Divergent Palladium-Catalyzed Tandem Reaction of Cyanomethyl Benzoates with Arylboronic Acids: Synthesis of Oxazoles and Isocoumarins

Article abstract of DOI:10.1002/adsc.202000125

A palladium-catalyzed tandem reaction of cyanomethyl benzoates with arylboronic acids has been achieved. Substitution at the 2-position of cyanomethyl benzoates was found to be crucial for the selective synthesis of oxazoles and isocoumarins. Cyanomethyl

Full text of DOI:10.1002/adsc.202000125

Title: Divergent Palladium-Catalyzed Tandem Reaction of
Cyanomethyl Benzoates with Arylboronic Acids: Synthesis of
Oxazoles and Isocoumarins
Authors: Ling Dai, Shuling Yu, Wenzhang Xiong, Zhongyan Chen,
Tong Xu, Yinlin Shao, and Jiuxi Chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000125
Link to VoR: http://dx.doi.org/10.1002/adsc.202000125

10.1002/adsc.202000125
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Divergent Palladium-Catalyzed Tandem Reaction of
Cyanomethyl Benzoates with Arylboronic Acids: Synthesis of
Oxazoles and Isocoumarins
Ling Dai,a Shuling Yu,a Wenzhang Xiong,a Zhongyan Chen,a,* Tong Xu,a Yinlin Shaoa
and Jiuxi Chena,*
aCollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, People’s Republic of China
E-mail: chenzhongyan@wzu.edu.cn; jiuxichen@wzu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A palladium-catalyzed tandem reaction of cyanomethyl benzoates with arylboronic acids has been achieved.
Substitution at the 2-position of cyanomethyl benzoates was found to be crucial for the selective synthesis of oxazoles
and isocoumarins. Cyanomethyl benzoates afforded 2,4-diaryloxazoles as products, while 2-benzoyl-substituted
cyanomethyl benzoates delivered 3-benzoyl-4-aryl-isocoumarins selectively. Furthermore, a possible mechanism for the
selective reaction of cyanomethyl benzoates with arylboronic acids was discussed.
Keywords: palladium-catalyzed; tandem reaction; oxazoles; isocoumarins; nitriles
benzoates afford 2,4-diaryloxazoles as the sole
Introduction
products, while 2-benzoyl-substituted cyanomethyl
benzoates deliver a new class of 3-benzoyl-4-aryl-
Owing to the ubiquity of heterocyclic compounds in
isocoumarins that are often difficult to prepare using
both organic chemistry and medicinal chemistry,[1]
traditional routes.
the discovery of new transition-metal-catalyzed
transformations for the construction of heterocycles
in a selective manner from readily available starting
materials is an active research area. Nitriles are an
important class of molecular building blocks in
organic synthesis.[2] Significant progress toward
understanding the carbopalladation of nitriles[3] has
promoted the development of transition-metal-
catalyzed transformations of various nitrile-
containing functional groups by our group[4] and
others[5] (Scheme 1a). The scope of this chemistry has
been successfully extended to sodium aryl sulfinates
or arylsulfinic acids,[6] aryl halides,[7] benzoic acids,[8]
and arylhydrazines[9] as coupling partners in the last
decade. Inspired by our recent studies on palladium-
catalyzed tandem reactions of o-cyanobiaryls with
arylboronic acids for the synthesis of seven-
membered 5H-dibenzo[c,e]azepines (Scheme 1b),[10]
we envisaged that the palladium-catalyzed addition of
arylboronic acids to cyanomethyl 2-halogenated
Scheme 1. Reactions associated with this study.
benzoates and sequential intramolecular Buchwald–
Hartwig coupling cyclization would offer a new
strategy
for
the
synthesis
of
2-
1c,
Our initial investigation commenced with an
examination of the reaction of cyanomethyl 2-
iodobenzoate with phenylboronic acid for reaction
condition optimization (Table S1, see SI for details).
We found that 2-(2-iodophenyl)-4-phenyloxazole was
isolated in 19% yield in the presence of Pd(OAc)2,
2,2'-bipyridine (L1), and methanesulfonic acid
(MsOH) at 95 °C in THF for 24 h, along with small
amounts of deiodinated product 2,4-diphenyloxazole.
arylbenzo[e][1,4]oxazepin-5-ones
(Scheme
proposed transformation). To our surprise,
substitution at the 2-position of cyanomethyl
benzoates was found to be crucial for the selective
synthesis of five-membered oxazoles[11] and six-
membered isocoumarins[12] (Scheme 1c, observed
transformation). Herein, we report the unexpected
discovery using this novel protocol that cyanomethyl
1
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10.1002/adsc.202000125
Advanced Synthesis & Catalysis
Therefore, we tested the reaction of readily available
cyanomethyl benzoate (1a) with phenylboronic acid
to screen reaction conditions (Table 1). 2,4-
Diphenyloxazole (3a) was obtained in 25% yield
when using a combination of Pd(OAc)2, L1, and
MsOH in THF (entry 1). Among other additives used,
including
camphorsulfonic acid (D-CSA), heptafluorobutyric
acid (HFBA), sulfuric acid, and
trifluoromethanesulfonic acid (TfOH) (entries 2–6),
TfOH exhibited the highest reactivity, affording 3a in
43% yield (entry 6). A brief survey of solvents
indicated that THF was the optimal choice (entries 6–
9). Other palladium catalysts were evaluated (entries
10–12), with Pd(acac)2 as catalyst improving the
yield of 3a to 58% (entry 12). The use of a ligand was
crucial for accelerating this tandem reaction. A
number of other bidentate pyridine-based ligands,
including 6,6'-dimethyl-2,2'-bipyridine (L2), 5,5'-
dimethyl-2,2'-bipyridine (L3), 4,4'-dimethyl-2,2'-
transformation (3a–3e). Notably, with an ortho-
substituent present on the phenyl ring, desired
products 3c–3e were obtained in 64–77% yields,
indicating that steric hindrance around the imine
moiety prevented further hydrolysis. Electron-
withdrawing groups, such as fluoro and chloro groups,
were also tolerated in this transformation, providing
corresponding products 3f–3i in 52–61% yields. The
tandem reaction with a strongly electron-withdrawing
trifluoromethyl group attached to the phenyl ring also
proceeded, albeit affording desired product 3j in 22%
yield. The scope of the cyanomethyl benzoates was
also examined (Table 2, 3k–3s). Both electron-rich
substituents (such as Me and OMe) (3k–3n) and
electron-deficient substituents (such as F, Cl, and
CF3) (3o–3q) were compatible with this
transformation. Notably, substrate cyanomethyl
thiophene-2-carboxylate also reacted successfully,
providing 3s in a low yield.
trifluoroacetic
acid
(TFA),
D-
bipyridine (L4), 4,4'-di-tert-butyl-2,2'-bipyridine (L5), Table 2. Synthesis of 2,4-diaryl oxazoles.[a]
and 4,4'-dimethoxy-2,2'-bipyridine (L6), were
screened (entries 13–17), with significantly improved
results observed were screened (entries 13–17), with
significant reaction improvements observed with L4
(81% yield, entry 15). Other reaction conditions,
including the amount of catalyst, additive, and ligand,
were also screened (Table S2, see SI for details).
Table 1. Optimization of reaction conditions.[a]
[a] Conditions: 1a (0.3 mmol), 2 (0.45 mmol), Pd(acac)2 (5
mol%), L4 (10 mol%), TfOH (2 equiv.), THF (2 mL), 95
oC, 24 h, air, isolated yield.
We next investigated the tandem reaction of a wide
range of readily available cyano(phenyl)methyl
benzoates with phenylboronic acid to give the
corresponding 2,4,5-triaryloxazoles (Table 3). We
found that cyano(phenyl)methyl benzoates bearing
substituents (such as OMe, Cl, CF3, and NO2) on the
aryl ring were compatible with this tandem reaction,
affording desired products 3t–3x in 68–91% yields.
Importantly, substrates with R1 substituents, such as
naphthyl (3y), pyridyl (3z), furyl (3za), and thienyl
(3zb) groups, delivered the corresponding products in
good to excellent yields. Alkyl-substituted substrates,
such as cyano(phenyl)methyl 3-phenylpropanoate
(3zc) and cyano(phenyl)methyl acetate (3zd), were
also tolerated in this transformation. Pleasingly,
substituents attached to theα-position of the cyano
group (R2), including aryl substituents (such as p-
tolyl, p-methoxyphenyl, p-chlorophenyl, and p-
fluorophenyl), heterocyclic substituents (such as
pyridyl, furyl, and thienyl), and alkyl substituents
(such as phenethyl, propyl, and cyclohexyl),
[a] Conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd catalyst
(5 mol %), ligand (10 mol %), additive (2 equiv.), solvent
(2 mL), 95 oC, 24 h, air.
[b] Isolated yield.
To examine the scope of this tandem reaction, we
first tested the reaction of cyanomethyl benzoate (1a)
with arylboronic acids for the synthesis of 2,4-diaryl
oxazoles (Table 2, 3a–3j). Pleasingly, electron-
donating groups, including methyl, ethyl, and
isopropyl groups, were tolerated in this
2
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10.1002/adsc.202000125
Advanced Synthesis & Catalysis
delivered the corresponding products (3ze–3zn) in
66–93% yields.
Table 4. Scope of arylboronic acids.[a]
Table 3. Synthesis of 2,4,5-triaryl oxazoles.[a]
[a] Conditions: 1 (0.3 mmol), 2 (0.6 mmol), Pd(TFA)2 (5
mol%), L1 (10 mol%), TFA (2 equiv.), dioxane (2 mL), 95
oC, 24 h, N2, isolated yield.
We next examined the scope of arylboronic acids
(Table 4). The tandem reaction of 1zj with p- and m-
tolylboronic acids gave 4b and 4c in 82% and 80%
yields, respectively, while o-tolylboronic acid
afforded 4d in 61% yield. Moderately electron-
i
t
donating groups, such as Pr (4e), Bu (4f), and
dimethyl (4g) groups, were compatible with this
reaction, affording the corresponding products in 64–
75% yields. However, the substrate bearing strongly
electron-donating group OMe did not retard the
reaction, affording 4h in 55% yield. Substrates
bearing moderately electron-withdrawing halogens,
such as fluoro (4i, 4k) and chloro (4j, 4l) groups,
were also well-tolerated, while the substrate bearing a
strongly electron-donating group NO2 afforded a
decreased yield of 42% (4m). The naphthyl-
substituted substrate gave 4n in 73% yield. Notably,
4-phenyl-3-(thiophene-3-carbonyl)-1H-isochromen-
1-one (4o) was obtained in 50% yield.
[a] Conditions: 1 (0.3 mmol), 2 (0.45 mmol), Pd(TFA)2 (5
mol%), L4 (10 mol%), TFA (2 equiv.), THF (2 mL), 95 oC,
12 h, air, isolated yield.
Interestingly,
when
cyanomethyl
2-
benzoylbenzoate (1zj) was used, desired product
phenyl(2-(4-phenyloxazol-2-yl)phenyl)methanone
(3zo) was obtained in 51% yield, accompanied
with
byproduct
3-benzoyl-4-phenyl-1H-
isochromen-1-one (4a) in 31% yield from
hydrolysis of the imine intermediate followed by
cyclization (Scheme 2). The structure of compound
4a was determined by X-ray diffraction analysis.[13]
Table 5. Scope of cyanomethyl 2-benzoylbenzoates.[a]
Scheme 2. Reaction of 1zj with phenylboronic acid.
The importance of isocoumarins12 in organic and
medicinal chemistry attracted our attention to the
development of a new tandem reaction for the
synthesis of 3-benzoyl-4-aryl-isocoumarins. We
investigated the tandem reaction of cyanomethyl 2-
benzoylbenzoate (1zj) with phenylboronic acid to
optimize the reaction conditions (Table S3, see SI for
details). We found that desired product 4a was
isolated in 85% yield using a combination of
Pd(TFA)2, L1, and TFA for 24 h in dioxane at 95 C
under N2.
[a] Conditions: 1 (0.3 mmol), 2 (0.6 mmol), Pd(TFA)2 (5
mol%), L1 (10 mol%), TFA (2 equiv.), dioxane (2 mL), 95
oC, 24 h, N2, isolated yield.
3
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10.1002/adsc.202000125
Advanced Synthesis & Catalysis
As shown in Table 5, both electron-rich
in the presence of ammonium trifluoroacetate
(Scheme 3c). Of note, this reaction did not work in
the absence of Pd catalyst (Table S3 in SI, entry 24).
However, the cyclization of 7a gave the desired 4a in
a relatively low yield (65%) without a Pd catalyst and
ligand (Scheme 3d), indicating that the Pd catalyst is
essential for the formation of intermediate 7a but not
crucial for further cyclization.
substituents, such as methyl (4p–4s) and methoxy
(4t–4v), and electron-deficient substituents, such as
fluoro (4w–4z) and chloro (4za–4zd), at the para-
position of the phenyl ring (Ar1) were tolerated,
affording the desired products in moderate yields.
Table 6. Synthesis of bromo- and iodo-substituted
oxazoles and isocoumarins.[a]
Scheme 3. Control experiments.
[a] Conditions: 1 (0.3 mmol), 2 (0.45 mmol), Pd(acac)2 (5
mol%), L4 (10 mol%), TfOH (2 equiv.), THF (2 mL), 95
oC, 24 h, air, isolated yield.
A possible pathway for the formation of oxazoles
and isocoumarins was proposed (Scheme 4). This
reaction involves the following key steps: (i)
Transmetalation between the Pd catalyst and
arylboronic acid to form a Pd–aryl species; (ii)
coordination of the nitrile to Pd to form intermediate
A; (iii) carbopalladation of the nitrile to give imine-
Pd complex B; (iv) protonation of intermediate B in
the presence of acid to generate imine intermediate C
(or tautomerization of the imine to enamine
intermediate D) and regenerate the Pd catalyst.
Substitution at the 2-position of cyanomethyl
benzoates was found to be crucial for the selective
synthesis of oxazoles and isocoumarins. The
cyanomethyl benzoates afforded 2,4-diaryloxazoles
as the sole products via intermediate E (path a), while
[b]
Pd(TFA)2 (5 mol%), L4 (10 mol%), TFA (2 equiv.),
THF (2 mL), 95 oC, 12 h, air, isolated yield.
[c] 1 (0.3 mmol), 2 (0.6 mmol), Pd(TFA)2 (5 mol%), L1 (10
o
mol%), TFA (2 equiv.), dioxane (2 mL), 95 C, 24 h, N2,
isolated yield.
To obtain halogen-substituted products for further
synthetic transformations, we examined the scope of
bromo- and iodo-substituted substrates (Table 6).
Several representative bromo-substituted substrates
were amenable to the reaction conditions, affording
the corresponding bromo-substituted oxazoles (5a–
5e) in 44–75% yields. A representative iodo-
substituted oxazole (5f) was obtained in 42% yield.
Furthermore, bromo- and iodo-substituted substrates
for the synthesis of isocoumarins (5g–5l) showed
good compatibility with this reaction.
Several control experiments were performed under
the optimized conditions. The attempted reaction in
the absence of phenyboronic acid failed to afford 6a
(Scheme 3a). This result indicated that the tandem
transformation was initiated by carbopalladation of
the nitrile. 2-Oxo-2-phenylethyl 2-benzoylbenzoate
(7a) was obtained in 83% yield from hydrolysis of
the ketimine intermediate in the presence of H2O
(Scheme 3b). We found that desired product 4a was
obtained in 81% yield when 7a was used as substrate
2-benzoyl-substituted
cyanomethyl
benzoates
delivered new class of 3-benzoyl-4-aryl-
a
isocoumarins selectively via intermediate F (path b).
We assumed that carbonyl activation in the presence
of acid would accelerate the intramolecular
cyclization of intermediate C or D.
Scheme 4. Proposed reaction pathway.
4
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10.1002/adsc.202000125
Advanced Synthesis & Catalysis
Conclusion
General Experimental Procedure for the Synthesis of
Isocoumarins
In summary, we have demonstrated a palladium-
catalyzed tandem reaction of readily available
cyanomethyl benzoates with arylboronic acids. This
methodology allows the efficient and selective
synthesis of oxazoles and isocoumarins with good
functional group tolerance under mild reaction
conditions.
Cyanomethyl benzoates 1 (0.3 mmol), arylboronic acid 2
(0.6 mmol), Pd(TFA)2 (5 mol%), L1 (10 mol%), TFA (0.6
mmol) and dioxane (2.0 mL) were successively added into
a Schlenk reaction tube under a nitrogen atmosphere. The
reaction mixture was stirred vigorously at 95 °C in an oil
bath for 24 h. After the reaction equilibrium, the mixture
was poured into ethyl acetate, which was washed with
saturated NaHCO3 (2 × 10 mL) and then brine (10 mL).
After the aqueous layer was extracted with ethyl acetate,
the combined organic layers were dried over anhydrous
Na2SO4 and evaporated under a vacuum. The residue was
purified by flash column chromatography with petroleum
ether/ethyl acetate (8:1) to afford the desired products 4a-
4zd, 5g-5l.
Experimental Section
1
General Information. Melting points are uncorrected. H
NMR and 13C NMR spectra were measured on a 400 MHz
or 500 MHz spectrometer using DMSO-d6 or CDCl3 as the
solvent with tetramethylsilane (TMS) as an internal
standard at room temperature. Chemical shifts are given n
δ relative to TMS, and the coupling constants J are given
in hertz. High-resolution mass spectra were recorded on an
ESI-Q-TOF mass spectrometer. Cyanomethyl benzoates[14]
was synthesized according to the method described in the
literature. Column chromatography was performed using
EM silica gel 60 (300−400 mesh). X-ray crystallographic
analysis was performed at the X-ray crystallography
facility, Shanghai Institute of Organic Chemistry (SIOC),
Chinese Academy of Sciences (CAS).
Acknowledgements
We acknowledge financial support from the NSFC (No.
21572162), and the Natural Science Foundation of Zhejiang
Province (Nos. LY20B020015 and LQ18B020006).
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5
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10.1002/adsc.202000125
Advanced Synthesis & Catalysis
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10.1002/adsc.202000125
Advanced Synthesis & Catalysis
FULL PAPER
Divergent Palladium-Catalyzed Tandem Reaction
of Cyanomethyl Benzoates with Arylboronic
Acids: Synthesis of Oxazoles and Isocoumarins
Adv. Synth. Catal. Year, Volume, Page – Page
Ling Dai, Shuling Yu, Wenzhang Xiong, Zhongyan
Chen,* Tong Xu, Yinlin Shao and Jiuxi Chen*
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