Iron-Catalyzed Oxidative Decarbonylative α-Alkylation of Acyl-Substituted Furans with Aliphatic Aldehydes as the Alkylating Agents

Article abstract of DOI:10.1021/acs.joc.0c01002

A protocol for FeCl2-catalyzed oxidative decarbonylative α-alkylation of acyl furans using alkyl aldehydes as the alkylating agents has been developed. This protocol affords α-alkyl-α-acylfurans in moderate to good yields in a practical and sustainable fa

Full text of DOI:10.1021/acs.joc.0c01002

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Note
Iron-catalyzed oxidative decarbonylative #-alkylation of acyl-
substituted furans with aliphatic aldehydes as the alkylating agents
Wenkun Luo, Yongjie Yang, Bo Liu, and Biaolin Yin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01002 • Publication Date (Web): 11 Jun 2020
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The Journal of Organic Chemistry
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Iron-catalyzed oxidative decarbonylative α-
alkylation of acyl-substituted furans with aliphatic
aldehydes as the alkylating agents
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Wenkun Luoa, Yongjie Yanga, Bo Liu*b and Biaolin Yin*a
a Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou, 510640, P. R. China
Email: blyin@scut.edu.cn
b The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510006, P.R. China
E-mail: doctliu@263.net
Supporting Information Placeholder
ABSTRACT: A protocol for FeCl2-catalyzed oxidative decarbonylative α-alkylation of acyl furans using alkyl aldehydes as
the alkylating agents has been developed. This protocol affords α-alkyl-α-acylfurans in moderate to good yields in a prac-
tical and sustainable fashion. Mechanistic studies suggest that the reaction proceeds via generation of an alkyl radical
from the alkyl aldehyde, addition of the radical to the furan ring, and subsequent rearomatization.
Producing fuel and valuable chemicals from biomass
and its resulting compounds is an important research area
with the potential to reduce global dependence on fossil
resources.1 Furans, which are among the principal prod-
ucts obtained from the biomass feedstocks, are receiving
considerable attention as key intermediates in the genera-
tion of more high-value products because they can act as
masked alkenes, dienes, enol ethers, and carbonyl com-
pounds.2 Conventional transformations of furans fall into
three categories: (1) modification of substituents on the
intact furan ring,3 (2) opening of the furan ring accompa-
nied by release of the masked carbonyl group,4 (3)
dearomatizing functionalization to form dihydrofurans or
tetrahydrofurans.5 Alkylation of the furan ring falls into
the first category and is more frequently accomplished
from furyl anions and alkyl halides by means of nucleo-
philic substitution.6 There are several requirements for
this manner that strong base and water-free conditions
are necessary to form the furyl anions, and the stoichio-
metric alkyl halides are not sustainable and environmen-
tally friendly.
As one of the most valuable furans derivatives, α-
alkyl-α’-acyl furans (1) serve as important building blocks
in organic synthesis,7 as well as possess various biological
activities, such as inhibition of HIV reverse-transcriptase8,
lipoxygenase9 and HIV-1 integrase.10 However, the afore-
mentioned method is unsuitable for the alkylation of acyl
furans to produce 1 due to the incompatibility of the acyl
group and elimination of tertiary alkyl halides under
strongly basic conditions. Currently, there are two feasi-
ble pathways for synthesizing 1 that have been reported as
undergoing furyl anion: (1) alkylation of furan with an
alkyl halide and subsequent Friedel-Crafts acylation,11 (2)
protection of the carbonyl group of furfurals as an acetal,12
α-alkylation of the furan ring, and subsequent removal of
the protecting group (a, Scheme 1). Both these two meth-
ods may confront with multiple steps and relatively harsh
reaction conditions. Therefore, given that acyl-substituted
furan derivatives such as furfural and furoic acid are
readily available from sustainable sources, pristine meth-
od for direct access to alkylated carbonyl-containing fu-
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rans from acyl-substituted furan derivatives would be
highly desirable.
To test our hypothesis, we chose pivaldehyde 3a and
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8
α-carboxamide substituted furan 2a as model compounds
(Table 1). We were pleased to discover that reaction at 120
°C for 12 h in PhCl containing di-tert-butyl peroxide
(DTBP) as the oxidant resulted in complete consumption
of 2a and afforded desired α-alkylation product 1a in 32%
yield, along with multiple unidentified by-products (entry
1). The low yield may ascribe to degradation or polymeri-
zation of the furan ring on starting material or product.
We next evaluated several metal catalysts in an effort to
improve the yield of 1a (entries 2–6). Addition of 0.1 equiv
Fe salts, i.e. Fe(OAc)2, FeCl2 or FeCl3, promoted the alkyla-
tion reaction, giving 1a in 56%, 70% and 68% yield, re-
spectively. Surprisingly, The results show that the reactiv-
ity of Fe(II) is slightly higher than Fe(III). Using FeCl2 as
the catalyst, we evaluated other solvents (BuOAc, PhF,
HFIP and DMSO), and found that PhF reacted best (en-
tries 7–10). To our delight, the reaction was not signifi-
cantly different between air and argon atmosphere (entry
11). Longer reaction time proved to be beneficial to further
improve yield of the product (entry 12). Interestingly, de-
creasing the amount of FeCl2 from 0.1 to 0.05 equiv in-
creased the yield of 1a to 78% (entry 13), but increasing
the catalyst loading to 0.2 equiv did not improve the yield
any further (entry 14). These results suggest that at a low
loading, FeCl2 controlled the rate of homolytic cleavage of
DTBP so that it matched the rate of the subsequent alkyl-
ation reaction.29 Finally, careful examination of the
amounts of aldehyde revealed that the highest yield (81%)
was obtained with 5 equiv of 3a (entries 15 and 16).
Recently, various alkylating reagents have been used
to generate alkyl radicals for use in Minisci-type alkyla-
tion reactions of heteroarenes. These reagents include
amine,13 alkyl-trifluoroborate,14 alcohols,15 acid,16 alde-
hydes,17 ethers,18 sulfinates,19 alkyl halides,20 olefins,21 and
even the C–H bonds of alkanes.22 However, for the most
part, Minisci-type radical additions are effective only for
certain electron-deficient N-heteroarenes.23 The use of
such reagents for the alkylation of electron-rich furan
rings received less attention, especially for those in radical
pathway. With the rapid development of organometallic
chemistry, transition metal catalyzed alkylation of acyl-
substituted furans, such as Pd-,24 Cu-,25 and Fe-26, have
achieved tremendous breakthrough in this area. However,
these pioneering methods using alkyl halides as alkylating
agents can only be applied to the formation of secondary
and tertiary carbon radicals (b1, Scheme 1). Further viable
solution that reported by Bao et al27 addressed an untradi-
tional iron-catalyzed primary radical alkylation of furfural
with alkyl diacyl peroxides as both oxidant and alkylating
agents (b2, Scheme 1), whereas it might be limited by us-
ing excess furfural as the solvent. Thus, the new alterna-
tive method for carbonyl-containing furans to simultane-
ously tolerate the primary, secondary and tertiary radicals
is under pressing concern. On the other hand, aliphatic
aldehydes, which are readily available from sustainable
sources, have frequently been used as alkylating reagents
in the presence of peroxides or oxygen.28 However, to our
knowledge, aliphatic aldehydes have not been used for
furan alkylation, possibly because the electron-rich furan
ring cannot tolerate the oxidative conditions necessary to
generate alkyl radicals from aldehydes. We hypothesized
that this problem could be circumvented by introducing a
suitable electron-withdrawing group, such as an acyl
group, on the furan ring to lower its electron density, thus
making it more tolerant to oxidative conditions. In this
way, alkylation with aliphatic aldehydes via an oxidative
radical pathway might be accomplished (b3, Scheme 1).
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Table 1. Optimization of reaction conditionsa
entry
1
catalyst (equiv)
Fe(OAc)2 (0.1)
Solvent
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
BuOAc
PhF
yield (%)b
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56
15
2
3
Cu(OAc)2 (0.1)
Pd(OAc)2 (0.1)
FeCl2 (0.1)
FeCl3 (0.1)
FeCl2 (0.1)
FeCl2 (0.1)
FeCl2 (0.1)
FeCl2 (0.1)
FeCl2 (0.1)
FeCl2 (0.1)
FeCl2 (0.05)
FeCl2 (0.2)
FeCl2 (0.05)
FeCl2 (0.05)
4
31
Scheme 1. Methods for synthesis of alkylated carbon-
yl-containing furans
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70
68
62
71
6
7
8
9
HFIP
DMSO
PhF
0
10
11c
12d
13d
14d
15d,e
16d,f
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71
PhF
74
78
71
PhF
PhF
PhF
79
81
PhF
aReaction conditions: 2a (0.2 mmol, 1 equiv), 3a (3 equiv),
DTBP (3 equiv), catalyst, solvent (1 mL), 120 °C, 12 h, under
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The Journal of Organic Chemistry
b
c
d
air. Isolated yields are reported. Argon atmosphere. Per-
e
f
1
2
formed for 24 h. 4 equiv of 3a was used. 5 equiv of 3a was
used.
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With the optimized reaction conditions in hand (Ta-
ble 1, entry 16), we investigated the generality of this al-
kylation reaction. Furans with a variety of electron-
withdrawing groups at the α-position were subjected to
the optimized condition with pivalaldehyde (3a) as the
alkylating agent (Scheme 2). N,N-Dialkyl-amide-
substituted furans 2b, 2c, 2f, and 2g could be α-alkylated
to afford 1b, 1c, 1f, and 1g in good yields (74–79%). N-
Alkyl,N-phenyl-amide-substituted furans 2a, 2d, and 2e
also underwent the alkylation reaction, giving products
1a, 1d, and 1e in 69–81% yields. Notably, N-OMe-amide-
substituted furan 2h could also be alkylated, affording 1h
in 61% yield. In addition to the amides, methyl furoate
(2i), ethyl furoate (2j), and isopropyl furoate (2k) esters
afforded 1i–1k in 55%, 53%, and 59% yields, respectively.
To our delight, furan-2-yl(phenyl)methanone (2l)
smoothly gave desired product 3al in an excellent yield
(90%). Compared with the furan amides and furoates,
furfuraldehyde (2m) and 2-acetylfuran (2n) were more
easily oxidized, owing to the aldehyde group and the ac-
tive α-H adjacent to the carbonyl group, respectively.
Therefore, we were able to decrease the reaction time to
18 h and the reaction temperature to 110 °C, and under
these conditions, corresponding alkylation products 1m
and 1n were obtained in 44% and 59% yields, respectively.
In addition, 1-(furan-2-yl)-2,2-dimethylpropan-1-one (2o),
which does not bear an α-H atom adjacent to the carbon-
yl group, was successfully converted to alkylation product
1o in 73% yield. It is worth noting that 2-phenyl furan
(2p), which lacks a carbonyl group on the furan ring, was
also a suitable substrate, affording 1p in excellent yield
(88%). However, 2-nitrofuran (2q) could not be converted
into the target alkylation product owing to the very low
electron density of the furan ring. With benzofuran (2r)
as the starting material, many complex byproducts from
suspected polymerization in the system were observed,
which resulted in a moderate yield of the desired product.
Interestingly, 3-substituted furan (2s) gave bis-alkylated
product 1s in 75% yield (tert-butyl both at 2- and 5-
position), while no mono-alkylated product was observed
under standard condition. Further, we evaluated the syn-
thetic potential of this oxidative decarbonylative α-
alkylation protocol by performing a gram-scale reaction.
Specifically, 1.14 g (64% yield) of 1c was synthesized from
3a (24 mmol) and 2c (8 mmol) under the slightly adjusted
conditions.
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aReaction conditions: 2a–2s (0.2 mmol), 3a (5 equiv), FeCl2
(0.05 equiv), DTBP (3 equiv), PhF (1 mL), 120 °C, 24 h, under
air. bPerformed at 110 °C for 18 h.
Next, we explored the reaction scope for aliphatic al-
dehydes (Scheme 3). First, we tested another tertiary al-
dehyde, 1-methylcyclohexanecarbaldehyde (3c), which
gave corresponding tert-alkylated product 1t in 76% yields
under the optimized conditions. Next, we evaluated the
reactivity of several secondary aldehydes, including cyc-
lamen aldehyde (3d), lily aldehyde (3e), cyclohexanecarb-
aldehyde (3f), cyclopentanecarbaldehyde (3g), 3-
Cyclohexene-1-carboxaldehyde (3h), isobutyraldehyde
(3i), 2-ethylhexanal (3j), 2-ethylbutanal (3k), 2-
methylpentanal (3l), and 2-methylbutanal (3m). At a
slightly elevated reaction temperature (130 °C), these sub-
strates afforded corresponding alkylated furans 1u–1ad in
51–67% yields, although some of 2a remained. Remarka-
bly, the internal C=C bond of aldehyde 1h remained intact
under these conditions. Finally, primary aliphatic alde-
hydes, such as butyraldehyde (3n), 3-methylbutanal (3o),
and pentanal (3p), provided the desired alkylated furans
(1ae–1ag), although the yields were low (29–30%), and a
substantial amount of 2a was recovered. The main by-
product in those less efficient cases is carboxylic acid oxi-
dized from aldehyde, and the low yield of long-chain al-
dehydes may be due to the poor stability of the generated
carbon radicals and competitive intermolecular aldol
condensation at high temperatures. Several aryl and het-
Scheme 2. Scope of the furansa
eroaryl
aldehydes
including
benzaldehyde,
4-
tolualdehyde and 2-thiophenecarboxaldehyde have been
tested, but they are not suitable for this reaction system.
Despite our many efforts, α,β-unsaturated aldehydes such
as citral and cinnamaldehyde were failed to obtain the
target product.
Scheme 3. Scope of the aldehydes a
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substrates. First, with the assistance of the iron-catalyst
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and/or elevated temperature, homolytic cleavage of the
DTBP generates a tert-butoxy radical A. Meanwhile, single-
electron transfer (SET) from the Ln-Fe(II) species produces
the Fe(III) species.27 Then, intermediate A abstracts a hydro-
gen atom of 3a to give acyl radical B along with tert-butyl
alcohol as a by-product. Decarbonylation of B generates alkyl
radical intermediate C, which adds to 2a to generate radical
intermediate D. Then the single electron transfer (SET) be-
tween the Fe(III) species and intermediate D produces the
corresponding delocalized carbocation intermediate E, and
at the same time the Ln-Fe(II) species was regenerated. Fi-
nally, intermediate E forms product 1a, which undergoes
aromatization-driven deprotonation.
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Scheme 5. Proposed mechanism
aReaction conditions: 2a (0.2 mmol), 3c–3p (5 equiv), FeCl2
(0.05 equiv), DTBP (3 equiv), PhF (1 mL), 130 °C, 24 h, under
air. bPerformed at 120 °C. cYield of recovered 2a. d3h (8 equiv)
and DTBP (4.5 equiv) were used.
Scheme 4. Control experiments
In summary, we have developed a protocol for FeCl2-
catalyzed oxidative decarbonylative α-alkylation of acyl-
substituted furans with readily available and environmentally
benign aliphatic aldehydes as the alkylating agents. Mecha-
nistic studies suggest that the reaction proceeds via a radical
pathway with DTBP acting as an oxidant and a radical initia-
tor. Using this protocol, we synthesized a variety of tertiary,
secondary, and primary alkylated acyl furans in moderate to
good yields in a convenient and sustainable manner. Readily
available aliphatic aldehydes, biomass-derived substrates,
simple operation of reaction and good compatibility to func-
tional groups encourage this protocol to be an attractive
pathway for organic synthesis and biomass transformation.
We then conducted four control experiments to gain
insight into the reaction mechanism (Scheme 4). In the
absence of DTBP, the reaction of 3a and 2a did not pro-
vide 1a (Scheme 4a). Under the standard conditions, the
reaction was markedly inhibited by the addition of a radi-
cal quencher (1,1-diphenylethylene); the product of alkyl
radical trapping (4a) was detected by means of GC-MS
(Scheme 4b). These two experiments indicate that the
reaction may proceed via a radical pathway. We also eval-
uated the activity of different types of alkyl radicals. Spe-
cifically, subjecting an equimolar mixture of 3a and 3m to
the standard conditions afforded the corresponding alkyl-
ation products (1a and 1ad) in 54% and 23% yields, re-
spectively (Scheme 4c). In contrast, when 3i and 3n were
tested in the same way, 1z was obtained (51% yield) but
1ae was not detected (Scheme 4d). These outcomes indi-
cate that the activity of the alkyl radicals decreased in the
order tertiary > secondary > primary, which is consistent
with the experimental outcomes shown in Scheme 3.
EXPERIMENTAL SECTION
General experimental information. Unless otherwise not-
ed, all reagents were obtained from commercial suppliers
(Adamas, TCI, Bide-pharm and Energy). All workup and pu-
rification procedures were carried out with reagent-grade
solvents in air. Thin layer chromatography analyses were
performed on silica gel-coated glass plates (0.25 mm) using
the fluorescence indicator UV254. Infrared (IR) spectra were
1
obtained on a Bruker Vector 22 spectrometer. H (400 MHz)
and 13C (100 MHz) NMR spectra were recorded using CDCl3
as a solvent. Chemical shifts for 1H NMR spectra are reported
in ppm downfield to tetramethylsilane (CDCl3: δ 7.26 ppm).
Chemical shifts for 13C NMR spectra are reported in parts per
million (ppm) from tetramethylsilane with the solvent as the
internal standard (CDCl3: δ 77.16 ppm). Coupling constants
are reported and expressed in Hz; The following abbrevia-
tions are used to describe spin multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, dd = doublet of doublets, dt =
On the basis of these control experiments, we propose
the mechanism outlined in Scheme 5, with pivaldehyde 3a
and N-methyl-N-phenylfuran-2-carboxamide 2a as example
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The Journal of Organic Chemistry
doublet of triplets, m = multiplet, br = broad signal. Mass
water. The combined organic layers were dried by Na2SO4
and the solvents removed in vacuo. The residue was purified
by flash column chromatography to give the desired product.
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3
4
5
6
7
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spectra were obtained from high resolution ESI mass spec-
trometer. All reactions were carried out using freshly dis-
tilled and dry solvents. Column chromatography was per-
formed over silica gel (200-300 Mesh) using petroleum ether
and ethyl acetate as the eluent.
Method E:34 General Procedure for Compounds 3c. Potassi-
um t-butoxide (3.9 mmol, 1.3 equiv) was added to a solution
of cyclohexanecarboxaldehyde (3 mmol, 1 equiv) in dry
CH2Cl2 (20 mL) at 0 °C for 30 min. Iodomethane (6 mmol, 2
equiv) was then added to the solution. The reaction was
stirred for 30 min at 0 °C, and then stirred at room tempera-
ture for an additional 1.5 hr. The reaction was washed with
water (2 x 50 mL) and dried over Na2SO4. The solvent was
removed by rotovaping under a reduced pressure due to
product volatility. The crude oil was purified by column
chromatography on silica gel to give the desired product.
General procedure for the synthesis of starting materi-
als. Furan carboxamide was synthesized according to proce-
dures previously reported in the literature. Method A: 30 Gen-
eral Procedure for Compounds 2a-2c, 2f-2h, 2s. The amine (30
mmol, 1 equiv) and Et3N (60 mmol, 2 equiv) were dissolved
in 120 mL of dry CH2Cl2 and cooled to 0 °C using an ice bath.
The furan carbonyl chloride (33 mmol, 1.1 equiv) was added
to the amine solution drop-wise over 10 min. Afterwards the
mixture was stirred overnight at room temperature. The mix-
ture was then poured into a separatory funnel and washed
with saturated NaCl (aq). The organic layer was then dried
over anhydrous Na2SO4, filtered and concentrated in vacuo.
The crude amide was purified by flash column chromatog-
raphy to give the desired product.
Method B:31 General Procedure for Compounds 2d and 2e.
The aniline (30 mmol, 1 equiv) and Et3N (60 mmol, 2 equiv)
were dissolved in 120 mL of dry CH2Cl2 and cooled to 0 °C
using an ice bath. The furan-2-carbonyl chloride (33 mmol, 1.1
equiv) was added to the amine solution drop-wise over 10
min. Afterwards the reaction mixture was stirred overnight
at room temperature. The mixture was then poured into a
separatory funnel and washed with saturated NaCl (aq). The
organic layer was then dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. Then the crude amide was direct-
ly dissolved in 100 mL dry DMF without further purification
and cooled to 0 °C using an ice bath. The NaH (45 mmol, 1.5
equiv) was added to the mixture solution carefully. After-
wards the reaction mixture was stirred 1 h at 0 °C. Then the
methyl iodide (60 mmol, 2 equiv) was added to the mixture
solution drop-wise over 20 min. Subsequently, the reaction
mixture was stirred overnight at room temperature. The so-
lution, diluted with CH2Cl2, was washed with saturated NaCl
(aq), dried over Na2SO4 and concentrated under reduced
pressure for silica gel column. The crude amide was purified
by column chromatography to give the desired product.
Method C:32 General Procedure for Compounds 2l and 2o.
The acyl chloride (5 mmol, 5 equiv) and ZnO (0.5 mmol, 0.5
equiv) were dissolved in 5 mL of dry CH2Cl2 and cooled to
0 °C using an ice bath. The Furan (1 mmol, 1 equiv) was add-
ed to the mixture solution drop-wise over 10 min. Afterwards
the reaction mixture was stirred 0.25 h at 0 °C, the reaction
mixture was diluted with dichloromethane, the solution was
filtered to separate the catalyst, and the CH2Cl2 extract was
then washed with an aqueous solution of sodium bicar-
bonate and dried over anhydrous sodium sulfate. Evapora-
tion of solvent furnished practically pure corresponding
product.
Method D:33 General Procedure for Compounds 2p. Furan
boronic acid (5 mmol, 1 equiv), aryl bromide (6 mmol, 1.2
equiv), K3PO4 (6 mmol, 1.2 equiv) and Pd(PPh3)4 (0.25 mmol,
0.05 equiv) were added in MeOH (40 mL). The reaction was
heated for 12 h at 80 °C until the consumption of the starting
material detected by TLC. The reaction mixture was filtered
through a lay of silica gel and the filtrate was evaporated
under reduced pressure to provide the residue. The resulting
mixture was then re-dissolved in EtOAc and washed with
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General procedure for the synthesis of products. General
Procedure for Compounds 1a-1t. An oven-dried Schlenk flask
(approximate diameter: 18mm) was charged with the
appropriate acyl-substituted furans (0.2 mmol, 1 equiv), FeCl2
(1.2 mg, 0.01 mmol, 0.05 equiv), DTBP (87.6 mg, 0.6 mmol, 3
equiv), aldehydes (1.0 mmol, 5 equiv) and fluorobenzene (1.0
mL) under air. The Schlenk flask was sealed and heated at
120 °C (oil bath temperature) for 24 h. Afterwards the result-
ing mixture was cooled to room temperature, transferred to
silica gel column directly and purified by flash column chro-
matography to give the desired product.
5-(tert-butyl)-N-methyl-N-phenylfuran-2-carboxamide (1a).
Isolated as light-yellow oil using petroleum ether/ethyl ace-
tate/triethylamine (8/1/0.01) as the eluent (41.6 mg, yield
1
81%). H NMR (400 MHz, CDCl3) δ 7.42-7.34 (m, 2H), 7.31-
7.27 (m, 1H), 7.21-7.18 (m, 2H), 6.53 (d, J = 3.4 Hz, 1H), 5.85 (d,
J = 3.4 Hz, 1H), 3.41 (s, 3H), 0.97 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.6, 159.7, 145.9, 144.9, 129.4, 127.3, 127.2,
117.9, 103.8, 38.6, 32.7, 28.6. IR: 2966, 1640, 1592, 1367, 1110,
850, 747, 698 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C16H19NO2Na 280.1313; found 280.1310.
5-(tert-Butyl)-N, N-dimethylfuran-2-carboxamide (1b). Iso-
lated as light-yellow oil using petroleum ether/ethyl ace-
tate/triethylamine (4/1/0.01) as the eluent (28.8 mg, 74%). 1H
NMR (400 MHz, CDCl3) δ 6.93 (d, J = 3.4 Hz, 1H), 6.06 (d, J =
3.4 Hz, 1H), 3.19 (br, 6H), 1.30 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.1, 160.7, 146.6, 117.3, 104.1, 33.0, 29.0. Note: The
methyl peaks from the amide group are not visible in 13C
NMR. IR: 2925, 1628, 1532, 1385, 1098, 744 cm-1. HRMS (ESI)
m/z: [M+Na]+ calcd for C11H17NO2Na 218.1157; found 218.1144.
5-(tert-butyl)-N, N-diethylfuran-2-carboxamide (1c). Isolat-
ed as light-yellow oil using petroleum ether/ethyl ace-
1
tate/triethylamine (5/1/0.01) as the eluent (33.4 mg, 75%). H
NMR (400 MHz, CDCl3) δ 6.97 (d, J = 3.4 Hz, 1H), 6.05 (d, J =
3.4 Hz, 1H), 3.56 (br, 4H), 1.30 (s, 9H), 1.25 (br, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 165.8, 159.8, 147.1, 117.3, 104.2, 32.9,
29.1. Note: The ethyl peaks from the amide group are not
visible in 13C NMR. IR: 2969, 2872, 1622, 1530, 1426, 1290, 1109,
747 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for C13H21NO2Na
246.1470; found 246.1459.
N-(2-bromophenyl)-5-(tert-butyl)-N-methylfuran-2-
carboxamide (1d). Isolated as light-yellow oil using petrole-
um ether/ethyl acetate/triethylamine (8/1/0.01) as the eluent
1
(46.2 mg, 69%). H NMR (400 MHz, CDCl3) δ 7.68 (dd, J =
8.0, 1.2 Hz, 1H), 7.35 (td, J = 8.0, 1.2 Hz, 1H), 7.29-7.25 (m, 1H),
7.24-7.19 (m, 1H), 6.70 (d, J = 3.4 Hz, 1H), 5.88 (d, J = 3.4 Hz,
1H), 3.33 (s, 3H), 0.96 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)
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δ 166.9, 159.3, 146.0, 143.7, 133.7, 130.0, 129.4, 128.7, 123.6, 118.1,
1138, 1029, 802 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C11H16O3Na 219.0997; found 219.0985.
1
2
3
4
5
6
7
8
104.1, 37.3, 32.8, 28.5. IR: 2966, 1640, 1526, 1478, 1366, 1273,
1115, 765 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C16H18BrNO2Na 358.0419; found 358.0399.
isopropyl 5-(tert-butyl)furan-2-carboxylate (1k). Isolated as
light-yellow oil using petroleum ether/ethyl acetate (25/1) as
1
5-(tert-butyl)-N-(3-methoxyphenyl)-N-methylfuran-2-
carboxamide (1e). Isolated as light-yellow oil using petroleum
ether/ethyl acetate/triethylamine (4/1/0.01) as the eluent
the eluent (23.5 mg, 56%). H NMR (400 MHz, CDCl3) δ 7.02
(s, 1H), 6.08 (s, 1H), 5.26-5.14 (m, 1H), 1.35-1.30 (m, 15H);
13C{1H} NMR (100 MHz, CDCl3) δ 168.9, 158.8, 143.5, 118.6,
104.6, 68.1, 33.2, 29.0, 22.1. IR: 2960, 2882, 1733, 1647, 1540,
1457, 1362, 1271, 1106 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C12H18O3Na 233.1148; found 233.1153.
1
(44.7 mg, 78%). H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 8.0
Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.73
(s, 1H), 6.56 (d, J = 3.4 Hz, 1H), 5.87 (d, J = 3.4 Hz, 1H), 3.76 (s,
3H), 3.40 (s, 3H), 1.00 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)
δ 166.6, 160.5, 159.6, 146.0, 145.9, 130.0, 119.5, 117.8, 113.1, 113.0,
103.9, 55.5, 38.5, 32.7, 28.6. IR: 2966, 1640, 1597, 1366, 1106,
800, 745, 700 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C17H21NO3Na 310.1419; found 310.1404.
9
(5-(tert-butyl)furan-2-yl)(phenyl)methanone (1l). Isolated
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
as light-yellow oil using petroleum ether/ethyl acetate (50/1)
1
as the eluent (41.0 mg, 90%). H NMR (400 MHz, CDCl3) δ
7.84 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6
Hz, 2H), 7.03 (d, J = 3.4 Hz, 1H), 6.10 (d, J = 3.4 Hz, 1H), 1.27
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.2, 170.1, 150.9,
137.9, 132.2, 129.2, 128.3, 122.2, 105.5, 33.3, 28.9. IR: 2966, 2869,
1714, 1679, 1545, 1459, 1364, 1276, 1198, 1066, 784, 758, 690 cm-1.
HRMS (ESI) m/z: [M+Na]+ calcd for C15H16O2Na 251.1048;
found 251.1040.
(5-(tert-butyl)furan-2-yl)(pyrrolidin-1-yl)methanone
(1f).
Isolated as light-yellow oil using petroleum ether/ethyl ace-
tate/triethylamine (6/1/0.01) as the eluent (34.9 mg, 79%). 1H
NMR (400 MHz, CDCl3) δ 7.00 (d, J = 3.4 Hz, 1H), 6.07 (d, J =
3.4 Hz, 1H), 3.86 (t, J = 6.8 Hz, 2H), 3.64 (t, J = 6.8 Hz, 2H),
2.05-1.94 (m, 2H), 1.92-1.83 (m, 2H), 1.31 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.2, 158.4, 147.1, 116.8, 104.2, 47.7, 47.0,
32.9, 28.9, 26.7, 23.8. IR: 2967, 2874, 1619, 1530, 1417, 1366,
1274, 1014, 800, 747 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C13H19NO2Na 244.1313; found 244.1305.
5-(tert-butyl)furan-2-carbaldehyde (1m). Isolated as light-
yellow oil using petroleum ether/ethyl acetate (25/1) as the
1
eluent (13.3 mg, 44%). H NMR (400 MHz, CDCl3) δ 9.54 (s,
1H), 7.16 (d, J = 3.4 Hz, 1H), 6.22 (d, J = 3.4 Hz, 1H), 1.35 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.4, 171.5, 151.8, 106.0,
33.5, 28.9. IR: 2968, 2873, 1714, 1679, 1516, 1397, 1367 cm-1.
HRMS (ESI) m/z: [M+H]+ calcd for C9H13O2 153.0916; found
153.0907.
(5-(tert-butyl)furan-2-yl)(piperidin-1-yl)methanone
(1g).
Isolated as light-yellow oil using petroleum ether/ethyl ace-
tate/triethylamine (6/1/0.01) as the eluent (36.6 mg, 78%). 1H
NMR (400 MHz, CDCl3) δ 6.86 (d, J = 3.4 Hz, 1H), 6.04 (d, J =
3.4 Hz, 1H), 3.72-3.64 (m, 4H), 1.75-1.58 (m, 6H), 1.30 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 165.6, 159.6, 146.5, 116.7,
103.9, 32.9, 29.1, 24.9. Note: The four methylene peaks from
the amide group are not visible in 13C NMR. IR: 2936, 2860,
1624, 1528, 1435, 1366, 1275, 1118, 1015, 799, 747 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C14H21NO2Na 258.1470; found
258.1462.
1-(5-(tert-butyl)furan-2-yl)ethenone (1n). Isolated as light-
yellow oil using petroleum ether/ethyl acetate (25/1) as the
eluent (20.0 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J
= 3.4 Hz, 1H), 6.14 (d, J = 3.4 Hz, 1H), 2.44 (s, 3H), 1.33 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 169.5, 151.5, 118.8,
105.5, 33.3, 28.9, 25.9. IR: 2965, 2871, 1715, 1660, 1512, 1366, 1265
cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for C9H13O2Na
189.0891; found 189.0880.
5-(tert-butyl)-N-methoxy-N-methylfuran-2-carboxamide
(1h). Isolated as light-yellow oil using petroleum ether/ethyl
acetate/triethylamine (5/1/0.01) as the eluent (25.7 mg, 61%).
1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 3.4 Hz, 1H), 6.10 (d, J
= 3.4 Hz, 1H), 3.78 (s, 3H), 3.33 (s, 3H), 1.33 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 167.6, 159.8, 144.3, 118.8, 104.6, 61.5,
33.5, 33.1, 29.0. IR: 2968, 1645, 1519, 1366, 1275, 993, 955, 800,
744 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for C11H17NO3Na
234.1106; found 234.1096.
1-(5-(tert-butyl)furan-2-yl)-2,2-dimethylpropan-1-one (1o).
Isolated as white solid using petroleum ether/ethyl acetate
o
(100/1) as the eluent (30.1 mg, 73%). Melting point: 44-45 C.
1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 3.6 Hz, 1H), 6.11 (d, J
= 3.6 Hz, 1H), 1.35 (s, 9H), 1.34 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 194.7, 167.6, 151.3, 119.0, 104.8, 42.9, 33.1, 29.0,
26.9. IR: 2962, 1716, 1647, 1540, 1457 cm-1. HRMS (ESI) m/z:
[M+Na]+ calcd for C13H20O2Na 231.1356; found 231.1355.
2-(tert-butyl)-5-phenylfuran (1p). Isolated as light-yellow
methyl 5-(tert-butyl)furan-2-carboxylate (1i). Isolated as
1
oil using petroleum ether as the eluent (35.0 mg, 88%). H
light-yellow oil using petroleum ether/ethyl acetate (25/1) as
NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 2H), 7.35 (t, J =
7.6 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.52 (d, J = 3.4 Hz, 1H),
6.03 (d, J = 3.4 Hz, 1H), 1.33 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.13, 151.97, 131.48, 128.69, 126.84, 123.45, 105.49,
104.12, 32.91, 29.28.
1
the eluent (20.0 mg, 55%). H NMR (400 MHz, CDCl3) δ 7.07
(d, J = 3.4 Hz, 1H), 6.10 (d, J = 3.4 Hz, 1H), 3.86 (s, 3H), 1.32 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 159.5, 142.9, 119.1,
104.9, 51.7, 33.2, 29.0. IR: 2957, 1731, 1520, 1436, 1365, 1265, 1128,
741 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for C10H14O3Na
205.0841; found 205.0829.
2-(tert-butyl)benzofuran (1r). Isolated as colorless oil using
1
petroleum ether as the eluent (16.4 mg, 47%). H NMR (400
ethyl 5-(tert-butyl)furan-2-carboxylate (1j). Isolated as
MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H),
7.22- 7.10 (m, 2H), 6.34 (s, 1H), 1.37 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 167.5, 154.8, 129.1, 123.2, 122.4, 120.5, 110.9, 99.1,
33.1, 29.0.
light-yellow oil using petroleum ether/ethyl acetate (25/1) as
1
the eluent (20.7 mg, 53%). H NMR (400 MHz, CDCl3) δ 7.06
(d, J = 3.4 Hz, 1H), 6.09 (d, J = 3.4 Hz, 1H), 4.33 (q, J = 7.2 Hz,
2H), 1.37 (d, J = 7.2 Hz, 3H), 1.32 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 168.9, 159.1, 143.1, 118.8, 104.7, 60.6, 33.2, 29.0,
14.50. IR: 2962, 2872, 1729, 1637, 1524, 1464, 1366, 1302, 1271,
2,5-di-tert-butyl-N-methyl-N-phenylfuran-3-carboxamide
(1s). Isolated as light-yellow oil using petroleum ether/ethyl
acetate/triethylamine (12/1/0.01) as the eluent (46.9 mg,
1
75%). H NMR (400 MHz, CDCl3) δ 7.29-7.23 (m, 2H), 7.22-
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The Journal of Organic Chemistry
7.10 (m, 3H), 5.51 (s, 1H), 3.41 (s, 3H), 1.27 (s, 9H), 1.11 (s, 9H);
145.5, 144.8, 129.5, 127.4, 117.8, 104.8, 38.6, 37.2, 31.0, 26.0, 25.8.
13C{1H} NMR (100 MHz, CDCl3) δ 167.8, 160.4, 157.9, 144.2,
128.8, 126.6, 126.5, 114.7, 103.4, 34.0, 32.3, 28.8, 28.7. HRMS
(ESI) m/z: [M+H]+ calcd for C20H28NO2 314.2120; found
314.2120.
IR: 2929, 2854, 1726, 1640, 1593, 1495, 1370, 1110, 1016, 850, 797,
746, 698 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for C18H22NO2
284.1651; found 284.1644.
1
2
3
4
5-cyclopentyl-N-methyl-N-phenylfuran-2-carboxamide (1x).
5-(1-methylcyclohexyl)-N-methyl-N-phenylfuran-2-
Isolated as light-yellow oil using petroleum ether/ethyl ace-
tate/triethylamine (8/1/0.01) as the eluent (33.9 mg, 63%). H
5
6
7
8
1
carboxamide (1t). Isolated as light-yellow oil using petroleum
ether/ethyl acetate/triethylamine (8/1/0.01) as the eluent
NMR (400 MHz, CDCl3) δ 7.41-7.35 (m, 2H), 7.31 (t, J = 7.2 Hz,
1H), 7.21-7.17 (m, 2H), 6.18 (d, J = 3.4 Hz, 1H), 5.84 (d, J = 3.4
Hz, 1H), 3.41 (s, 3H), 2.92-2.82 (m, 1H), 1.82-1.73 (m, 2H), 1.60-
1.47 (m, 4H), 1.40-1.30 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.6, 159.7, 145.7, 144.8, 129.5, 127.4, 127.4, 117.8,
105.4, 38.6, 38.6, 31.6, 25.3. IR: 2954, 2870, 1639, 1592, 1524,
1495, 1418, 1369, 1265, 1111, 1016, 743, 700 cm-1. HRMS (ESI) m/z:
[M+Na]+ calcd for C17H19NO2Na 292.1313; found 292.1304.
1
(45.1 mg, 76%). H NMR (400 MHz, CDCl3) δ 7.40-7.34 (m,
2H), 7.29 (d, J = 7.2 Hz, 1H), 7.21-7.16 (m, 2H), 6.60 (d, J = 3.4
Hz, 1H), 5.89 (d, J = 3.4 Hz, 1H), 3.40 (s, 3H), 1.56-1.49 (m,
2H), 1.40-1.12 (m, 8H), 0.88 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 165.7, 159.7, 145.8, 145.0, 129.4, 127.2, 127.1, 117.9,
105.3, 38.7, 36.5, 36.2, 25.9, 22.5. IR: 2929, 2855, 1726, 1638,
1592, 1522, 1495, 1373, 1110, 950, 747, 698 cm-1. HRMS (ESI)
m/z: [M+Na]+ calcd for C19H23O2NNa 320.1626; found
320.1611.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(cyclohex-3-en-1-yl)-N-methyl-N-phenylfuran-2-
carboxamide (1y). Isolated as light-yellow oil using petroleum
ether/ethyl acetate/triethylamine (8/1/0.01) as the eluent
General Procedure for Compounds 1u-1ag. An oven-dried
Schlenk flask (approximate diameter: 18mm) was charged
with the appropriate acyl-substituted furans (0.2 mmol, 1
equiv), FeCl2 (1.2 mg, 0.01 mmol, 0.05 equiv), DTBP (87.6 mg,
0.6 mmol, 3 equiv), aldehydes (1.0 mmol, 5 equiv) and
fluorobenzene (1.0 mL) under air. The Schlenk flask was
sealed and heated at 130 °C (oil bath temperature) for 24 h.
Afterwards the resulting mixture was cooled to room tem-
perature, transferred to silica gel column directly and puri-
fied by flash column chromatography to give the desired
product.
1
(28.7 mg, 51%). H NMR (400 MHz, CDCl3) δ 7.41-7.35 (m,
2H), 7.31 (t, J = 7.2 Hz, 1H), 7.21-7.17 (m, 2H), 6.17 (d, J = 3.4
Hz, 1H), 5.86 (d, J = 3.4 Hz, 1H), 5.68-5.57 (m, 2H), 3.41 (s,
3H), 2.75-2.66 (m, 1H), 2.18-1.75 (m, 5H), 1.46-.35 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.5, 159.7, 145.8, 144.8,
129.5, 127.5, 127.4, 126.9, 125.5, 117.8, 105.3, 38.6, 33.3, 29.4, 26.9,
24.7. IR: 3024, 2915, 2839, 1726, 1640, 1592, 1524, 1495, 1369,
1111, 1017, 747, 699 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C18H19NO2Na 304.1313; found 304.1305.
5-isopropyl-N-methyl-N-phenylfuran-2-carboxamide
(1z).
5-(1-(4-isopropylphenyl)propan-2-yl)-N-methyl-N-
Isolated as light-yellow oil using petroleum ether/ethyl ace-
tate/triethylamine (8/1/0.01) as the eluent (32.0 mg, 66%). 1H
NMR (400 MHz, CDCl3) δ 7.41-7.35 (m, 2H), 7.34-7.28 (m,
1H), 7.22-7.18 (m, 2H), 6.18 (d, J = 3.4 Hz, 1H), 5.83 (dd, J = 3.4,
0.6 Hz, 1H), 3.42 (s, 3H), 2.75-2.67 (m, 1H), 1.00 (d, J = 7.0 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.1, 159.7, 145.7, 144.8,
129.5, 127.5, 127.4, 117.8, 104.7, 38.5, 27.9, 20.7. IR: 2967, 2931,
1642, 1593, 1527, 1495, 1417, 1112, 1015, 797, 747, 698 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C15H17NO2Na 266.1157; found
266.1151.
phenylfuran-2-carboxamide (1u). Isolated as light-yellow oil
using petroleum ether/ethyl acetate/triethylamine (8/1/0.01)
1
as the eluent (48.3 mg, 67%). H NMR (400 MHz, CDCl3) δ
7.39 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.6
Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 6.88 (d, J = 7.6 Hz, 2H), 6.32
(d, J = 2.4 Hz, 1H), 5.79 (d, J = 2.4 Hz, 1H), 3.42 (s, 3H), 2.91-
2.74 (m, 2H), 2.71-2.65 (m, 1H), 2.38-2.31 (m, 1H), 1.22 (d, J =
6.8 Hz, 6H), 0.93 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.3, 159.6, 146.7, 145.9, 144.8, 137.0, 129.5, 129.1,
127.5, 127.4, 126.3, 118.0, 106.1, 41.1, 38.6, 35.2, 33.8, 24.1, 17.8. IR:
2961, 2928, 2872, 1640, 1591, 1522, 1495, 1368, 1111, 1016, 809,
746, 697 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C24H27O2NNa 384.1939; found 384.1921.
5-(heptan-3-yl)-N-methyl-N-phenylfuran-2-carboxamide
(1aa). Isolated as light-yellow oil using petroleum ether/ethyl
acetate/triethylamine (8/1/0.01) as the eluent (32.3 mg, 54%).
1H NMR (400 MHz, CDCl3) δ 7.41-7.34 (m, 2H), 7.33-7.27 (m,
1H), 7.21-7.16 (m, 2H), 6.38 (d, J = 3.4 Hz, 1H), 5.85 (d, J = 3.4
Hz, 1H), 3.41 (s, 3H), 2.37-2.29 (m, 1H), 1.40-1.14 (m, 6H), 1.00-
0.95 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H), 0.63 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 161.8, 159.8, 146.0, 144.9,
129.5, 127.4, 127.3, 117.8, 107.1, 40.9, 38.6, 33.1, 29.5, 26.7, 22.7,
14.1, 11.8. IR: 2959, 2931, 2871, 1728, 1641, 1593, 1496, 1369, 1111,
1014, 949, 746, 698 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for
C19H26NO2 300.1964; found 300.1957.
5-(1-(4-(tert-butyl)phenyl)propan-2-yl)-N-methyl-N-
phenylfuran-2-carboxamide (1v). Isolated as light-yellow oil
using petroleum ether/ethyl acetate/triethylamine (8/1/0.01)
1
as the eluent (48.0 mg, 64%). H NMR (400 MHz, CDCl3) δ
7.39 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.26-7.20 (m,
4H), 6.89 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 2.8 Hz, 1H), 5.80 (d, J
= 2.8 Hz, 1H), 3.42 (s, 3H), 2.85-2.76 (m, 1H), 2.69 (dd, J = 13.2,
5.8 Hz, 1H), 2.34 (dd, J = 13.2, 8.8 Hz, 1H), 1.29 (s, 9H), 0.93 (d,
J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 159.6,
148.9, 145.9, 144.8, 136.6, 129.5, 128. 8, 127.5, 127.4, 125.1, 118.0,
106.0, 41.0, 38.6, 35.1, 34.4, 31.5, 17.8; IR: 2962, 2870, 1640, 1592,
1523, 1366, 1111, 1017, 953, 805, 746, 697 cm-1. HRMS (ESI) m/z:
[M+Na]+ calcd for C25H29O2NNa 398.2096; found 398.2079.
N-methyl-5-(pentan-3-yl)-N-phenylfuran-2-carboxamide
(1ab). Isolated as light-yellow oil using petroleum ether/ethyl
acetate/triethylamine (8/1/0.01) as the eluent (35.7 mg, 66%).
1H NMR (400 MHz, CDCl3) δ 7.40-7.34 (m, 2H), 7.31 (d, J = 7.0
Hz, 1H), 7.21-7.17 (m, 2H), 6.36 (d, J = 3.4 Hz, 1H), 5.87 (d, J =
3.4 Hz, 1H), 3.41 (s, 3H), 2.31-2.23 (m, 1H), 1.44-1.16 (m, 4H),
0.64 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
161.5, 159.8, 146.0, 144.9, 129.5, 127.4, 127.3, 117.8, 107.3, 42.6,
38.6, 26.2, 11.8. IR: 2963, 2932, 2874, 1731, 1640, 1593, 1496,
1368, 1110, 1014, 951, 7467, 698 cm-1. HRMS (ESI) m/z: [M+Na]+
calcd for C17H21NO2Na 294.1470; found 294.1461.
5-cyclohexyl-N-methyl-N-phenylfuran-2-carboxamide (1w).
Isolated as light-yellow oil using petroleum ether/ethyl ace-
tate/triethylamine (8/1/0.01) as the eluent (37.9 mg, 67%). 1H
NMR (400 MHz, CDCl3) δ 7.41-7.35 (m, 2H), 7.34-7.29 (m,
1H), 7.21-7.16 (m, 2H), 6.13 (d, J = 3.4 Hz, 1H), 5.81 (d, J = 3.4
Hz, 1H), 3.41 (s, 3H), 2.46-2.37 (m, 1H), 1.75-1.60 (m, 4H), 1.30
– 1.05 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 159.7,
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N-methyl-5-(pentan-2-yl)-N-phenylfuran-2-carboxamide
mL) under air. The Schlenk flask was sealed and heated at
1
2
3
4
5
6
7
8
(1ac). Isolated as light-yellow oil using petroleum ether/ethyl
acetate/triethylamine (8/1/0.01) as the eluent (30.9 mg, 57%).
1H NMR (400 MHz, CDCl3) δ 7.41-7.35 (m, 2H), 7.33-7.28 (m,
1H), 7.21-7.17 (m, 2H), 6.27 (d, J = 3.4 Hz, 1H), 5.83 (d, J = 3.4
Hz, 1H), 3.41 (s, 3H), 2.63-2.53 (m, 1H), 1.38-1.07 (m, 4H), 0.97
(d, J = 7.0 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.3, 159.8, 145.8, 144.8, 129.5, 127.5, 127.4,
117.8, 105.5, 38.6, 37.5, 33.1, 20.3, 18.7, 14.0. IR: 2960, 2931, 2872,
1728, 1640, 1593, 1495, 1369, 1110, 1016, 746, 698 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C17H21NO2Na 294.1470; found
294.1459.
120 °C (oil bath temperature) for 24 h. Afterwards the result-
ing mixture was cooled to room temperature, transferred to
silica gel column directly and purified by flash column chro-
matography to give the desired product 1c (1.14 g, 64%). Se-
curity note: for gram scale preparation, this method must use
pressure-resistant glass bottles and reduce the amount of
aldehyde to ensure safety due to the large amount of carbon
monoxide gas released.
9
ASSOCIATED CONTENT
Supporting Information
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5-(sec-butyl)-N-methyl-N-phenylfuran-2-carboxamide
(1ad). Isolated as light-yellow oil using petroleum ether/ethyl
acetate/triethylamine (8/1/0.01) as the eluent (33.4 mg, 65%).
1H NMR (400 MHz, CDCl3) δ 7.41-7.35 (m, 2H), 7.33-7.28 (m,
1H), 7.21-7.17 (m, 2H), 6.25 (d, J = 3.4 Hz, 1H), 5.84 (d, J = 3.4
Hz, 1H), 3.41 (s, 3H), 2.55-2.45 (m, 1H), 1.42-1.24 (m, 2H), 0.97
(d, J = 7.0 Hz, 3H), 0.71 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.0, 159.7, 145.8, 144.8, 129.5, 127.4, 127.3,
117.8, 105.7, 38.6, 34.8, 28.1, 18.2, 11.5. IR: 2966, 2931, 2875, 1731,
1649, 1593, 1495, 1417, 1110, 1015, 949, 797, 747, 698 cm-1. HRMS
(ESI) m/z: [M+H]+ calcd for C16H20NO2 258.1494; found
258.1488.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/
1H NMR and 13C NMR spectra for all prepared starting mate-
rials new compounds
AUTHOR INFORMATION
Corresponding Author
Biaolin Yin
* E-mail: blyin@scut.edu.cn
orcid.org/0000-0002-2547-0231
Bo Liu
N-methyl-N-phenyl-5-propylfuran-2-carboxamide (1ae). Iso-
lated as light-yellow oil using petroleum ether/ethyl ace-
* E-mail: doctliu@263.net
1
tate/triethylamine (8/1/0.01) as the eluent (14.1 mg, 29%). H
NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 3H), 7.22-7.18 (m,
2H), 5.94 (d, J = 3.4 Hz, 1H), 5.82 (d, J = 3.4 Hz, 1H), 3.42 (s,
3H), 2.43 (t, J = 7.4 Hz, 2H), 1.49-1.39 (m, 2H), 0.82 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 159.0, 145.7,
144.7, 129.6, 127.6, 127.5, 117.8, 106.9, 38.6, 30.1, 20.9, 13.7. IR:
2962, 2932, 2874, 1732, 1643, 1594, 1496, 1371, 1112, 1015, 749,
699 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for C15H17NO2Na
266.1157; found 266.1146.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by grants from the National Pro-
gram on Key Research Project (2016YFA0602900), the Na-
tional Natural Science Foundation of China (21871094),
Guangdong Natural Science Foundation (2017A030312005),
and the Science and Technology Planning Project of Guang-
dong Province, China (2017A020216021).
5-isobutyl-N-methyl-N-phenylfuran-2-carboxamide
(1af).
Isolated as light-yellow oil using petroleum ether/ethyl ace-
1
tate/triethylamine (8/1/0.01) as the eluent (15.4 mg, 30%). H
NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 3H), 7.22-7.18 (m,
2H), 6.01 (d, J = 3.2 Hz, 1H), 5.83 (d, J = 3.2 Hz, 1H), 3.41 (s,
3H), 2.30 (d, J = 7.2 Hz, 2H), 1.75-1.66 (m, 1H), 0.78 (d, J = 6.6
Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 158.2, 145.8,
144.7, 129.5, 127.6, 127.5, 117.8, 107.7, 38.6, 37.2, 27.6, 22.4. IR:
2958, 2870, 1727, 1642, 1593, 1522, 1496, 1366, 1112, 1014, 750,
699 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for C16H20NO2
258.1494; found 258.1486.
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