Efficient Preparation of Methyl 2-Oxo-3-aryl (heteroaryl)-2H-pyran-5-carboxylate via Pd-Catalyzed Negishi Coupling

Article abstract of DOI:10.1002/ejoc.202100608

Methyl 3-bromocoumalate, readily obtained from methyl 2-pyrone-5-carboxylate (methyl coumalate), is easily substituted by cross-coupling reactions with arylzinc reagents under palladium catalysis, leading to methyl 2-oxo-3-aryl (heteroaryl)-2H-pyran-5-carboxylates.

Full text of DOI:10.1002/ejoc.202100608

Full Papers
doi.org/10.1002/ejoc.202100608
Efficient Preparation of Methyl 2-Oxo-3-aryl (heteroaryl)-
2H-pyran-5-carboxylate via Pd-Catalyzed Negishi Coupling
Tania Xavier,[a] Christophe Pichon,[a] Marc Presset,[a] Erwan Le Gall,[a] and Sylvie Condon*[a]
Methyl 3-bromocoumalate, readily obtained from methyl 2-
pyrone-5-carboxylate (methyl coumalate), is easily substituted
by cross-coupling reactions with arylzinc reagents under
palladium catalysis, leading to methyl 2-oxo-3-aryl (heteroaryl)-
2H-pyran-5-carboxylates.
Introduction
species which disrupts the coupling reaction. Therefore,
synthetic methods allowing to maintain the pyrone unit remain
of high consideration to prospect new bioactive products with
simpler structures[44–45] or synthetic intermediates for further
transformations.[46]
Thus, we wish to disclose herein an efficient and mild
method to prepare 3-arylcoumalates, a new family of biobased
molecules, through Pd-catalyzed Negishi cross-coupling reac-
tions of methyl 3-bromocoumalate and functionalized arylzinc
species.
Natural products[1–3] containing a pyran-2-one core are wide-
spread in microbials, bacteria, fungi,[4] plant, alga, animal
sources and are characterized by remarkably diverse bioactiv-
ities ranging from sex pheromone,[5] anti-bacterial,[6]
antifungal,[7] cardioactive, cytotoxic,[8] insecticidal,[9] neuropro-
tective and anti-cancer activities.[10] In the framework of a
project aiming biomass valorization we got interested in methyl
2-pyrone-5-carboxylate (methyl coumalate, MC),[11] a renewable
feedstock ultimately accessible from malic acid[12] that holds a
significant role as aromatic ring precursor.[13–19] MC can be
considered as a good molecular platform candidate as this Results and Discussion
ambivalent compound possesses an extrinsic reactivity that
depends on its reaction partners.[20] Therefore, beside involve-
ment in cycloaddition reaction,[21–25] another feature related to
the electron deficient conjugated diene moiety is its propensity
to undergo 1,6 addition reactions with organometallic reagents
followed by an opening electrocyclic reaction to give function-
alized β,γ unsaturated carboxylic acids,[26] or α,γ dienoic acids.[27]
In addition, reactions with soft nucleophiles such as β-
ketoesters, 1,3-diketones, or amines allow access to 2H-
pyrans,[28] aromatic compounds,[29] and pyridines,[30–31] respec-
tively. To the best of our knowledge, the involvement of methyl
coumalate in a cross-vinylogous Rauhut-Currier reaction[32] and
in a Morita-Baylis-Hillman reaction[33] are the scarce examples of
processes giving access to coumalate adducts. Surprisingly,
there is no report of carbon-carbon bond formation from
methyl 3-bromo coumalate (3-BrMC) and an organometallic
species under transition metal catalysis, whereas brominated,
triflyloxy- or tosyloxy-pyran-2-ones readily react under
Sonogashira,[34] Negishi,[5] Suzuki,[35–38] Stille[39–42]À type couplings
or with Me3AlÀ dimethylaminoethanol complex as coupling
reagent.[43] The reason may lie on the high reactivity of the
more electron-depleted coumalate ring towards nucleophilic
This work was initialized by examining whether classical
methods developed in our laboratory could be appropriate for
the arylation of either MC or methyl 3-bromocoumalate (3-
BrMC). This latter could be easily obtained from MC using
bromine and triethylamine.[47] It first appeared that the electro-
chemical conjugate addition[48,49] of bromobenzene onto MC as
Michael acceptor to get 1,4 and/or 1,6 addition products is not
appropriate for MC as substrate (Table 1, entry 1). Similarly,
electrochemical coupling of 3-BrMC with bromobenzene to get
Table 1. Initial findings.
Entry Substrate
Reagent
PhBr
Conditions
Yield
[%][a]
[b]
1
2
3
4
1
NiBr2.xH2O (5 mol%), e-, iron
–
(2.5 equiv.) (1.0 equiv.) rod, NBu4Br, DMF/pyridine or
°
DMF/acetonitrile, 70 C
[b]
2
2
2
PhBr
(1.0 equiv)
NiBr2.bpy (5 mol%), eÀ , alumi-
num or zinc rod, NBu4Br, DMF,
rt
–
[a] T. Xavier, Dr. C. Pichon, Dr. M. Presset, Prof. E. Le Gall, Prof. S. Condon
Université Paris-Est Créteil, CNRS, Institut de Chimie et des Matériaux Paris-
Est, UMR 7182
[b]
Ph3Bi
PEPPSI IPr (5 mol%), PPh3
–
(0.33 equiv) (10 mol%), CsF (3.0 equiv.)
2-8 rue Henri Dunant, 94320, Thiais, France
E-mail: condon@icmpe.cnrs.fr
https://www.icmpe.cnrs.fr/recherche/departement-c3m/
°
DMF, 90 C, 14 h
PhZnBr
(1.5 equiv)
PdCl2(PPh3)2 (0.5 mol%), DMF/
32
°
Acetonitrile, 50 C, 14 h
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100608
[a] Isolated yield. [b] Substrate degradation.
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biaryl derivatives[50] such 3 failed (Table 1, entry 2). Thus, we
obtained in satisfactory yield after removal of the unreacted
zinc dust (entry 2), hence indicating chemical incompatibility
between Zn(0) and catalyst and/or 3-BrMC 2. It can be noted
that no coupling product was detected by GC in the absence of
PdCl2(PPh3)2, thus indicating that the remaining traces of cobalt
salts in the organozinc solution did not catalyze the coupling
reaction (entry 3). The corresponding Ni-based pre-catalyst was
assessed instead of PdCl2(PPh3)2, but these conditions failed to
deliver the expected product (entry 4). We observed that a
more important amount of the arylzinc species (1.5 equiv.) is
beneficial to the reaction (entries 2 and 5) whereas longer
definitively turned our attention to chemical methods involving
cross-coupling reaction of 3-BrMC with organometallic species
under palladium catalysis. First the stability of 3-BrMC and
methyl 3-phenylcoumalate have been evaluated in toluene in
the presence of K2CO3 or t-BuOK (2 equiv.). Degradation of both
products, ranging from 50% to 100%, was observed after
°
3 hours at 120 C or even at room temperature, although more
slowly. For these reasons, we did not investigate further the
Suzuki cross-coupling strategy.
If the use of triphenybismuth[51] (Table 1, entry 3), a soft
organometallic species,[52] led to a degradation of the starting
material, the use of phenylzinc bromide, prepared according to
Gosmini’s method,[53] with a simple PdCl2(PPh3)2 precatalyst
delivered the expected product 3 in a promising 32% yield
(Table 1, entry 4). Thus, this initial hit prompted us to carry out
the optimization of the reaction conditions with phenylzinc
bromide as the nucleophilic partner. Results are reported in
Table 2.
reaction times resulted in decreased yields, indicating
a
probable instability of the coupling product under the reaction
conditions (entry 6). Therefore, the reaction temperature was
°
logically lowered from 50 C to room temperature (entry 7),
resulting in improved yields, even with only 1.2 equiv. of the
arylzinc compound (entry 8). However, only partial conversion
°
of the starting material occurred at 0 C (entry 9). Other solvents
combinations like ACN/THF (entry 10) or pure ACN (entry 11)
also gave significant results, thus demonstrating the robustness
of these conditions.
As a preamble, it is important to keep in mind that
organozinc reagents were prepared by activation of the
corresponding aryl bromide under
a
cobalt catalysis in
The scope of the reaction was then explored with various
substituted arylzinc reagents easily reached and bearing
electro-withdrawing or -donating groups under ACN or ACN/
DMF combination. The best results are reported in Table 3.
Thus, the optimized reaction conditions could be applied to
a variety of substituted arylzinc reagents and isolated yields are
generally high (>75% in most cases). The introduction of
electron-withdrawing groups such as a fluorine (99%, entry 2),
a trifluoromethyl (79%, entry 3) or an ester group (85–92%,
entry 4–5) is well-tolerated in the para position and is also
possible in the meta position as illustrated by the use of ketone
derivative (92%, entry 6). However, no reaction was observed
with the organozinc species prepared from 4-bromobenzoni-
trile, probably due to catalyst poisoning. In the case of electron-
donating groups, yields were slightly lower as 83% and 82%
yield were obtained with a methyl (entry 7) or a methoxy group
(entry 8), respectively. Moreover, the study of the methoxy
°
acetonitrile (ACN) in the presence of an excess of Zn dust
(3 equiv.) prior to cross-coupling. In a previous study, it was
found that DMF as co-solvent of ACN could advantageously
enhance the efficiency of Negishi cross-coupling reactions.[54]
Therefore, at this stage, we decided to perform this study under
this solvent combination. In a first series of experiments, we
tried to determine whether the organozinc reagent could be
used in the presence of remaining zinc dust or if a decantation
was necessary to remove this reducing metal. Thus, whereas
the addition of 3-BrMC and PdCl2(PPh3)2 as a catalyst to a freshly
prepared heterogeneous solution of organozinc reagent led to
the decomposition of methyl 3-bromocoumalate 2 and for-
mation of biphenyl (entry 1), the coupling product was
Table 2. Optimization of the reaction conditions.
Table 3. Scope of arylzinc reagents.[a]
Entry[a]
x
Co-Solvent
T [ C]
Time [h]
Yield [%][b]
°
[d]
1
2
excess[c]
1.0
1.0
1.5
1.5
1.5
1.5
1.2
1.2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
–
rt
4
4
4
4
4
18
4
4
4
4
4
–
50
50
20
50
50
rt
rt
0
rt
rt
53
e
Entry
R
Product
Yield [%][b]
3
–
4[f]
5
–
[e]
65
32
74
70
1
2
3
4
5
6
7
8
9
H
p-F
p-CF3
p-CO2Me
p-CO2Et
m-COCH3
p-CH3
p-OMe
m-OMe
o-OMe
3a
3b
3c
3d
3e
3f
3g
3h
3i
91
6
7
8
9
10
11
99
79c
85c
92
[g]
–
1.2
1.2
84
91
92
83c
82c
88c
51c
[a] Reaction conditions: 3-BrMC: 1 mmol, co-solvent (1 M). [b] Isolated
yield. [c] No filtration of the organozinc solution made from PhBr
(10.0 mmol), leading to PhZnBr: 14.0 mL, 0.43 M. [d] Substrate degrada-
tion. [e] No reaction. [f] NiBr2(PPh3)2 0,5% was tested as catalyst. [g] Partial
conversion. The product was not isolated.
10
3j
[a] Reaction conditions: 3-BrMC: 1–5 mmol. [b] Isolated yield. [c] Use of a
co-solvent: DMF (1 M).
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recorded on a Bruker Avance II 400 MHz spectrometer. 1H NMR
chemical shifts were referenced to the residual solvent signal; 13C
NMR chemical shifts were referenced to the deuterated solvent
signal. Multiplicity was defined by DEPT 135 analysis. 19F NMR
chemical shifts were referenced to external CFCl3 (0.0 ppm). Data
are presented as follows: chemical shift δ (ppm), multiplicity (s=
singlet, d=doublet, t=triplet, q=quartet, quint=quintet, hept=
heptuplet, m=multiplet, br=broad), coupling constant J (Hz),
integration.
Scheme 1. Optimization in the preparation of thienyl adducts.
Preparation of methyl 3-bromocoumalate (3-BrMC)
Compound 2.[42] A 500 mL RBF equipped with a stir bar was
charged with methyl coumalate (7.706 g, 50.0 mmol, 1 equiv) and
CCl4 (100 mL, 0.5 M). A solution of bromine (5.6 mL, 115 mmol,
2.3 equiv) in CCl4 (40 mL) was added dropwise to the stirred
mixture with a pressure-equalizing dropping funnel at rt. Then, the
RBF was equipped with a reflux condenser and the reaction was
heated at reflux for 4 h. After cooling to rt, the excess of bromine
was removed by bubbling argon (or air) in the reaction for 10 min.
derivatives (entries 8–10) revealed not only the influence of the
electronics factors (improved 88% yield with a meta substitu-
tion) but also of the steric effects as only 51% yield was
obtained with the ortho-substituted organozinc reagent (en-
try 10).
To expand the usefulness of this methodology, we also
examined the cross-coupling reactions of 2 and 3-thienylzinc
bromide with 3-BrMC (Scheme 1). Whereas a good yield (75%)
was obtained with 2-thienylzinc bromide under ACN as sole
solvent, the cross-coupling reaction with 3-thienylzinc bromide
was less efficient and only gave a partial conversion of 3-BrMC
(Scheme 1). However, a significant improvement was obtained
by conducting the reaction with a higher excess of the
organozinc reagent (2 equiv.).
°
The mixture was cooled to 0 C (ice/water bath) and Et3N (16.0 mL,
115 mmol, 2.3 equiv) was added dropwise with a pressure-equaliz-
ing dropping funnel. The reaction was then allowed to warm to rt
and stirred for 1 h. After addition of 50 mL of DCM, the resulting
mixture was washed with water (3*100 mL) and NaCl sat (100 mL),
dried over Na2SO4, and evaporated. The desired product was
obtained after purification by FC [V(SiO2)=200 mL, PE/DCM: 40/60
(1000 mL), 30/70 (1000 mL)] as a beige solid (5.858 g, 49%). mp:
°
°
133–134 C (litt: 131–134 C). Rf (DCM, UV+KMnO4): 0.51. GC (50+
10/250–5): 11.2 min. HRMS (ESI+): [M+H]+ Calcd. for C7H6BrO4:
232.9444. Found: 232.9444. 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H),
8.14 (s, 1H), 3.87 (s, 3H).13C{1H} NMR (100 MHz, CDCl3): δ 162.5 (C),
156.8 (C), 156.6 (CH), 142.7 (CH), 112.8 (C), 111.6 (C), 52.9 (CH3).
Conclusion
Preparation of methyl 3-arylcoumalates
In summary, we have disclosed an unprecedented access to
methyl 3-aryl- and 3-heteroaryl-coumalates. The reaction, which
is characterized by its simplicity, allows the efficient coupling of
arylzinc compounds and methyl 3-bromocoumalate at room
temperature with only low amounts of a simple palladium pre-
catalyst. Valorization of these new readily available products
through their involvement in post-transformation reactions is
underway and will be reported in due course.
General procedure 1 (GP1): Step 1. A 50 mL RBF equipped with a stir
bar, closed with a septum and purged with Ar, was charged with
Zn (3.0 equiv) and ACN (C=0.7 M). Trifluoroacetic acid (15 mol%)
and 1,2-dibromoethane (20 mol%)[55] were added with syringes and
the suspension was stirred and heated to reflux with a heat gun.
After cooling to rt, the (hetero)aryl bromide (y mmol) and CoBr2
(10 mol%) were added and the reaction was stirred at rt for 1 h. The
excess of zinc was decanted and the solution of organozinc reagent
was titrated by reaction with I2. Step 2. A 50 mL RBF equipped with
a stir bar, closed with a septum and purged with Ar, was charged
with methyl 2-bromocoumalate (x mmol), PdCl2(PPh3)2 (0.05 mol%)
closed with a septum and purged with Ar. The decanted solution of
organozinc reagent in ACN (v mL, c M, 1.2 equiv), and in some cases
DMF (C=1 M) were successively added and the reaction was stirred
at rt for 4 h. Then, the reaction mixture was poured into sat aq
NH4Cl (50 mL) and the resulting solution was extracted with EA
(2*50 mL). The combined organic layers were washed with brine
(50 mL), dried over Na2SO4 and evaporated. Purification by FC
afforded the expected product.
Experimental Section
General Information. All commercially available reagents were
used as received. Solvents (Acetonitrile=ACN, DMF, THF, ethyl
acetate=EA, petroleum ether=PE, cyclohexane=Cy, CCl4, di-
chloromethane=DCM) were used as received. Room temperature
°
means 18–25 C. Melting points (mp) are uncorrected and were
measured on
a Büchi B-545 apparatus. Analytical thin layer
chromatography (TLC) was performed on TLC silica gel plates
(0.25 mm) precoated with a fluorescent indicator (Merck 60F254).
Visualization was effected using ultraviolet light (l=254 nm) and/or
a aqueous solution of KMnO4. Flash chromatography (FC) was
performed on 40–63 μm silica gel with mixtures of solvents. Gas
chromatography (GC) was recorded on a Shimadzu 2025 chromato-
Compound 3a. Following GP1, the reaction performed with
bromobenzene (1.1 mL, 10.0 mmol) afforded the corresponding
organozinc reagent (2.3 mL, C=0.53 M) and after reaction with
methyl 2-bromocoumalate (235 mg, 1.0 mmol) and PdCl2(PPh3)2
(3.5 mg, 5 μmol, 0.5 mol%), the desired product was obtained after
purification by flash chromatography [V(SiO2)=50 mL, PE/EA: 80/20
°
graph (Tinj =Tdet =250 C) with a ZB-5MSi capillary column (l=
°
(600 mL)] as a yellow solid (211 mg, 91%). mp: 90–92 C. Rf (PE/EA:
5,5 m), using nitrogen as carrier gas and a flame-ionization detector.
Retention times are given in minutes (min). High-Resolution Mass
Spectra were obtained at the ICOA of the Université of Orléans by
electrospray ionization using a Q-TOF analyzer. NMR spectra were
90/10, UV+KMnO4): 0.21. GC (50+10/250–5): 16.1 min. HRMS
1
(ESI+): [M+H]+ Calcd. for C13H11O4: 231.0652. Found: 231.0652. H
NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.92 (s, 1H), 7.67 (d, J=8.0 Hz,
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2H), 7.48–7.37 (m, 3H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
163.7 (C), 160.1 (C), 156.6 (CH), 137.7 (CH), 133.8 (C), 129.3 (CH),
128.6 (2 CH), 128.3 (2 CH), 127.2 (C), 112.7 (C), 52.6 (CH3).
NMR (100 MHz, CDCl3): 166.2 (C), 163.5 (C), 159.6 (C), 157.2 (CH),
138.7 (CH), 138.0 (C), 131.0 (C), 129.8 (2 CH), 128.3 (2 CH), 126.2 (C),
112.7 (C), 61.3 (CH2), 52.7 (CH3), 14.4 (CH3).
Compound 3b. Following GP1, the reaction performed with 1-
bromo-4-fluorobenzene (1.6 mL, 15.0 mmol) afforded the corre-
sponding organozinc reagent (12.8 mL, C=0.47 M) and after
reaction with methyl 2-bromocoumalate (1.175 g, 5.0 mmol) and
PdCl2(PPh3)2 (18.0 mg, 25 μmol, 0.5 mol%), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
100 mL, PE/EA: 80/20 (500 mL), 70/30 (500 mL)] as a yellow solid
Compound 3f. Following GP1, the reaction performed with methyl
4’-bromoacetophenone (2.0 mL, 15.0 mmol) afforded the corre-
sponding organozinc reagent (12.5 mL, C=0.42 M) and after
reaction with methyl 2-bromocoumalate (1.058 g, 4.5 mmol) and
PdCl2(PPh3)2 (16 mg, 23 μmol, 0.5 mol%), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
100 mL, PE/EA: 70/30 (500 mL), 60/40 (500 mL)] as a yellow solid
°
°
(1.284 g, quantitative). mp: 121–123 C. Rf (PE/EA: 80/20, UV+
(1.127 g, 92%). mp: 105–108 C. Rf (PE/EA: 80/20, UV+KMnO4): 0.13.
KMnO4): 0.36. GC (50+10/250-5): 15.9 min. HRMS (ESI+): [M+H]+
GC (50+10/250–5): 19.6 min. HRMS (ESI+): [M+H]+ Calcd. for
C15H13O5: 273.0757. Found: 273.0757. 1H NMR (400 MHz, CDCl3): δ
8.32 (s, 1H), 8.22 (s, 1H), 7.99–7.94 (m, 2H), 7.88 (d, J=7.5 Hz, 1H),
7.52 (t, J=7.5 Hz, 1H), 3.89 (s, 3H), 2.62 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 197.7 (C), 163.5 (C), 159.9 (C), 157.0 (CH), 138.4
(CH), 137.4 (C), 134.3 (C), 132.9 (CH), 129.0 (CH), 128.9 (CH), 128.1
(CH), 126.2 (C), 112.7 (C), 52.7 (CH3), 26.8 (CH3).
1
Calcd. for C13H10FO4: 249.0557. Found: 249.0560. H NMR (400 MHz,
CDCl3): δ 8.30 (s, 1H), 7.89 (s, 1H), 7.70 –7.62 (m, 2H), 7.11 (t, J=
8.6 Hz, 2H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.6 (d,
1JC-F =248.3 Hz, CF), 162.3 (C), 160.0 (C), 156.6 (CH), 137.5 (CH), 130.3
3
4
(d, JC-F =8.4 Hz, 2 CH), 129.8 (d, JC-F =3.3 Hz, C), 126.2 (C), 115.7 (d,
2JC-F =21.7 Hz, 2 CH), 112.7 (C), 52.7 (CH3). 19F{1H} NMR (377 MHz,
CDCl3): À 111.7 (s, 1 F).
Compound 3g. Following GP1, the reaction performed with 4-
bromotoluene (1.2 mL, 10.0 mmol) afforded the corresponding
organozinc reagent (5.5 mL, C=0.44 M) and after reaction with
methyl 2-bromocoumalate (470 mg, 2.0 mmol) and PdCl2(PPh3)2
(7.0 mg, 5 μmol, 0.5 mol%) in DMF (2 mL), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
50 mL, PE/EA: 90/10 (250 mL), 80/20 (250 mL), 70/30 (100 mL)] as a
Compound 3c. Following GP1, the reaction performed with 1-
bromo-4-(trifluoromethyl)benzene (1.4 mL, 10.0 mmol) afforded the
corresponding organozinc reagent (4.6 mL, C=0.52 M) and after
reaction with methyl 2-bromocoumalate (470 mg, 2.0 mmol) and
PdCl2(PPh3)2 (7.0 mg, 5 μmol, 0.5 mol%) in DMF (2 mL), the desired
product was obtained after purification by flash chromatography
[V(SiO2)=50 mL, PE/EA: 80/20 (500 mL), 70/30 (100 mL)] as a pale
°
yellow solid (410 mg, 83%). mp: 69–72 C. Rf (PE/EA: 90/10, UV+
yellow solid (474 mg, 79%). mp: 134–135 C. Rf (PE/EA: 80/20, UV+
KMnO4): 0.27. GC (50+10/250–5): 17.2 min. HRMS (ESI+): [M+H]+
°
KMnO4): 0.34. GC (150+10/250–10): 6.0 min. HRMS (ESI+): [M+H]+
Calcd. for C14H12O4: 245.0808. Found: 245.0806. H NMR (400 MHz,
1
1
Calcd. for C14H10F3O4: 299.0525. Found: 299.0523. H NMR (400 MHz,
CDCl3): δ 8.28 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.57 (d, J=
7.9 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 3.89 (s, 3H), 2.38 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 163.8 (C), 160.2 (C), 156.2 (CH), 139.4 (C),
137.0 (CH), 130.9 (C), 129.3 (2 CH), 128.2 (2 CH), 127.1 (C), 112.7 (C),
52.6 (CH3), 21.4 (CH3).
CDCl3): δ 8.34 (d, J=2.4 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.80 (d, J=
8.2 Hz, 2H), 7.69 (d, J=8.2 Hz, 2H), 3.91 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 163.5 (C), 159.6 (C), 157.4 (CH), 138.9 (CH), 137.3
(C), 131.2 (q, 2JC-F =32.6 Hz, C), 128.7 (2 CH), 125.9 (C), 125.6 (q,
3JC-F =3.7 Hz, 2 CH), 124.0 (q, 1JC-F =272.5 Hz, CF3), 112.7 (C), 52.8
(CH3). 19F{1H} NMR (377 MHz, CDCl3): À 62.8 (s, 3 F).
Compound 3d. Following GP1, the reaction performed with methyl
4-bromobenzoate (2.150 g, 10.0 mmol) afforded the corresponding
organozinc reagent (5.5 mL, C=0.44 M) and after reaction with
methyl 2-bromocoumalate (470 mg, 2.0 mmol) and PdCl2(PPh3)2
(7.0 mg, 5 μmol, 0.5 mol%) in DMF (2 mL), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
50 mL, PE/EA: 70/30 (500 mL), 60/40 (400 mL), 40/60 (200 mL)] as a
Compound 3h. Following GP1, the reaction performed with 4-
bromoanisole (1.3 mL, 10.0 mmol) afforded the corresponding
organozinc reagent (4.8 mL, C=0.50 M) and after reaction with
methyl 2-bromocoumalate (470 mg, 2.0 mmol) and PdCl2(PPh3)2
(7.0 mg, 5 μmol, 0.5 mol%) in DMF (2 mL), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
50 mL, PE/EA: 90/10 (250 mL), 80/20 (250 mL), 70/30 (100 mL)] as a
°
yellow solid (431 mg, 82%). mp: 115–118 C. Rf (PE/EA: 80/20, UV+
KMnO4): 0.39.
°
pale yellow solid (491 mg, 85%). mp: 138 C (decomposition). Rf
GC (150+10/250–5): 8.8 min. HRMS (ESI+): [M+H]+ Calcd. for
C14H13O5: 261.0757. Found: 261.0757. 1H NMR (400 MHz, CDCl3): δ
8.27 (d, J=2.1 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.65 (d, J=8.7 Hz,
2H), 6.95 (d, J=8.7 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 163.9 (C), 160.5 (C), 160.3 (C), 155.9 (CH), 136.3
(CH), 129.7 (2 CH), 126.8 (C), 126.1(C), 114.1 (2 CH), 112.7 (C), 55.5
(CH3), 52.6 (CH3).
(PE/EA: 70/30, UV+KMnO4): 0.33. GC (50+10/250–5): 20.2 min.
HRMS (ESI+): [M+H]+ Calcd. for C15H13O6: 289.0706. Found:
1
289.0705. H NMR (400 MHz, CDCl3): δ 8.34 (d, J=2.2 Hz, 1H), 8.09
(d, J=8.0 Hz, 2H), 7.99 (d, J=2.2 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H),
3.93 (s, 3H), 3.91 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.7 (C),
163.5 (C), 159.6 (C), 157.3 (CH), 138.8 (CH), 138.1 (C), 130.7 (C), 129.9
(2 CH), 128.3 (2 CH), 126.2 (C), 112.7 (C), 52.8 (CH3), 52.4 (CH3).
Compound 3i. Following GP1, the reaction performed with 3-
bromoanisole (1.3 mL, 10.0 mmol) afforded the corresponding
organozinc reagent (5.3 mL, C=0.45 M) and after reaction with
methyl 2-bromocoumalate (470 mg, 2.0 mmol) and PdCl2(PPh3)2
(7.0 mg, 5 μmol, 0.5 mol%) in DMF (2 mL), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
50 mL, PE/EA: 80/20 (250 mL), 70/30 (250 mL)] as a yellow solid
Compound 3e. Following GP1, the reaction performed with ethyl
4-bromobenzoate (2.4 mL, 15.0 mmol) afforded the corresponding
organozinc reagent (12.0 mL, C=0.45 M) and after reaction with
methyl 2-bromocoumalate (1.057 g, 4.5 mmol) and PdCl2(PPh3)2
(16.0 mg, 23 μmol, 0.5 mol%), the desired product was obtained
after purification by flash chromatography [V(SiO2)=100 mL, PE/EA:
70/30 (500 mL), 50/50 (400 mL)] as a yellow solid (1.260 g, 92%).
°
(461 mg, 88%). mp: 64–66 C. Rf (PE/EA: 80/20, UV+KMnO4): 0.34.
°
mp: 96–98 C. Rf (PE/EA: 70/30, UV+KMnO4): 0.47. GC (50+10/250–
GC (150+10/250–10): 8.4 min. HRMS (ESI+): [M+H]+ Calcd. for
C14H13O5: 261.0757. Found: 261.0758. 1H NMR (400 MHz, CDCl3): δ
8.30 (d, J=2.4 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H),
7.25–7.21 (m, 2H), 6.94 (d, J=8.2 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 163.7 (C), 159.9 (C), 159.7 (C), 156.6
5): 20.7 min.
HRMS (ESI+): [M+H]+ Calcd. for C16H15O6: 303.0863. Found:
1
303.0862. H NMR (400 MHz, CDCl3): δ 8.33 (d, J=2.6 Hz, 1H), 8.09
(d, J=7.8 Hz, 2H), 7.98 (d, J=2.6 Hz, 1H), 7.75 (d, J=7.8 Hz, 2H),
4.39 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 1.40 (t, J=7.1 Hz, 3H). 13C{1H}
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(CH), 137.9 (CH), 135.1 (C), 129.7 (CH), 127.0 (C), 120.7 (CH), 115.0
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Compound 3j. Following GP1, the reaction performed with 2-
bromoanisole (1.9 mL, 15.0 mmol) afforded the corresponding
organozinc reagent (11.3 mL, C=0.53 M) and after reaction with
methyl 2-bromocoumalate (1.175 g, 5.0 mmol) and PdCl2(PPh3)2
(18.0 mg, 25 μmol, 0.5 mol%), the desired product was obtained
after purification by flash chromatography [V(SiO2)=100 mL, DCM/
PE: 80/20 (500 mL), 90/10 (500 mL), 100/0 (400 mL)] as a yellow
°
solid (665 mg, 51%). mp: 78–81 C. Rf (DCM, UV+KMnO4): 0.34. GC
(50+10/250–5): 17.4 min. HRMS (ESI+): [M+H]+ Calcd. for C14H13O5:
261.0757. Found: 261.0757. 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H),
7.82 (s, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.04–6.94
(m, 2H), 3.87 (s, 3H), 3.81 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
163.8 (C), 159.7 (C), 157.1 (C), 156.8 (CH), 139.8 (CH), 130.7 (CH),
130.6 (CH), 125.6 (C), 123.3 (C), 120.7 (CH), 112.3 (C), 111.4 (CH), 55.8
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Compound 3k. Following GP1, the reaction performed with methyl
2-bromothiophene (0.96 mL, 10.0 mmol) afforded the correspond-
ing organozinc reagent (10.0 mL, C=0.50 M) and after reaction
with methyl 2-bromocoumalate (987 mg, 4.2 mmol) and
PdCl2(PPh3)2 (15 mg, 21 μmol, 0.5 mol%), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
100 mL, PE/EA: 90/10 (500 mL), 70/30 (500 mL)] as a yellow solid
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°
(753 mg, 75%). mp: 109–110 C. Rf (PE/EA: 80/20, UV+KMnO4): 0.30.
GC (50+10/250–5): 16.5 min. HRMS (ESI+): [M+H]+ Calcd. for
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8.25 (d, J=2.3 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.76 (d, J=3.7 Hz,
1H), 7.43 (d, J=5.1 Hz, 1H), 7.14–7.07 (m, 1H), 3.91 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 163.6 (C), 159.0 (C), 155.0 (CH), 135.1 (C),
133.3 (CH), 128.4 (CH), 127.8 (CH), 127.6 (CH), 121.3 (C), 112.7 (C),
52.7 (CH3).
Compound 3l. Following GP1, the reaction performed with methyl
3-bromothiophene (1.4 mL, 15.0 mmol) afforded the corresponding
organozinc reagent (16.0 mL, C=0.50 M, 2.0 equiv) and after
reaction with methyl 2-bromocoumalate (940 mg, 4.0 mmol) and
PdCl2(PPh3)2 (14 mg, 20 μmol, 0.5 mol%), the desired product was
obtained after purification by flash chromatography [V(SiO2)=
100 mL, PE/EA: 80/20 (500 mL), 70/30 (500 mL)] as a yellow solid
°
(776 mg, 82%). mp: 110–112 C. Rf (PE/EA: 80/20, UV+KMnO4): 0.39.
GC (50+10/250–5): 16.4 min. HRMS (ESI+): [M+H]+ Calcd. for
1
C11H9O4S: 237.0216. Found: 237.0218. H NMR (400 MHz, CDCl3): δ
8.25 (d, J=2.4 Hz, 1H), 8.18 (dd, J=3.0, 1.3 Hz, 1H), 8.02 (d, J=
2.4 Hz, 1H), 7.48 (dd, J=5.1, 1.3 Hz, 1H), 7.37 (dd, J=5.1, 3.0 Hz, 1H),
3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.8 (C), 159.5 (C),
155.4 (CH), 134.9 (CH), 133.5 (CH), 126.4 (CH), 126.1 (CH), 126.0 (CH),
121.8 (C), 112.5 (C), 52.6 (CH3).
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Keywords: CÀ C Coupling · Coumalate · Palladium · Zinc
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Manuscript received: May 19, 2021
Revised manuscript received: June 21, 2021
Accepted manuscript online: June 28, 2021
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FULL PAPERS
T. Xavier, Dr. C. Pichon, Dr. M.
Presset, Prof. E. Le Gall, Prof. S.
Condon*
1 – 7
Efficient Preparation of Methyl 2-
Oxo-3-aryl (heteroaryl)-2H-pyran-
5-carboxylate via Pd-Catalyzed
Negishi Coupling
A Negishi type coupling is reported
allowing access to methyl 3-aryl (het-
eroaryl) coumalates. The synthesis of
methyl coumalate adducts is charac-
terized by a low catalyst loading, high
functional tolerance, and high yields.