Synthesis of 2,5-Diaryl Nonsymmetric Furans C6-Platform Chemicals via Catalytic Conversion of Biomass and the Formal Synthesis of Dantrolene

Article abstract of DOI:10.1021/acs.joc.0c02236

Biomass-derived commodity chemical 5-hydroxymethyl furfural is an underutilized C6-platform chemical derived from cellulose that is ideal to prepare next-generation value-added products. We have developed an efficient synthetic strategy to access 2,5-diar

Full text of DOI:10.1021/acs.joc.0c02236

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Article
Synthesis of 2,5-Diaryl Nonsymmetric Furans C6-Platform Chemicals
via Catalytic Conversion of Biomass and the Formal Synthesis of
Dantrolene
́
Franklin Chacon-Huete, Juan David Lasso, Paul Szavay, Jason Covone, and Pat Forgione*
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ABSTRACT: Biomass-derived commodity chemical 5-hydroxy-
methyl furfural is an underutilized C6-platform chemical derived
from cellulose that is ideal to prepare next-generation value-added
products. We have developed an efficient synthetic strategy to
access 2,5-diaryl nonsymmetric furans from 5-hydroxymethyl
furfural utilizing decarboxylative cross-couplings. A key finding
was that the presence of the hydroxymethyl handle enhances the
yields of the palladium-catalyzed decarboxylative cross-coupling
reaction. The method provides access to a broad-range non-
symmetric 2,5-diaryl furans where each arene can be systematically introduced as required. Additionally, this green synthetic strategy
was employed for a formal synthesis of the muscle relaxant Dantrolene in excellent yields.
dients,20 polymer synthesis,21 among others.22,23 Several
INTRODUCTION
■
reports have described the synthesis of 2,5-diaryl furans 10.
The exponential growth of the demand on organic chemical
The employment of coinage metals such as Cu, Ag, and Au
materials has led to an uncontrolled exploitation of petroleum
toward the synthesis of substituted furans has been reported
feedstock sources.1−3 To reduce dependence on petroleum
with reactions including cyclization of alkynes with tethered
derivatives and mitigate climate change in the chemical
nucleophiles,24 cycloaddition reactions,25 radical cyclization of
sectors, the employment of alternative production systems is
haloalkenes or haloalkynes,26 among others.27 These method-
required. Toward this end, biomass has been explored as a
ologies, although helpful, require the synthesis of complex
potential renewable resource for the production of fuels and
starting materials that are often not commercially available,
starting materials for chemical synthesis.4,5 Initial efforts from
which results in a nonmodular approach that could limit their
academic research are now moving into pilot plants as
synthetic utility. Other reports have utilized preformed furan
evidenced by the recent efforts of the Avantium-BASF6 joint
cores. The Yin group reported the α-arylation of furans
venture for 50,000 MT/year production of biomass-derived
through cleavage of a primary alcohol utilizing boronic esters
furans and the ADM-DuPont7,8 pilot plant for the production
as the coupling partners (Scheme 1, 1→2),28 and the
of carbohydrate-derived platform chemicals.
advances on C−H activation by the Doucet group29,30 have
Within biomass, furans derived from carbohydrates have
allowed for the arylation of furan in combination with
been highlighted as “sleeping giants”9 in terms of their
decarboxylative couplings (Scheme 1, 4→5→6 and 1→3.).
potential use in a diverse range of applications. The
Although helpful, these methodologies rely on C5 furan
breakdown of cellulose and cyclodehydration of common
starting materials obtained from pentoses (derived from
hexoses leads to 5-hydroxymethyl furfural (HMF),10 which
hemicellulose), which are less abundant when compared to
serves as a platform chemical for the production of the fuel
the hexoses (derived from cellulose) and C6 derivatives, such
alternatives 2,5-dimethylfuran, 2,5-dihydroxymethyl furan
(DHMF), 2,5-furan dicarboxylic acid (terephthalic acid
as HMF (7).
In our approach, we propose the utilization of cellulose-
replacement molecule in PET polymers),11−13 and γ-
derived HMF 7 and sequential decarboxylative cross-
valerolactone14 (food additive), among others.15−17 It is
highly important to develop chemical tools that allow chemists
Received: September 16, 2020
to perform transformations on these biomass-derived starting
materials to obtain value-added next-generation chemicals.18
On this note, the synthesis of aryl-substituted furans remains
an important transformation because of the ubiquitous
presence of this moiety in a variety of compound classes
including natural products,19 active pharmaceutical ingre-
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A

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Scheme 1. Reported Synthetic Strategies for the Synthesis of 2,5-Nonsymmetric Diaryl Furans and the Proposed Present
Work
a
Table 1. Optimization of the Initial Decarboxylative Cross-Coupling
entry
R
Pd source
ligand
none
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
None
P(t-Bu)3
PCy3
P(t-Bu)3
MePhos
JohnPhos
yield (%)
1
2
3
4
5
6
7
8
9
10
TBDMS
TBDMS
TBDMS
Pd(OAc)2
Pd(OAc)2
PdCl2
0
23
28
54
61
51
44
67
85
93
H
H
H
H
H
H
H
PdCl2
Pd[P(t-Bu3)]2
Pd(dba)2
Pd(dba)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
a
General conditions: Furan substrate 0.4 mmol, p-bromo nitrobenzene 0.2 mmol, Cs2CO3 (1.5 equiv), n-Bu4NCl (30 mol %), Pd source (5 mol
%), ligand (10 mol %), DMF [0.1 M], 170 °C μw, 8 min, 900 rpm.
coupling31−37 steps to circumvent long-standing stepwise
transformations of nonaromatic precursors. This approach
circumvents the formation of heavy stoichiometric organo-
metallic waste, usually produced from classical Pd-mediated
methodologies. Previously, we reported the employment of a
double decarboxylative cross-coupling reaction on biomass-
derived 2,5-furandicarboxylic acid (FDCA, 8) for the synthesis
of symmetric 2,5-diaryl furans (9) with good to excellent
yields.38 Herein, we aim to expand the scope of biomass-
derived starting materials by generating 2,5-diaryl non-
symmetric furans from HMF (Scheme 1, 7→10). This
route would provide significant additional value by allowing
for differentiation between the 2- and 5-positions of the furan
while also utilizing a C6 biomass-derived starting material
(HMF) that is upstream in the biorefinery process, relative to
the previously employed FDCA.
RESULTS AND DISCUSSION
■
The proposed synthetic approach comprises a first oxidation
of the aldehyde moiety of HMF to obtain HMFA (11, R
H). There have been several strategies reported for this
transformation, typically employing transition metals sup-
ported on heterogeneous media for catalysis.39−42 Our group
previously reported the utilization of a solvent-free mecha-
nochemical disproportionation of HMF into DHMF and
HMFA in quantitative yields,43 and we employed this method
to obtain the required substrate for the inital cross-coupling
reactions (Table 1).
B
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We prepared the silyl ether-protected HMFA (11, R
tBuMe2Si) and evaluated the reaction with previously reported
decarboxylative cross-coupling conditions. In the absence of a
phosphine ligand (Table 1, entry 1), the reaction did not yield
the desired product, but when P(t-Bu)3 was added, a 23%
yield was obtained for the desired cross-coupling product
(entry 2). PdCl2 provided the product in a similar yield as
Pd(OAc)2 (entries 2 and 3). To our surprise, employing the
unprotected alcohol (HMFA) in the cross-coupling, resulted
in higher yields (entries 4−7), which led us to hypothesize
that the hydroxymethyl handle may be acting to facilitate the
cross-coupling. Finally, employing a combination of Pd(acac)2
and Buchwald-type ligands44 yielded the desired product in
excellent yields (entries 9−10).
Previous reports had demonstrated that free alcohols and
phenol functionalities when present on the aryl-bromide
electrophilic cross-coupling partner were not tolerated for
related palladium-mediated decarboxylative arylations.38 Based
on our initial results, we hypothesized that the employment of
HMFA (14) in the decarboxylative cross-coupling (Scheme
2), which includes a free hydroxymethyl group in the
provided an even lower yield of 55% of the desired cross-
coupling product 20c. Finally, the previously synthesized t-
butyldimethylsilyl ether 18d led to a 45% yield of 20d. These
experiments supported that there was an intrinsic beneficial
overall effect of having the free hydroxymethyl handle on the
furoic acid coupling partner.
Competition experiments were subsequently conducted to
further evaluate the importance of the hydroxymethyl
stabilizing group effect (Scheme 4). In the initial experiment
(Scheme 4, Top), HMFA 18a was compared with furoic acid
18b, from which a ratio of 1.5:1.0 (20a:20b) of the
corresponding products was obtained in favor of the
product-derived HMFA. However, because the electronics of
the furan ring were different for the two starting materials, we
performed a subsequent competition experiment (Scheme 4,
bottom), in which the C5-position was substituted for all
starting materials, while varying the steric environment around
the oxygen atom. The composition of the reaction crude
mixture was found to be predominantly of product 20a (from
HMFA), and lower quantities of 20c (from 18c) and 20d
(from 18d) were obtained, which suggests an energetically
favored reaction pathway for the starting material bearing the
hydroxymethyl handle. Overall, these experiments suggest that
the free hydroxyl group on the HMFA is responsible for the
improved yields. These possible interactions (hypothesized in
Scheme 2) of distal weakly coordinating functional groups in
palladium catalysis have been reported in related systems by
the Yu45,46 group based on the initial findings of van
Leeuwen47 and the Sanford group.48 Ongoing studies in our
group are being carried out to better describe the nature of
these interactions and their impact on the decarboxylative
cross-couplings.
Scheme 2. Proposed Catalytic Cycle for the Pd-Mediated
Cross-Coupling of HMFA (15) and Aryl Bromides
Oxidation of furfuryl alcohols to the corresponding
carboxylic acids remains a challenge because the typically
harsh oxidative conditions often lead to unwanted by-products
and have low functional group tolerance. In order to avoid
these issues, we evaluated a catalytic TEMPO-NaOCl
oxidation with NaClO2 (Table 2, entries 1 and 2), but the
corresponding products were obtained in a low yield.49 We
hypothesized that the electron-rich nature of this model
substrate (21a) may be problematic and thus prepared a
second model substrate with an electron-deficient substituent
(p-CF3, 21b), that improved the yield toward the aldehyde
(22b), but only a small quantity of the desired carboxylic acid
(23b) was obtained (entry 2). Oxidative conditions that
involve acidic media were noncompatible with the hydrox-
ymethyl furan derivatives as they induce the formation of
nondesired side products (entry 3). Interestingly, when metal
catalysis with peroxide was employed,50 a mixture between the
desired acid and the aldehyde derivative was obtained (entries
4 and 5).
nucleophilic cross-coupling partner, could potentially aid in
the stabilization of key intermediate 15 and facilitate the
electrophilic palladation (Scheme 2, 15→16) required for the
cross-coupling reaction.
In order to evaluate the influence of the hydroxymethyl
handle on the decarboxylative cross-couplings, single experi-
ments were designed to modify this group. Replacing the
alcohol group with the corresponding methyl ether resulted in
a lower yield (66%, Scheme 3, 18c→20c). Furoic acid 18b
Replacement of the BiCl3 with CuBr2 led to the selective
formation of the aldehyde in moderate yields.51 Harsher
Scheme 3. Cross-Coupling of HMFA Derivatives with Bromobenzene: Individual Reaction Yields
C
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Scheme 4. Competition Decarboxylative Cross-Coupling Reactions Between Furoic Acid Derivatives
Table 2. Oxidation of the Methyl Alcohol Moiety
a
entry
R
conditions
%22
%23
1
2
3
4-OCH3
4-CF3
4-CF3
NaClO2, NaOCl, TEMPO
NaClO2, NaOCl, TEMPO
Jones Reagent
20
48
0
0
<5
0
4
5
6
7
8
9
10
11
12
13
4-CF3
BiCl3, t-BuOOH
BiCl3, t-BuOOH
SiO2/KMnO4
CuBr2, t-BuOOH
<5
45
0
68
43
>98
90
>99
94
0
68
19
0
0
0
0
0
0
0
4-OCH3
4-OCH3
4-CF3
4-OCH3
4-CF3
4-OCH3
4-CF3
4-OCH3
4-CF3
CuBr2, t-BuOOH
Fe(NO3)39H2O, TEMPO, O2
Fe(NO3)3 9H2O, TEMPO, O2
[Cu(CH3CN)4]PF6, DBED, O2
[Cu(CH3CN)4]PF6, DBED, O2
1.[Cu(CH3CN)4]PF6, DBED, O2
2.NaClO2, sulphamic acid
1.[Cu(CH3CN)4]PF6, DBED, O2
95
14
4-OCH3
0
89
2.NaClO2, sulphamic acid
a
b
Full description of the reaction conditions can be found in Experimental Section. 60% of 4-methoxybenzoic acid was recovered.
oxidation conditions (KMnO4 adsorbed on silica52) cleaved
the furan moiety to produce the corresponding benzoic acid
(entry 6). Aerobic oxidation using TEMPO/O2 with Fe-
(NO3)3 gave excellent yields of the aldehyde derivative.53
Given the high cost of TEMPO, we envisioned that this step
would be nonoptimal, particularly for potential industrial
applications.54 To address this issue, we subsequently
employed a biomimetic copper system,55 in which the
reaction is performed at room temperature under an O2
atmosphere, obtaining high yields of the corresponding
aldehydes in significantly shorter reaction times. We
subsequently employed a two-step oxidation (entries 13 and
14) with the conditions reported in entries 11 and 12,
including an adapted Pinnick oxidation56,57 to obtain the
desired carboxylic acids (23).
of coupling partners (Table 3). As expected, electron-deficient
carboxylic acids (entries 1−3 and 7−9) typically produced the
corresponding product in higher yields. Correspondingly,
electron-neutral and -rich carboxylic acids (entries 4−6 and
10−12) provided the products in lower yields, possibly
because of the higher energetic barrier to overcome in the
decarboxylation step. Overall, a wide scope of 2,5-diaryl
nonsymmetric furans were prepared that tolerated different
functionalities, including substrates bearing sterically challeng-
ing ortho substituents (entries 7, 9, and 11) in good to
excellent yields.
Formal Synthesis of Dantrolene. Dantrolene 26 is a
hydantoin derivative furan that acts as a postsynaptic muscle
relaxant with important applications in the prevention and
treatment of malignant hyperthermia.20,58 The reported
patented synthesis59,60 involves the preparation of a diazonium
salt, followed by a Cu-catalyzed Meerwein arylation and an
iminium formation with 2-aminohydantoin to form the target
With the carboxylic acids prepared, we subjected the furoic
acids to a second decarboxylative cross-coupling based on the
conditions optimized for the first reaction with a wide variety
D
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Table 3. Scope of the Second-Decarboxylative Cross-Coupling Arylation
a
General conditions: furan carboxylic acid (1.5 equiv), aryl bromide 1 mmol, Pd(acac)2 (5 mol %), JohnPhos (10 mol %) Cs2CO3 (1.5 equiv), n-
Bu4NCl (30 mol %) DMF [0.1 M], 170 °C μw, 8 min, 900 rpm.
drug. Despite this synthetic approach involving only three
steps, it presents a challenge in the efficiency of the arylation
because of the very low yield (<20%) and requires the
preparation of the potentially dangerous diazonium salt. Other
methodologies have been reported that explore the C−H
arylation of C5-derived furans with solid-supported catalysis
(TiO2)61 and Pd-mediated C−H arylations.62
We propose employing a C6 biomass-derived starting
material for the synthesis of this drug molecule based on the
currently reported method (Scheme 5). HMFA (18a) was
obtained from HMF (7) through a solvent-free mechano-
chemical base-promoted disproportionation and used as the
starting material for the decarboxylative cross-coupling with p-
bromo nitrobenzene to obtain (13a). This step is critical
because it circumvents the two main problems of the patented
route, the low yield for the cross-coupling, and the
commercial availability of the starting materials. This
compound was subjected to a biomimetic Cu-catalyzed
aerobic oxidation to obtain the corresponding aldehyde (25)
in quantitative yield. The overall yield for this three-step
E
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Scheme 5. Synthetic Route for the Formal Synthesis of Dantrolene from Biomass-derived HMF
(2−5 mL), with a stir bar, was added 114 mg of HMFA (0.8 mmol,
2 equiv), 6.1 mg of Pd(acac)2 (0.02 mmol, 5 mol %), 11.9 mg of
JohnPhos (0.08 mmol, 10 mol %), 195 mg of Cs2CO3 (0.6 mmol,
1.5 equiv.), 0.4 mmol of the corresponding aryl bromide, 33 mg of n-
Bu4NCl (0.12 mmol, 30 mol %), and 4 mL of anhydrous DMF. The
reaction is prestirred for 30 s and then subjected to microwave
irradiation to achieve 170 °C for 8 min at 900 rpm. The reaction
crude is transferred to a 125 mL separating funnel, diluted with 30
mL of EtOAc, and washed with brine (2 × 20 mL) and
NaHCO3(sat) (1 × 20 mL). The combined aqueous phases are
reextracted with EtOAc (1 × 15 mL), and the combined organics are
dried over Na2SO4. The solvent is removed under vaccuo, and the
crude is purified by silica gel chromatography to obtain the pure
desired product. This procedure was scaled up in a 20 mL sealed
microwave vial, with 516 mg (3.6 mmol, 2 equiv) of HMFA and 340
mg (1.8 mmol, 1 equiv) of 4-bromo anisole, 27 mg (5 mol %) of
Pd(acac)2, 55 mg (10 mol %) of JohnPhos, 150 mg (30 mol %) of n-
Bu4NCl, 870 mg (2.7 mmol, 1.5 equiv), and 18 mL of anhydrous
DMF. In this case, the reaction was subjected to microwave
irradiation at 170 °C for 20 min. Work-up was done as previously
described, with extensive (six times) brine washing to assure removal
of DMF. Purification was done using an 80 g silica column on
CombiFlash with hexanes/DCM/EtOAC (4:4:2) to afford 332 mg of
the desired product (91%, pale-yellow solid).
process to the key aldehyde intermediate (25) of 93% starting
from biomass-derived HMF is the most efficient synthesis
reported to date for Dantrolene.
CONCLUSIONS
■
Highlighting the importance of employing C6 biomass-derived
furans, this work presents a new method to obtain 2,5-diaryl
nonsymmetric furans from cellulose-derived HMF with good
to excellent yields. Single and competition reactions support
the idea of a distal weakly coordinating stabilizing effect of the
hydroxyl handle that results in improved yields. With a
commitment toward green synthetic chemistry methodologies,
a biomimetic Cu-catalyzed aerobic oxidation was employed in
a two-step reaction sequence to obtain the key synthetic
intermediates to synthesize the double-arylated products.
Furthermore, with this key intermediate, a new formal
synthetic pathway for the commercially available muscle
relaxant Dantrolene was achieved, with excellent yields and
improved synthetic efficiency than those obtained from
previously reported routes. This work highlights the
importance of the employment of renewable resources as
starting materials for high-value synthetic targets.
Cu-Catalyzed Oxidation of the Primary Alcohol to the
Aldehyde. In a nitrogen glovebox, a Schlenk tube equipped with a
stir bar was charged with alcohol (0.5 mmol), [Cu(CH3CN)4]PF6
(0.025 mmol), DBED (0.025 mmol), DMAP (0.1 mmol), 4 Å
molecular sieves (100 mg), and CH2Cl2 (4 mL). The tube was
sealed, brought out of the glovebox, the nitrogen headspace was
evacuated, and then replaced at a constant pressure of 1 atm O2. The
resulting mixture was stirred at room temperature for 6 h. After this
time, 10% wt. NaHSO4 (15 mL) was added to quench the reaction.
The product was extracted with additional CH2Cl2 (3 × 10 mL), and
the combined organic layers were dried with Na2SO4, filtered, and
concentrated to afford the product. Purification was done (when
needed) with silica gel CombiFlash using hexanes/EtOAc (10:0 to
8:2) as the eluent. This reaction was scaled up according to the
corresponding yield of the first cross-coupling.
Adapted Pinnick Oxidation of the Aldehyde to the
Carboxylic Acid. The corresponding aldehyde (1 equiv) was
added in a 10 mL round-bottom flask and equipped with a stir bar.
To this flask, was added MeCN/H2O (3:1, 0.65 M to the
corresponding alcohol), NaH2PO4 (0.26 equiv), NaClO2 (1.39
equiv), and H2O2 30% (1 equiv). The flask was covered with
aluminum foil to avoid photoinduced decomposition and stirred at
room temperature for 18 h. In those cases where the reaction was not
completed in 18 h (electron-rich substrates), the reaction vessel was
EXPERIMENTAL SECTION
■
General Considerations. Flash chromatography was carried out
using 40−63 μm silica gel (SiliCycle), and some compounds were
isolated using a CombiFlash Teledyne Isco. All solvents were
purchased as ACS grade from Fisher Scientific or JT Baker and were
stored under an inert atmosphere with activated 3 or 4 Å molecular
sieves. Distilled water was obtained from an in-house water distillery.
All other reagents and chemicals were purchased from Sigma-Aldrich
1
or Alfa Aesar and used without further purification. H (500 MHz)
and 13C (125 MHz) NMR spectra were recorded in CDCl3 or d6-
DMSO using a Varian Inova 500 MHz spectrometer. Spectra were
referenced to the residual solvent signal or the TMS signal. Spectral
features are tabulated in the following order: chemical shift (δ, ppm),
multiplicity (s-singlet, d-doublet, t-triplet, q-quartet, dd-doublet of
doublets, m-multiplet, and ddd-doublet of doublets of doublets),
coupling constants (J and Hz), and number of protons. High-
resolution mass spectra were obtained with an LTQ Orbitrap Velos
ETD (positive and negative mode) mass spectrometer. Microwave
reactions were carried out in sealed vials using a Biotage Initiator
EXP US 355302 system (300 W and 2450 MHz).
General Procedure for the Decarboxylative Cross-Coupling
of HMFA and Aryl Bromides. To an oven-dried microwave vial
F
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opened and NaClO2 (1.05 equiv) and H2O2 30% (1 equiv) was
added and stirred for another 18 h. When the reaction was
completed, the stir bar was removed and the MeCN was removed
under vaccuo. The aqueous remaining solution was checked for high
acidity (pH 2, adjusted with 2 M HCl when necessary) and extracted
with EtOAc (3 × 10 mL). The combined organics were dried with
Na2SO4, and the solvent was removed under vaccuo to obtain the
desired product. When needed, purification of the product can be
done with acid-base extraction or silica gel chromatography with
DCM/MeOH (10:0 to 8:2, and a trace amount of AcOH).
General Procedure for the Decarboxylative Cross-Coupling
of 5-Aryl-2-furoic Acids and Aryl Bromides. To an oven-dried
microwave vial (0.5−2 mL), with a stir bar, was added 0.2 mmol of
the 5-aryl-2-furoic acid (1 equiv), 3.1 mg of Pd(acac)2 (0.01 mmol, 5
mol %), 6.0 mg of JohnPhos (0.02 mmol, 10 mol %), 98 mg of
Cs2CO3 (0.3 mmol, 1.5 equiv.), 0.4 mmol of the corresponding aryl
bromide, 16 mg of n-Bu4NCl (0.06 mmol, 30 mol %), and 2 mL of
anhydrous DMF. The reaction is prestirred for 30 s and then
subjected to microwave irradiation to achieve 170 °C for 8 min at
900 rpm. The reaction crude is transferred to a 125 mL separating
funnel, diluted with 30 mL of EtOAc, and washed with brine (2 × 20
mL) and NaHCO3(sat) (1 × 20 mL). The combined aqueous phases
are reextracted with EtOAc (1 × 15 mL), and the combined organics
are dried over Na2SO4. The solvent is removed under vaccuo, and
the crude is purified by silica gel chromatography to obtain the pure
desired product.
(2C), 124.1 (2C), 123.6 (2C), 111.4 (1C), 107.2 (1C), 21.4 (1C).
HRMS (ESI): m/z Calcd for C17H13NO3 [M+•]: 279.0895. Found:
279.0898 (1.1 ppm).
10b: 2-(3-methoxyphenyl)-5-(4-nitrophenyl)furan. Purified by
CC (Rf = 0.36) hexanes/DCM (1:1), 42 mg (72%) yield as a
1
yellow solid. H NMR (500 MHz, CDCl3): δ ppm 8.25 (d, J = 9.0
Hz, 2H), 7.83 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 5.1 Hz, 2H), 7.30 (dt,
J = 2.4, 0.9 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 6.91−6.87 (m, 1H),
6.80 (d, J = 3.6 Hz, 1H), 3.90 (s, 2H). 13C{1H} NMR (125 MHz,
CDCl3): δ ppm 160 (1C), 155.4 (1C), 150.9 (1C), 146.2 (1C),
136.2 (1C), 131.2 (1C), 124.37 (2C), 123.7 (2C), 116.74 (1C),
113.6 (1C), 111.3 (1C), 109.8 (1C), 108.1 (1C), 55.37 (1C).
HRMS (ESI): m/z Calcd for C17H13NO4 [M+•]: 295.0845. Found:
295.0851 (2.0 ppm).
10c: 2-(4-nitrophenyl)-5-(3-(trifluoromethyl)phenyl)furan. Puri-
fied by CC (Rf = 0.38) hexanes/DCM (1:1), 61 mg (91%) yield as
1
an orange/yellow solid. H NMR (500 MHz, CDCl3): δ ppm 8.29
(d, J = 9.0 HZ, 2H), 7.99 (m, 1H), 7.93 (m, 1H), 7.87 (d, J = 9.0
Hz, 2H), 7.57 (m, 2H), 7.00 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 3.6 Hz,
1H). 13C{1H} NMR (125 MHz, CDCl3): δ ppm 153.8 (1C), 151.7
(1C), 146.5 (1C), 135.8 (1C), 131.4 (q, C−F, 2JC−F = 32.5 Hz, 1C),
4
130.7 (1C), 129.4 (1C), 127.1(q, C−F, JC−F = 1.4 Hz, 1C),
3
124.6(q, C−F, JC−F = 3.8 Hz, 1C), 124.4 (2C), 124.0 (q, C−F,
3
1JC−F = 272.0 Hz, 1C), 123.9 (2C), 120.7(q, C−F, JC−F = 3.9 Hz,
1C), 111.2 (1C), 109.1 (1C). HRMS (ESI): m/z Calcd for
C17H10F3NO3 [M+•]: 333.0613. Found: 333.0618 (1.5 ppm).
10d: 2-(4-methoxyphenyl)-5-(p-tolyl)furan.64 Purified by CC (Rf
= 0.43) hexanes/DCM (1:1), 36 mg (69%) yield as a pale yellow
solid. 1H NMR (500 MHz, CDCl3): δ ppm 7.70−7.65 (m, 2H),
7.65−7.60 (m, 2H), 7.23−7.18 (m, 2H), 6.98−6.91 (m, 2H), 6.66
(d, J = 3.4 Hz, 1H), 6.59 (d, J = 3.4 Hz, 1H). 13C{1H} NMR (125
MHz, CDCl3): δ ppm 158.9 (1C), 153 (1C), 152.9 (1C), 136.9
(1C), 129.3 (2C), 128.2 (1C), 125.1 (2C), 124 (1C), 123.5 (2C),
114.1 (2C), 106.4 (1C), 105.5 (1C), 55.3 (1C), 21.2 (1C). HRMS
(ESI): exact mass calculated for C18H16O2 [M+•]: 264.1150. Found:
264.1152 (0.8 ppm).
3a: (5-(4-nitrophenyl)furan-2-yl)methanol.29 Purified by CC (Rf
= 0.42) hexanes/DCM/EtOAc (4:4:2), 81 mg (93%) yield as a
1
yellow solid. H NMR (500 MHz, CDCl3): δ ppm 8.23 (d, J = 9.0
Hz, 2H), 7.78 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 3.4 Hz, 1H), 6.46 (d,
J = 3.4 Hz, 1H), 4.71 (s, 2H), 1.86 (br s, 1H). 13C{1H} NMR (125
MHz, CDCl3): δ ppm 155.8 (1C), 151.6 (1C), 146.4 (1C), 136.2
(1C), 124.3 (2C), 123.9 (2C), 110.5 (1C), 109.7 (1C), 57.6 (1C).
−
HRMS (ESI): m/z Calcd for C11H8NO4 [M − 1]−• 218.0459.
Found: 218.0455 (−1.8 ppm).
3b: (5-(4-methoxyphenyl)furan-2-yl)methanol.29 Purified by CC
(Rf = 0.53) hexanes/DCM/EtOAc (4:4:2), 78 mg (95%) yield as a
1
10e: 2-(4-methoxyphenyl)-5-(3-nitrophenyl)furan. Purified by
CC (Rf = 0.31) hexanes/DCM (7:3), 45 mg (76%) yield as a
yellow solid. 1H NMR (500 MHz, CDCl3): δ ppm 8.51 (ddd, J = 2.2,
1.6, 0.4 Hz, 1H), 8.06 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.98 (ddd, J =
8.0, 1.6, 1.0 Hz, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.55 (dd, J = 8.0, 0.4
Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 3.5 Hz, 1H), 6.64 (d,
J = 3.5 Hz, 1H), 3.86 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ
ppm 159.5 (1C), 154.8 (1C), 150 (1C), 148.7 (1C), 132.4 (1C),
129.6 (1C), 128.8 (2C), 125.5 (1C), 123.1 (1C), 121.2 (1C), 118,08
(1C), 114.2 (2C), 109.5 (1C), 105.8 (1C), 55.36 (1C). HRMS
(ESI): m/z Calcd for C17H13NO4 [M+•]: 295.0845. Found: 295.0852
(2.4 ppm).
pale yellow solid. H NMR (500 MHz, CDCl3): δ ppm 7.60 (d, J =
8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.46 (d, J = 3.2 Hz, 1H), 6.34
(d, J = 3.2 Hz, 1H), 4.64 (s, 2H), 3.83 (s, 3H), 2.19 (br s, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ ppm 159.1 (1C), 154.2 (1C),
152.9 (1C), 125.3 (2C), 123.8 (1C), 114.1 (2C), 109.9 (1C), 104.1
−
(1C), 57.6 (1C), 55.3 (1C). HRMS (ESI): m/z Calcd for C12H11O3
[M − 1]−• 203.0708. Found: 203.0705 (−1.3 ppm).
3c: (5-(4-(trifluoromethyl)phenyl)furan-2-yl)methanol.29 Purified
by CC (Rf = 0.30) hexanes/DCM/EtOAc (4:4:2), 85 mg (88%)
yield as a white solid. 1H NMR (500 MHz, CDCl3): δ ppm 7.74 (d, J
= 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 3.3 Hz, 1H),
6.40 (d, J = 3.3 Hz, 1H), 4.68 (s, 2H), 2.34 (br s, 1H). 13C{1H}
NMR (125 MHz, CDCl3): δ ppm 154.7 (1C), 152.4 (1C), 133.7
10f: 2-(4-methoxyphenyl)-5-(4-nitrophenyl)furan. Purified by
CC (Rf = 0.38) hexanes/DCM (7:3), 48 mg (82%) yield as a
2
3
(1C), 129.0 (q, C−F, JC−F = 32.5 Hz, 1C), 125.7 (q, C−F, JC−F
=
1
1
yellow solid. H NMR (500 MHz, CDCl3): δ ppm 8.24 (d, J = 9.0
3.9 Hz, 2C), 124.1 (q, C−F, JC−F = 271.2 Hz, 1C), 123.7 (2C),
110.1 (1C), 107.7 (1C), 57.5 (1C). HRMS (EI): m/z Calcd For
Hz, 2H), 7.81 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 6.97 (d,
J = 8.8 Hz, 2H), 6.94 (d, J = 3.6 Hz, 1H), 6.67 (d, J = 3.56 Hz, 1H),
3.86 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ ppm 159.8 (1C),
155.8 (1C), 150.3 (1C), 146.0 (1C), 136.4 (1C), 125.6 (2C), 124.4
(2C), 123.4 (2C), 122.9 (2C), 114.3 (1C), 111.5 (1C), 106.4 (1C),
55.4 (1C). HRMS (ESI): m/z Calcd for C17H13NO4 [M+•]:
295.0845. Found: 295.0851 (2.0 ppm).
−
C12H8F3O2 [M − 1]−• 241.0477. Found: 241.0472 (−1.9 ppm).
3d: (5-Phenylfuran-2-yl)methanol.63 Purified by CC (Rf = 0.34)
hexanes/DCM/EtOAc (4:4:2), 54 mg (78%) yield as a yellow solid.
1H NMR (500 MHz, CDCl3): δ ppm 7.69 (m, 2H), 7.39 (m, 2H),
7.28 (m, 1H), 6.61 (d, J = 3.3 Hz, 1H), 6.39 (d, J = 3.3 Hz, 1H),
4.68 (s, 2H), 1.98 (br s, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ
ppm 154.0 (1C), 153.6 (1C), 130.7 (1C), 128.7 (2C), 127.5 (1C),
123.8 (2C), 110.0 (1C), 105.7 (1C), 57.7 (1C). HRMS (ESI): m/z
10g: 2-(2-methyl-4-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)-
furan. Purified by CC (Rf = 0.58) hexanes/DCM (7:3), 57 mg
1
−
Calcd for C11H9O2 [M − 1]−• 173.0603. Found: 173.0599 (−2.1
(83%) yield as a yellow solid. H NMR (500 MHz, CDCl3): δ ppm
8.63 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.4, 2.5 Hz, 1H), 7.85 (d, J =
8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 6.92
(d, J = 3.6 Hz, 1H), 6.82 (d, J = 3.6 Hz, 1H), 2.67 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ ppm 152.6 (1C), 151.6 (1C), 146.6
ppm).
10a: 2-(4-nitrophenyl)-5-(p-tolyl)furan. Purified by CC (Rf1 =
0.42) hexanes/DCM (1:1), 43 mg (77%) yield as a yellow solid. H
NMR (500 MHz, CDCl3): δ ppm 8.25 (d, J = 9.0 Hz, 2H), 7.82 (d, J
= 9.0 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H)
6.95 (d, J = 3.6 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 2.40 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3): δ ppm 155.9 (1C), 150.6 (1C),
146.1 (1C), 138.3 (1C), 136.4 (1C), 129.5 (2C), 127.3 (1C), 124.4
4
(1C), 141.6 (1C), 133.2 (q, C−F, JC−F = 1.4 Hz, 1C), 132.3 (1C),
2
130.8 (1C), 129.5 (q, C−F, JC−F = 32.6 Hz, 1C), 125.9 (q, C−F,
1
3JC−F = 3.8 Hz, 2C), 124.0 (q, C−F, JC−F = 271.7 Hz, 1C), 124.0
(2C), 121.9 (1C), 121.7 (1C), 112.7 (1C), 109.1 (1C), 22.3 (1C).
G
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J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
HRMS (EI): exact mass Calcd for C18H12F3NO3 [M+•]: 347.0769.
Found: 347.0774 (1.4 ppm).
10h: 2-(4-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)furan. Pu-
AUTHOR INFORMATION
■
Corresponding Author
Pat Forgione − Department of Chemistry and Biochemistry,
Concordia University, Montreal QC H4B 1R6, Canada;
Centre in Green Chemistry and Catalysis, McGill University,
Montreal QC H3A 2K6, Canada; orcid.org/0000-0002-
6029-2194; Email: pat.forgione@concordia.ca
rified by CC (Rf = 0.39) hexanes/DCM (7:3), 42 mg (69%) yield as
a yellow solid. H NMR (500 MHz, CDCl3): δ ppm 7.81 (d, J = 7.4
1
Hz, 2H), 7.72 (m, 2H), 7.65 (d, J = 7.4, 2H), 7.12 (m, 2H), 6.84 (d,
J = 3.5 Hz, 1H), 6.70 (d, J = 3.5 Hz, 1H). 13C{1H} NMR (125 MHz,
1
CDCl3): δ ppm 162.4 (d, C−F, JC−F = 248.3 Hz, 1C), 153.6 (1C),
4
151.8 (1C), 133.7 (q, C−F, JC−F = 1.23 Hz, 2C), 128.9 (q, C−F,
3
2JC−F = 32.8 Hz, 1C), 126.7, 125.7 (q, C−F, JC−F = 3.8 Hz, 2C),
Authors
3
1
́
Franklin Chacon-Huete − Department of Chemistry and
125.7 (d, C−F, JC−F = 8.0 Hz, 2C), 124.2 (q, C−F, JC−F = 271.4
2
Biochemistry, Concordia University, Montreal QC H4B 1R6,
Canada; Centre in Green Chemistry and Catalysis, McGill
University, Montreal QC H3A 2K6, Canada
Hz, 1C), 123.6 (1C), 115.8 (d, C−F, JC−F = 22.0 Hz, 2C), 109.2
(1C), 107.1 (d, C−F, 4JC−F = 1.4 Hz, 1C). HRMS (ESI): m/z Calcd
for C17H10F4O [M+•]: 306.0668. Found: 306.0669 (0.3 ppm).
10i: Methyl 3-Methyl-4-(5-(4-(trifluoromethyl)phenyl)furan-2-
yl)benzoate. Purified by CC (Rf = 0.38) hexanes/DCM (7:3), 46
mg (64%) yield as a pale yellow solid. 1H NMR (500 MHz, CDCl3):
δ ppm 7.90 (m, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.1 Hz,
2H), 7.66 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 3.5 Hz, 1H), 6.80 (d, J =
3.5 Hz, 1H), 3.94 (s, 3H), 2.62 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ ppm 166.8 (1C), 153.1 (1C), 152.3 (1C), 134.3 (1C),
133.5 (2C), 132.6 (1C), 129.3 (q, C−F, 2JC−F = 32.3 Hz, 1C), 128.8
Juan David Lasso − Department of Chemistry and
Biochemistry, Concordia University, Montreal QC H4B 1R6,
Canada
Paul Szavay − Department of Chemistry and Biochemistry,
Concordia University, Montreal QC H4B 1R6, Canada
Jason Covone − Department of Chemistry and Biochemistry,
Concordia University, Montreal QC H4B 1R6, Canada
3
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02236
(1C), 127.3 (1C), 126.5 (1C), 125.8 (q, C−F, JC−F = 3.8 Hz, 2C),
1
124.1 (q, C−F, JC−F = 272.0 Hz, 1C), 123.8 (2C), 112.6 (1C),
109.1 (1C), 52.1 (1C), 22.2 (1C). HRMS (ESI): m/z Calcd for
C20H15F3O3 [M+•]: 360.0973. Found: 360.0979 (1.7 ppm).
10j: Ethyl 4-(5-phenylfuran-2-yl)benzoate. Purified by CC (Rf =
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
1
0.41) hexanes/DCM (7:3), 43 mg (74%) yield as a white solid. H
NMR (500 MHz, CDCl3): δ ppm 8.08 (d, J = 8.7 Hz, 2H), 8.08 (d, J
= 8.7 Hz, 2H), 7.76 (m, 2H), 7.42 (m, 2H), 7.30 (m, 1H), 6.87 (d, J
= 3.5 Hz, 1H), 6.77 (d, J = 3.5 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H),
1.42 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ ppm
166.3 (1C), 154.4 (1C), 152.3 (1C), 134.5 (1C), 130.4 (2C), 130.1
(1C), 128.8 (1C), 128.7 (2C), 127.8 (1C), 123.9 (2C), 123.2 (2C),
109.5 (1C), 107.5 (1C), 61.0 (1C), 14.4 (1C). HRMS (ESI): m/z
Calcd for C19H16O3 [M+•]: 292.1099. Found: 292.1105 (2.1 ppm).
10k: 2-(2-methyl-4-nitrophenyl)-5-phenylfuran. Purified by CC
(Rf = 0.40) hexanes/DCM (7:3), 46 mg (74%) yield as a yellow
solid. 1H NMR (500 MHz, CDCl3): δ ppm 8.63 (d, J = 2.5 Hz, 1H),
8.01 (dd, J = 8.3, 2.5 Hz, 1H), 7.75 (m, 2H), 7.44 (dd, J = 8.4, 7.2
Hz, 2H), 7.39 (dd, J = 8.4, 0.8 Hz, 1H), 7.32 (m, 1H), 6.80 (d, J =
3.5 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H), 2.65 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3): δ ppm 154.2 (1C), 150.5 (1C), 146.6 (1C),
141.3 (1C), 132.2 (1C), 131.1 (1C), 130.1 (1C), 128.8 (2C), 128.0
(1C), 124.0 (2C), 121.4 (1C), 121.4 (1C), 112.6 (1C), 107.1 (1C),
22.4 (1C). HRMS (ESI): m/z Calcd for C17H13NO3 [M+•]:
279.0895. Found: 279.0893 (−0.7 ppm).
10m: 2-(3-ethylphenyl)-5-phenylfuran. Purified by CC (Rf1 =
0.52) hexanes/DCM (7:3), 41 mg (83%) yield as a white solid. H
NMR (500 MHz, CDCl3): δ ppm 7.76 (m, 2H), 7.72 (m, 1H), 7.43
(m, 2H), 7.31 (m, 2H), 6.79 (d, J = 3.4 Hz, 1H), 6.64 (d, J = 3.4 Hz,
1H), 2.97 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ ppm 153.4 9 (1C), 153.2 (1C), 141.2
(1C), 130.9 (1C), 129.7 (1C), 129.5 (1C), 128.7 (2C), 128.0 (1C),
127.9 (1C), 127.3 (1C), 125.9 (1C), 123.7 (2C), 110.3 (1C), 106.8
(1C), 27.4 (1C), 15.4 (1C). HRMS (ESI): m/z Calcd for C18H16O
[M+•]: 248.1201. Found: 248.1203 (0.8 ppm).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the Natural Sciences and
Engineering Research Council (NSERC), Le Fonds de
́
Recherche du Quebec, Nature et Technologies (FRQNT).
Additional support was also kindly provided by the Centre for
́
Green Chemistry and Catalysis (CGCC), Le Reseau
́
́
́
Quebecois de Recherche sur les Medicaments (RQRM),
Richard and Edith Strauss Foundation and Concordia
University. Special thanks to Dr. Xavier Ottenwaelder for
his invaluable suggestions.
ABBREVIATIONS
■
FDCA 2,5-furandixylic acid
HMF 5-hydroxymethyl furfural
DHMF bis-2,5-hydroxymethyl furan
μw
microwave.
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