Component Coupling of 2-Halobenzoic Acid, Alkynylcarboxylic
Acid and Ammonium Acetate. Adv. Synth. Catal. 2014, 356, 3433–3442.
ehenden Mitteln auf Säureanhydride. Ber. Dtsch. Chem. Ges. 1877, 10,
2199–2210; (b) Chopard, P.; Hudson, R.; Searle, R. The Reaction of Sta-
ble Phosphoranes with Phthalic Anhydride Case of Cis-trans Isomerism.
Tetrahedron Lett. 1965, 6, 2357–2360; (c) Dussart, N.; Trinh, H. V.;
Gueyrard, D. Modified Julia Olefination on Anhydrides: Extension and
Limitations. Application to the Synthesis of Maculalactone B. Org. Lett.
2016, 18, 4790–4793; (d) Safari, Naeimi, J. H.; Khakpour, A. A.; Jondani,
R. S.; Khalili, S. D. A Rapid and Efficient Method for Synthesis of New
3-Arylideneisobenzofuran-1(3H)-one Derivatives Catalyzed by Acetic
Anhydride under Solvent-free and Microwave Conditions. J. Mol. Cat.
A Chem. 2007, 270, 236–240.
(a) Cámpora, J.; Maya, C. M.; Palma, P.; Carmona, E.; Gutiérrez-Puebla.
E.; Ruiz, C. Synthesis and Aldol Reactivity of O−and C−Enolate Com-
plexes of Nickel. J. Am. Chem. Soc. 2003, 125, 1482–1483; (b) Zhang,
M.; Zhang, H.; Han, T.; Ruan, W.; Wen, T. Rh (III)-Catalyzed Oxidative
Coupling of Benzoic Acids with Geminal-Substituted Vinyl Acetates:
Synthesis of 3-Substituted Isocoumarins. J. Org. Chem. 2015, 80, 620–
627; (c) Nandi, D.; Ghosh, D.; Chen, S. J. B.; Kuo, C.; Wang, N. M.; Lee,
H. M. One-Step Synthesis of Isocoumarins and 3-Benzylidenephthal-
ides via Ligandless Pd-Catalyzed Oxidative Coupling of Benzoic Acids
and Vinylarenes. J. Org. Chem. 2013, 78, 3445–3451; (d) Zhao, D.; Lied,
F.; Glorius, F. Rh (III)-catalyzed C−H Functionalization/aromatization
Cascade with 1, 3-Dienes: a Redox-neutral and Regioselective Access
to Isoquinolines. Chem. Sci. 2014, 5, 2869–2873; (e) Chaudhary, S.;
Shyamlal, B. R. K.; Yadav, L.; Tiwari, M. K.; Kumar, K. Ag2O Nanoparti-
cle-catalyzed Substrate-controlled Regioselectivities: Direct Access to
3-Ylidenephthalides and Isocoumarins. RSC Adv. 2018, 8, 23152–
23162; (f) Jambu, S.; Tamizmani, M.; Jeganmohan, M. Ruthenium (II)-
Catalyzed Cyclization of Aromatic Acids with Allylic Acetates via Redox-
Free Two-Fold Aromatic/Allylic C−H Activations: Combined Experi-
mental and DFT Studies. Org. Lett. 2018, 20, 1982–1986; (g) Han, W.;
Pu, F.; Fan, J.; Liu, Z.; Shi, X. Rhodium (III)-Catalyzed Tandem C−H Ole-
fination and Oxidative Cyclization of Aromatic Acids with Acrylates for
the Synthesis of (E)-3-Ylidenephthalides. Adv. Synth. Catal. 2017, 359,
3520–3525; (h) Liu, Y.; Yang, Y.; Shi, Y.; Wang, X.; Zhang, L.; Cheng, Y.;
You, J. Rhodium-Catalyzed Oxidative Coupling of Benzoic Acids with
Terminal Alkynes: An Efficient Access to 3-Ylidenephthalides. Organo-
metallics. 2016, 35, 1350–1353.
(a) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara,
M.; Hiroya, K.; Sakamoto, T. Regiocontrolled Intramolecular Cycliza-
tions of Carboxylic Acids to Carbon−Carbon Triple Bonds Promoted by
Acid or Base Catalyst. Org. Lett. 2006, 8, 5517–5520; (b) Novák, P.; Cor-
rea, A.; Gallardo-Donaire, J.; Martin, R. Synergistic Palladium-Cata-
lyzed C(sp3)−H Activation/C(sp3)−O Bond Formation: A Direct, Step-
Economical Route to Benzolactones. Angew. Chem. Int. Ed. 2011, 50,
12236–12239; (c) Park, J. H.; Bhilare, S. V.; Youn, S. W. NHC-catalyzed
Oxidative Cyclization Reactions of 2-Alkynylbenzaldehydes under Aer-
obic Conditions: Synthesis of O-heterocycles. Org. Lett. 2011, 13,
2228–2231.
Danoun, G.; Mamone, P.; Gooßen, L. J. One-Pot Synthesis of 3-Alkyli-
denephthalides from Benzoic Acids by a Rhodium-Catalyzed ortho-
C−H Acylation Process. Chem. Eur. J. 2013, 19, 17287–17290.
(a) Hori, K.; Takaishi, N. A Convenient Synthesis of 3-Phenacylideneph-
thalides. Bull. Chem. Soc. Jpn.,1988, 61, 1791–1792; (b) He, X.; Xue, F.
Transition-metal-free Synthesis of (Z)-3-Ylidenephthalides from 2-
Acyl-benzoic Acids. Tetrahedron Lett. 2014, 55, 1956–1958; (c) Wang,
Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
Manuscript accepted: XXXX, 2021
Accepted manuscript online: XXXX, 2021
Version of record online: XXXX, 2021
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Entry for the Table of Contents
Regio- and Stereoselective Synthesis of (Z)-3-Ylidenephthalides via H3PMo12O40-Catalyzed Cyclization of 2-Acylbenzoic Acids with Benzylic
Alcohols
Guoping Yang, Ke Li, Xiaoling Lin, Yijin Li, Chengxing Cui, Shixiong Li,* Yuanyuan Cheng,* Yufeng Liu*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
A regio- and stereoselective synthesis of (Z)-3-ylidenephthalides via H3PMo12O40-catalyzed cyclization of 2-acylbenzoic acids with benzylic alcohols was
developed.
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de