DDQ-mediated oxidative coupling: An approach to 2,3-dicyanofuran (thiophene)

Article abstract of DOI:10.1021/jo4026034

A facile oxidative coupling of α-carbonyl radicals to 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) for the synthesis of 2,3-dicyanofurans and thiophenes starting from readily available β-diketones, simple ketones, and β-keto thioamides in up to 95% yield in one step was developed. Mechanistic investigations revealed that a radical process could be involved in this transformation, and a water promoted C-C bond cleavage pathway is proposed for the formation of 2,3-dicyanofurans and thiophenes.

Full text of DOI:10.1021/jo4026034

Article
pubs.acs.org/joc
DDQ-Mediated Oxidative Coupling: An Approach to 2,3-
Dicyanofuran (Thiophene)
Zheng-Lin Wang,† Hong-Liang Li,† Li-Shi Ge,† Xing-Lan An,† Zi-Gang Zhang,† Xiaoyan Luo,*,†
John S. Fossey,†,‡ and Wei-Ping Deng*,†
†Shanghai Key Laboratory of New Drug Design & School of Pharmacy, East China University of Science and Technology, 130
Meilong Road, Shanghai 200237, China
‡School of Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, U.K.
S
* Supporting Information
ABSTRACT: A facile oxidative coupling of α-carbonyl radicals to 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) for the
synthesis of 2,3-dicyanofurans and thiophenes starting from readily available β-diketones, simple ketones, and β-keto thioamides
in up to 95% yield in one step was developed. Mechanistic investigations revealed that a radical process could be involved in this
transformation, and a water promoted C−C bond cleavage pathway is proposed for the formation of 2,3-dicyanofurans and
thiophenes.
novelty and diversity in both material science and drug
discovery.
INTRODUCTION
■
The possibility of direct C−H functionalization, especially
oxidative coupling, to form C−C bonds represents a significant
challenge,1 and application of these strategies to construct
polysubstituted furans is especially attractive.1l−n Generally,
electrophilic substrates in these transformations feature either
aryl/vinyl groups2,3 or heteroatoms (such as N, O, and S)2,4
adjacent to the C(sp3)−H being activated (Scheme 1, eq a−c).
Although great progress has already been made in this area,
there is still a requirement to develop highly efficient and
environmentally benign synthetic methods via oxidative
coupling strategies due to the increasing demands of structural
Therefore, we envisaged an oxidative coupling protocol
utilizing C(sp3)−H nucleophiles, such as ketones instead of the
aforementioned electrophiles, providing electrophilic α-carbon-
yl radicals (Scheme 1, eq d). Electrophilic radicals, typically
characterized by adjacent carbonyl groups, can be conveniently
generated by transition metal-mediated oxidation of acidic
ketones.5 Mn(OAc)3 and cerium(IV) ammonium nitrate
(CAN) are most commonly used as stoichiometric oxidants
for the oxidative activation of ketones to generate α-carbonyl
radicals, which can subsequently react with a variety of
nucleophilic alkenes.6,7 Consequently, a mild and metal-free
process for oxidative activation of C(sp3)−H bonds of
nucleophiles is still a highly desirable goal.
We recently reported the first successful example of a DDQ-
mediated coupling of a terminal allylic C(sp3) to a C(sp2) of
styrene via an unconventional reaction mode.8 We wished to
investigate the possibility of oxidative coupling of α-C(sp3)−H
bonds of a carbonyl compound to styrene via DDQ-mediated
formation of an α-carbonyl radical.9 Hence, we initially
performed a reaction employing methyl acetoacetate 1a and
styrene in the presence of DDQ (1.5 equiv) in CH3CN at room
temperature. Unexpectedly, 2,3-dicyanofuran 2a was obtained
in 22% yield [eq 1]. From inspection of the structure of 2a, it is
clear that the 2,3-dicyanofuran backbone partly derives from
Scheme 1. Strategies for C−H Functionalization
Received: November 22, 2013
© XXXX American Chemical Society
A
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equiv) and DDQ (3.0 equiv) in CH3CN at room temperature
were found to be the optimal reaction conditions (Table 1,
entry 12), providing 2,3-dicyanofuran 2a in 93% yield.
In order to understand the generality and scope of this highly
efficient 2,3-dicyanofuran formation process, a number of 1,3-
dicarbonyl compounds were investigated, as shown in Scheme
2. It was found that ethyl, isopropyl, tert-butyl, and benzyl
DDQ molecule and not from styrene. This implies that a DDQ-
mediated α-carbonyl radical formation may occur, and resulting
α-carbonyl radical can further react with DDQ via an
unconventional reaction pathway to afford 2,3-dicyanofuran
2a.10,11
Scheme 2. Substrate Scope for Oxidative Coupling of
a
Carbonyl Compounds 1 to DDQ
Notably, dicyanoaryl (heteroaryl) compounds have been
successfully used for preparation of phthalocyanines, which
show various practical applications such as dyes, pigments,
photoelectric materials and other applications.12,13 In view of
the unconventional formation of 2,3-dicyanofuran and its
potential utility as a building block for the synthesis of
phthalocyanines, we further explored this unconventional
reaction system and reported the preliminary result in a
Chinese patent application with limited substrate scope.14
Herein, we would like to describe in full detail the facile
reaction of the in situ generated α-carbonyl radicals with DDQ
itself, constructing not only 2,3-dicyanofurans but also 2,3-
dicyanothiophenes in excellent yields under metal-free
conditions. In addition, a hypothetical radical involved oxidative
coupling and water-promoted C−C bond cleavage pathway was
also discussed on the basis of both NMR spectroscopy studies
and radical trapping experiments.
a
b
Yields of the isolated products. 5.0 equiv of DDQ was used.
RESULTS AND DISCUSSION
■
With the encouragement of our interesting finding of 2,3-
dicyanofuran formation via presumably an unconventional
reaction pathway [eq 1], we then further explored the reaction
conditions (Table 1). The combination of substrate 1a (1.0
acetoacetates all reacted smoothly affording the 2,3-dicyanofur-
an products in excellent yields (Scheme 2, 2b−2e). Never-
theless, the treatment of ethyl 4-chloroacetoacetate with DDQ
under these standard conditions resulted in the formation of
products 2b and 2f in 18 and 65% yields, respectively.
Compound 2b might be generated through reduction of 2f by
in situ formed DDQH2. Interestingly, when using 5.0 equiv of
DDQ in this reaction, only 2f was obtained, in good yield
(85%). The reaction of ethyl trifluoroacetoacetate with DDQ
delivered 2,3-dicyanofuran 2g in 69% yield. Subtle change to
the acetyl group of 1 to propionyl and isobutyryl led to the
formation of both 2h and 2i in comparable yields. However,
use of methyl pivaloylacetate led to 2j in only moderate yield,
probably due to the steric hindrance imparted by the tert-butyl
group. A substrate with a benzyloxy group underwent this
reaction to afford the corresponding product 2k in 82% yield.
In addition, symmetric β-diketones 1l and 1m as well as 3-
oxobutanenitrile 1n can also be transformed to corresponding
2,3-dicyanofurans 2l, 2m, and 2n in excellent yields.
Next, we further extended the scope to aryl substrates
(Scheme 3). Most of the aryl substrates tried gave the desired
products (Scheme 3, 4a−4l) in good yields (62−92%).
Although substrate 3j, bearing an electron-donating methoxy
substituent on the aryl ring, gave a mixture of furan 4j and p-
methoxybenzoic acid in 41 and 30% yields, respectively.
Unsymmetrical β-diketone 3c was found to give a 1:2 mixture
of two regioisomeric products 4c in 62% yield (Scheme 3).
Single crystal X-ray diffraction analysis of 4k confirmed the 2,3-
dicyanofuran structure (CCDC 943604) . Moreover, substrates
containing furan, thiophene, and pyridine moieties could also
be used in this transformation affording the corresponding
Table 1. Optimization of Reaction Conditions
a
d
entry
solvent
DDQ (equiv)
yield (%)
22
1
CH3NO2
CH3NO2
DCE
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
4.0
3.0
b
2
23
3
26
15
62
7
4
toluene
CH3CN
DMSO
DMF
5
6
7
9
8
DCM
29
22
56
60
93
92
9
CHCl3
THF
10
11
12
13
14
EtOAc
CH3CN
CH3CN
CH3CN
c
86
a
Reaction conditions: Methyl acetoacetate 1a (0.2 mmol) and DDQ
(0.6 mmol) in dry solvent (2.0 mL) at rt under N2, which was stirred
b
until the reaction was complete, as judged by TLC. The reaction was
c
d
performed at 60 °C. The solvent was not dried. Yields of isolated
products.
B
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absence of an adjacent proton and then cyclization and
subsequent deprotonation to form the key intermediate G,1l,16
which was found to be quite stable in anhydrous CD3CN in an
NMR tube. The carbonyl group of G is then attacked by H2O
(water is actually introduced by opening the reaction flask to air
during the workup) and leads to the ring-opening17 forming the
free acid I. Intermediate I can then easily cyclize to form 2,3-
dichloromaleic anhydride, which is accompanied by the release
of dihydrofuran K. Finally, a third equivalent of DDQ is
consumed in the aromatization of K to afford 2,3-dicyanofuran
2a. However, the formation of 2a from the key intermediate G
via a retro-Diels−Alder pathway may also be possible.14b,c
In order to further test our hypothesis, we needed to answer
the following questions: (1) Is this really a radical-mediated
process? (2) Is intermediate G involved in the reaction? (3)
Does water promote the reaction affording 2,3-dichloromaleic
anhydride? First, the reaction of 3b was repeated with the
addition of 3.0 equiv of TEMPO, providing a trace of 4b and
vicinal tricarbonyl compound 3bb in 91% yield [eq 2]. This
Scheme 3. Substrate Scope for Oxidative Coupling of
Carbonyl Compounds 3 with DDQ
a
a
Yields of the isolated products. bThe ratio of two regioisomeric
products was determined by 1H NMR spectroscopy. cp-Methox-
observation implies that an α-carbonyl radical does form since
it can be easily trapped by TEMPO to afford 3bb, after further
DDQ oxidation. Furthermore, electron paramagnetic resonance
(EPR) experiments using 1a and 3h as model substrates
revealed signals corresponding to radicals (see the Supporting
Information, Figures S1 and S2).18
ybenzoic acid was obtained in 30% yield.
furan-containing scaffold in moderate to excellent yields
(Scheme 3, 4m−4o).
All of the products contain the 2,3-dicyano unit derived from
DDQ itself, which indicated that an oxidative radical coupling
pathway might be involved. Interestingly, DDQ has rarely been
reported as electrophile in reactions with carbonyl nucleophi-
les.9c Therefore, we proposed the tentative reaction pathway for
this unexpected transformation shown in Figure 1. A single
electron transfer (SET) from carbonyl compound 1a to DDQ
generates radicals B and C, which then selectively cross couple
to each other to form a DDQ-substrate adduct D, probably due
to the persistent radical effect (PRE).15 The adduct D is then
subjected to a DDQ-mediated hydride abstraction due to the
Next, to prove the formation of intermediate G and 2,3-
dichloromaleic anhydride, a series of NMR spectroscopy
experiments in situ were also performed. It is notable that
attempts to monitor and purify intermediate G by TLC and
silica gel chromatography were not successful, although
treatment of substrate 1a with DDQ in CD3CN afforded a
new unidentified product, presumably the intermediate G, after
1
5 min, by analysis of the H NMR spectra (Scheme 4, (2)).
Interestingly, the NMR signal corresponding to this unidenti-
fied product gradually increased as substrate 1a was consumed,
Figure 1. Proposed reaction pathway for oxidative radical addition.
C
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1
Scheme 4. Reactions Were Monitored by H NMR
Spectroscopy
Scheme 5. Reactions Were Monitored by 13C NMR
Spectroscopy
a
a
a
Reaction conditions: Carbonyl compound 1a (0.1 mmol) was added
to a solution of DDQ (0.3 mmol) in CD3CN (1.0 mL) at room
temperature under N2. The resulting mixture was monitored by H
NMR spectroscopy with time. (1) Substrate 1a; (2) after 5 min; (3)
after 30 min; (4) after 1 h; (5) after 2 h; (6) addition of 1.0 equiv of
H2O for additional 1 h.
a
(1) After 1 h; (2) after 2 h; (3) after 1.0 equiv of H2O for additional 1
1
h; (4) product 2a; (5) DDQH2; (6) 2,3-dichloromaleic anhydride.
genation product, in 61% yield and accompanied by 10% of
6aa, an oxidative aromatization product from 6a. It was found
that 6-methoxy tetralone 5b also reacted smoothly affording 6b
in 40% yield, and 6bb in 28% yield, respectively (Scheme 6).
accompanied by the formation of a small amount of 2a after 30
min, which gradually increased over 2 h. The 1H NMR spectra
(Scheme 4, (5)) did not change further, even if the reaction
time was further prolonged to 5 h. Therefore, it is sensible to
conclude that a new product, possibly the proposed
intermediate G, gradually converted to product 2a. Attempts
to chromatographically isolate this intermediate have so far
proved unsuccessful, suggesting that this new unidentified
intermediate may be not stable and prone to hydrolysis by trace
water in the solvent used for NMR spectroscopy, as proposed
in Figure 1.
Scheme 6. Substrate Scope for Oxidative Coupling of
Carbonyl Compounds 5 to DDQ
a b
,
Recently, it was reported that the [2 + 2] cycloadducts of
DDQ and 2-ethynylpyrroles are stable at room temperature,
although a ring-opening reaction was found at higher
temperature in the presence of MeOH affording rearrangement
products.17,19 However, in our case, intermediate G was
completely converted into product 2a within one hour of
addition of 1 equiv of H2O to the sample in an NMR tube
(Scheme 4, (5)). Furthermore, we also analyzed the 13C NMR
spectra of the same reaction, and both DDQH2 and 2,3-
dichloromaleic anhydride (as judged by comparison of the 13C
NMR spectra of authentic samples) were found following
addition of 1.0 equiv of H2O after an additional hour (Scheme
5, (3)). These NMR spectra provide supporting evidence
consistent with the proposed mechanism.
a
Reaction conditions: Carbonyl compounds 5 (0.2 mmol) and DDQ
(0.6 mmol) in dry CH3CN (2.0 mL) at reflux under N2, which was
b
stirred until the reaction was complete, as judged by TLC. Yields of
isolated products. cYield when using 5.0 equiv of DDQ in the
parentheses.
On the basis of our reaction pathway hypothesis, we believed
that simple ketones 5 could be useful in this system as long as
the formation of an α-carbonyl radical in the presence of DDQ
is possible. Despite the fact that successful formation of α-
carbonyl radicals has been reported through transition metal-
mediated oxidation for simple ketones,20 only one example of a
DDQ-mediated α-carbonyl radical formation from simple
ketones has been reported.21 With this in mind, we initially
used a challenging tetralone 5a as a substrate under the
described optimal conditions. This substrate could also form an
enone via a well-known DDQ-mediated dehydrogena-
tion.9b,14b,22 No reaction occurred upon treatment of 5a with
DDQ at room temperature in CH3CN. To our delight,
treatment of 5a with DDQ under reflux successfully delivered
the corresponding 2,3-dicyanofuran 6a, instead of a dehydro-
Use of 5.0 equiv of DDQ in reactions with 5a and 5b gave 6aa
and 6bb only in 70 and 66% yields, respectively. Simple cyclic
ketones 5c−5f also showed good reactivity to giving 2,3-
dicyanofurans in moderate to good yields (Scheme 6, 6c−6f).
However, acetophenone was found unsuitable for this reaction,
presumably because of the difficulty in the formation of α-
carbonyl radical; an electron-rich 2-methoxy acetophenone 5g
was found to give the corresponding furan 6g in moderate yield
(Scheme 6). In addition, treatment of 2-methoxy acetophenone
5g and DDQ with LDA in THF failed to give any 6g, which
provided evidence that a Michael addition process could be
ruled out in this system.
Following the successful reactions of β-diketones and simple
ketones, we next turned our attention to the β-keto thioamide
D
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substrates. According to our hypothesis, DDQ-substrate adduct
D will undergo a DDQ-mediated hydride abstraction and
subsequent cyclization. It is reasoned that, due to the stronger
nucleophilicity of the thiocarbonyl group, the sulfur should
dominate over the carbonyl’s oxygen atom in the cyclization
step, thus affording a thiophene unit. Therefore, a number of β-
keto thioamide substrates 7 were employed, as shown in
Scheme 7. It was found that methyl, ethyl, tert-butyl and benzyl
substrates, and then the DDQ-substrate adduct D undergoes a
DDQ-mediated hydride abstraction and subsequent cyclization
to form the key intermediate G. The existence of G was
supported by the NMR spectroscopy studies; however, it was
unstable and prone to an unconventional ring-opening
promoted by trace amounts of H2O and a subsequent ring-
contraction to release the dihydrofuran K. From a synthetic
point of view, this protocol represents a powerful, simple, and
efficient approach to the construction of 2,3-dicyanofurans and
thiophene units, which might be useful in biological scenarios.
Further studies extending substrate scope of this oxidative
coupling of α-carbonyl radicals and application of 2,3-
dicyanofuran and thiophene derivatives to multistep syntheses
are currently underway.
Scheme 7. Substrate Scope for Oxidative Coupling of β-Keto
a b
,
Thioamides 7 to DDQ
EXPERIMENTAL SECTION
■
General Information. Melting points were obtained in open
capillary tubes using a melting point microapparatus, which were
uncorrected. Mass spectra were recorded on TOF mass spectrometer.
1H nuclear magnetic resonance (NMR) spectra were recorded using
CDCl3 (δ = 7.26 ppm), (CD3)2SO (δ = 2.50 ppm), and CD3CN (δ =
1.94 ppm) as solvent at ambient temperature on 400 MHz
spectrometer. Data are presented as follows: chemical shift (in
ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, and m = multiplet), coupling constant (J/Hz), and
interpretation. 13C NMR spectra were recorded by broadband spin
decoupling for CDCl3 (δ = 77.2 ppm), (CD3)2SO (δ = 39.5 ppm), and
CD3CN (δ = 118.3 ppm) at ambient temperatures on 100 MHz
spectrometer. Chemical shift values are reported in ppm on the scale.
Infrared spectra were recorded as thin films. Absorbtion frequencies
are given in wave numbers (cm−1). Thin layer chromatography (TLC)
was performed using commercially prepared 100−400 mesh silica gel
plates, and visualization was effected at 254 or 365 nm. Unless
otherwise noted, all reagents and solvents were used as purchased.
Acetonitrile was dried and distilled from calcium hydride under
nitrogen. Toluene and tetrahydrofuran were dried and distilled from
sodium/benzophenone under nitrogen.
General Procedure for Synthesis of Polysubstituted Furans
2a−2n, 4a−4o and Thiophenes 8. Carbonyl compounds (0.2
mmol) were added to a solution of DDQ (137 mg, 0.6 mmol) in dry
CH3CN or EtOAc (2 mL) at room temperature under an atmosphere
of N2. The resulting mixture was stirred until the reaction was
complete as judged by TLC. Then the resulting yellow solid was
removed by filtration, and the solvent was evaporated to dryness,
which was further purified by column chromatography on 100−200
mesh silica gel to afford pure polysubstituted furans 2a−2n, 4a−4o,
and 8.
a
Reaction conditions: β-keto thioamides 7 (0.2 mmol) and DDQ (0.6
mmol) in dry EtOAc (2.0 mL) at rt under N2, which was stirred until
the reaction was complete as judged by TLC. Yields of isolated
products.
b
3-(dimethylamino)-3-thioxopropanoate all reacted smoothly
giving the 2,3-dicyanothiophene products in excellent yields
(Scheme 7, 8a−8d). The dimethyl thioamide motif was
replaced with diethyl, morpholine and monomethyl function-
alities, leading to the formation of 8e, 8f and 8g in good yields.
In addition, β-keto thioamide substrates 7h−7k as well as 2-
cyano-N,N-dimethylethanethioamide 7l also showed good
reactivity giving 2,3-dicyanothiophenes in moderate to good
yields (Scheme 7, 8h−8l). Single crystal X-ray diffraction
analysis of 8j, confirmed the 2,3-dicyanothiophene structure.23
Furthermore, 2,3-dicyanofuran 2a was selectively trans-
formed to imidate 9 in 99% yield [eq 3],23 which might be
of interest in future biological activity studies.
Methyl 4,5-dicyano-2-methylfuran-3-carboxylate (2a). A
white solid (35 mg, 93%, yield): Rf = 0.22 (petroleum ether/ethyl
acetate = 7:1); mp 70−72 °C; 1H NMR (400 MHz, CDCl3) δ 3.96 (s,
3H), 2.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.1, 160.1,
130.4, 115.1, 108.9, 108.8, 107.9, 52.7, 14.3; HRMS (EI-TOF) calcd.
for C9H6N2O3 [M]+ 190.0378, found 190.0376; IR (KBr) 2957, 2249,
2235, 1722, 1561, 1457, 1419, 1311, 1228, 1127, 1088, 992 cm−1.
Ethyl 4,5-dicyano-2-methylfuran-3-carboxylate (2b). A yel-
lowish viscous oil (37 mg, 91%, yield): Rf = 0.23 (petroleum ether/
1
ethyl acetate = 7:1); H NMR (400 MHz, CDCl3) δ 4.41 (q, J = 7.1
Hz, 2H), 2.72 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.0, 159.6, 130.3, 115.2, 108.9, 107.9, 62.2, 14.2, 13.9;
HRMS (EI-TOF) calcd. for C10H8N2O3 [M]+ 204.0535, found
204.0536; IR (KBr) 2987, 2249, 2236, 1717, 1600, 1444, 1308,
1227, 1132, 1088, 1025 cm−1.
CONCLUSION
■
In conclusion, we have demonstrated a facile oxidative coupling
of α-carbonyl radicals to DDQ for the synthesis of 2,3-
dicyanofurans and thiophenes from readily available β-
diketones, simple ketones, and β-keto thioamides in up to
95% yield in one step. Mechanistic studies revealed that DDQ-
mediated radical formation is involved in the initial step for all
Isopropyl 4,5-dicyano-2-methylfuran-3-carboxylate (2c). A
red viscous oil (38 mg, 88%, yield): Rf = 0.28 (petroleum ether/ethyl
1
acetate = 20:1); H NMR (400 MHz, CDCl3) δ 5.24 (septet, J = 6.3
Hz, 1H), 2.71 (s, 3H), 1.40 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 164.8, 159.1, 130.2, 115.5, 109.0, 108.9, 108.0, 70.5, 21.7,
14.2; HRMS (EI-TOF) calcd. for C11H10N2O3 [M]+ 218.0691, found
E
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1
218.0689; IR (film) 2986, 2938, 2238, 1728, 1600, 1554, 1434, 1304,
1258, 1238, 1128, 1104, 1084 cm−1.
tert-Butyl 4,5-dicyano-2-methylfuran-3-carboxylate (2d). A
mp 96−98 °C; H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H), 2.63 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 189.7, 164.4, 130.4, 122.2,
109.8, 107.9, 107.8, 29.9, 15.1; HRMS (EI-TOF) calcd. for C9H6N2O2
[M]+ 174.0429, found 174.0427; IR (KBr) 3000, 2920, 2240, 1679,
1553, 1413, 1298, 1075, 963, 625 cm−1.
light yellow viscous oil (40 mg, 86%, yield): Rf = 0.30 (petroleum
1
ether/ethyl acetate = 20:1); H NMR (400 MHz, CDCl3) δ 2.69 (s,
3H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 164.6, 158.7,
129.9, 116.3, 109.1, 109.1, 108.1, 84.4, 28.0, 14.1; HRMS (EI-TOF)
calcd. for C12H12N2O3 [M]+ 232.0848, found 232.0850; IR (film)
2982, 2934, 2236, 1726, 1598, 1554, 1415, 1371, 1312, 1258, 1121,
1085, 842 cm−1.
4-Oxo-4,5,6,7-tetrahydrobenzofuran-2,3-dicarbonitrile
(2m). A white solid (31 mg, 84%, yield): Rf = 0.19 (petroleum ether/
ethyl acetate = 2:1); mp 107−109 °C; 1H NMR (400 MHz,
(CD3)2SO) δ 2.92 (t, J = 6.2 Hz, 2H), 2.44 (t, J = 7.0 Hz, 2H), 2.08−
2.02 (m, 2H); 13C NMR (100 MHz, (CD3)2SO) δ 191.9, 172.7, 131.6,
120.0, 110.0, 109.3, 104.8, 37.4, 23.4, 21.6; HRMS (EI-TOF) calcd. for
C10H6N2O2 [M]+ 186.0429, found 186.0428; IR (KBr) 2948, 2241,
1689, 1550, 1456, 1407, 1011, 672 cm−1.
Benzyl 4,5-dicyano-2-methylfuran-3-carboxylate (2e). A
white solid (46 mg, 86%, yield): Rf = 0.27 (petroleum ether/ethyl
1
acetate = 10:1); mp 123−125 °C; H NMR (400 MHz, CDCl3) δ
7.47−7.45 (m, 2H), 7.42−7.34 (m, 3H), 5.39 (s, 2H), 2.70 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 165.2, 159.4, 134.6, 130.4, 128.8,
128.8, 128.6, 115.1, 108.9, 108.9, 107.9, 67.7, 14.4; HRMS (EI-TOF)
calcd. for C15H10N2O3 [M]+ 266.0691, found 266.0693; IR (KBr)
2921, 2244, 1723, 1595, 1556, 1422, 1307, 1259, 1234, 1124, 1083,
778, 737 cm−1.
5-Methylfuran-2,3,4-tricarbonitrile (2n). A white solid (29 mg,
91%, yield): Rf = 0.25 (petroleum ether/ethyl acetate = 3:1); mp 50−
1
52 °C; H NMR (400 MHz, CDCl3) δ 2.66 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 167.1, 130.8, 109.3, 108.5, 107.2, 107.0, 98.3, 14.0;
HRMS (EI-TOF) calcd. for C8H3N3O [M]+ 157.0276, found
157.0278; IR (KBr) 2245, 1696, 1597, 1565, 1416, 1170, 1083 cm−1.
Methyl 4,5-dicyano-2-phenylfuran-3-carboxylate (4a). A
white solid (42 mg, 83%, yield): Rf = 0.21 (petroleum ether/ethyl
Ethyl 2-(chloromethyl)-4,5-dicyanofuran-3-carboxylate (2f).
A light yellow viscous oil (40 mg, 85%, yield): Rf = 0.21 (petroleum
1
1
ether/ethyl acetate = 20:1); H NMR (400 MHz, CDCl3) δ 4.91 (s,
acetate = 20:1); mp 124−126 °C; H NMR (400 MHz, CDCl3) δ
2H), 4.45 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 160.4, 158.5, 131.8, 117.1, 108.9, 108.3, 107.4, 63.0,
33.9, 13.9; HRMS (EI-TOF) calcd. for C10H7ClN2O3 [M]+ 238.0145,
found 238.0144; IR (film) 2987, 2242, 1728, 1554, 1432, 1310, 1244,
1122, 1062,737, 686 cm−1.
7.95−7.93 (m, 2H), 7.60−7.50 (m, 3H), 3.96 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 162.5, 159.8, 132.3, 130.7, 129.2, 128.8, 126.1, 114.3,
110.4, 109.0, 108.0, 52.9; HRMS (EI-TOF) calcd. for C14H8N2O3
[M]+ 252.0535, found 252.0534; IR (KBr) 2956, 2237, 1734, 1532,
1489, 1438, 1307, 1269, 1219, 1098, 1017, 771, 692 cm−1.
Ethyl 4,5-dicyano-2-(trifluoromethyl)furan-3-carboxylate
(2g). A light yellow viscous oil (36 mg, 69%, yield): Rf = 0.24
(petroleum ether/ethyl acetate = 30:1); 1H NMR (400 MHz, CDCl3)
δ 4.48 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 156.3, 147.5 (q, J = 45.5 Hz), 132.3, 120.9 (q, J = 2.2
Hz), 116.6 (q, J = 270.7 Hz), 110.0, 107.1, 106.5, 63.7, 13.6; HRMS
(EI-TOF) calcd. for C10H5F3N2O3 [M]+ 258.0252, found 258.0253;
IR (film) 2990, 2922, 2251, 1744, 1608, 1419, 1315, 1249, 1204, 1159,
1032, 790, 723 cm−1.
Ethyl 4,5-dicyano-2-phenylfuran-3-carboxylate (4b). A white
solid (45 mg, 84%, yield): Rf = 0.23 (petroleum ether/ethyl acetate =
20:1); mp 108−110 °C; H NMR (400 MHz, CDCl3) δ 7.96−7.94
(m, 2H), 7.60−7.50 (m, 3H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 159.3, 132.3, 130.6,
129.2, 128.7, 126.2, 114.5, 110.6, 109.1, 108.1, 62.6, 13.8; HRMS (ESI-
TOF) calcd. for C15H9N2O3 [M − H]+ 265.0613, found 265.0616; IR
(KBr) 2979, 2926, 2237, 1711, 1546, 1427, 1307, 1230, 1123, 1021,
771, 699 cm−1.
1
Methyl 4,5-dicyano-2-ethylfuran-3-carboxylate (2h). A light
4-Acetyl-5-phenylfuran-2,3-dicarbonitrile; 4-Benzoyl-5-
methylfuran-2,3-dicarbonitrile (4c). Ratio of the two isomers
was 1:2. A light yellow viscous oil (29 mg, 62%, yield): Rf = 0.23
(petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, CDCl3)
δ 7.76−7.75 (m, 4H), 7.70−7.66 (m, 4H), 7.63−7.59 (m, 1H), 7.56−
7.53 (m, 6H), 2.49 (s, 6H), 2.46 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 190.2, 186.8, 162.6, 161.3, 136.3, 134.5, 132.4, 131.1, 130.4,
129.3, 129.1, 129.1, 126.4, 123.0, 122.3, 109.4, 109.1, 108.8, 108.0,
30.0, 14.5. MS(EI-TOF) m/z 236.1 [M]+.
5-Phenylfuran-2,3,4-tricarbonitrile (4d). A white solid (40 mg,
92%, yield): Rf = 0.21 (petroleum ether/ethyl acetate = 20:1); mp
149−151 °C; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.4 Hz, 2H),
7.69−7.59 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 164.0, 133.7,
130.1, 129.9, 126.7, 124.6, 111.0, 109.7, 107.3, 107.2, 94.1; HRMS (EI-
TOF) calcd. for C13H5N3O [M]+ 219.0433, found 219.0434; IR (KBr)
2237, 1543, 1488, 1450, 1407, 778, 706, 687 cm−1.
yellow viscous oil (36 mg, 89%, yield): Rf = 0.25 (petroleum ether/
1
ethyl acetate = 20:1); H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H),
3.11 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 169.8, 160.0, 130.4, 114.2, 109.0, 108.8, 108.0, 52.7,
21.7, 11.4; HRMS (EI-TOF) calcd. for C10H8N2O3 [M]+ 204.0535,
found 204.0537; IR (film) 2987, 2958, 2236, 1729, 1553, 1447, 1307,
1252, 1119, 1030, 784 cm−1.
Methyl 4,5-dicyano-2-isopropylfuran-3-carboxylate (2i). A
white solid (38 mg, 87%, yield): Rf = 0.26 (petroleum ether/ethyl
1
acetate = 20:1); mp 55−57 °C; H NMR (400 MHz, CDCl3) δ 3.94
(s, 3H), 3.84 (septet, J = 7.0 Hz, 1H), 1.31 (d, J = 7.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 173.0, 160.0, 130.3, 113.2, 109.0, 108.8,
108.1, 52.7, 28.0, 20.2; HRMS (EI-TOF) calcd. for C11H10N2O3 [M]+
218.0691, found 218.0692; IR (KBr) 2988, 2958, 2244, 2235, 1724,
1552, 1448, 1294, 1226, 1115, 1038, 816 cm−1.
Methyl 2-tert-butyl-4,5-dicyanofuran-3-carboxylate (2j). A
Methyl 2-(2-bromophenyl)-4,5-dicyanofuran-3-carboxylate
white solid (22 mg, 48%, yield): Rf = 0.28 (petroleum ether/ethyl
1
(4e). A white solid (51 mg, 78%, yield): Rf = 0.22 (petroleum
acetate = 30:1); mp 72−74 °C; H NMR (400 MHz, CDCl3) δ 3.96
1
(s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.0, 159.9,
129.0, 114.5, 110.2, 109.2, 108.0, 52.8, 35.9, 27.8; HRMS (EI-TOF)
calcd. for C12H12N2O3 [M]+ 232.0848, found 232.0846; IR (KBr)
2987, 2961, 2233, 1718, 1437, 1305, 1249, 1113, 1023, 808, 791 cm−1.
Ethyl 2-(benzyloxymethyl)-4,5-dicyanofuran-3-carboxylate
(2k). A light yellow viscous oil (51 mg, 82%, yield): Rf = 0.24
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3)
δ 7.35−7.32 (m, 5H), 4.87 (s, 2H), 4.64 (s, 2H), 4.40 (q, J = 7.0 Hz,
2H), 1.40 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8,
158.9, 136.8, 131.5, 128.6, 128.3, 128.0, 117.1, 108.7, 108.6, 107.8,
73.9, 62.6, 62.4, 13.9; HRMS (EI-TOF) calcd. for C17H14N2O4 [M]+
310.0954, found 310.0955; IR (film) 2986, 2868, 2239, 1728, 1553,
1432, 1308, 1247, 1123, 1067, 743, 700 cm−1.
ether/ethyl acetate = 10:1); mp 90−92 °C; H NMR (400 MHz,
CDCl3) δ 7.73−7.70 (m, 1H), 7.48−7.43 (m, 3H), 3.84 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 161.3, 159.1, 133.4, 133.1, 132.2, 131.5,
127.8, 127.5, 123.5, 117.4, 109.2, 108.7, 107.8, 53.0; HRMS (EI-TOF)
calcd. for C14H7BrN2O3 [M]+ 329.9640, found 329.9647; IR (KBr)
2954, 2239, 1730, 1441, 1308, 1233, 1132, 1013, 779 cm−1.
Methyl 2-(3-bromophenyl)-4,5-dicyanofuran-3-carboxylate
(4f). A white solid (55 mg, 83%, yield): Rf = 0.23 (petroleum ether/
ethyl acetate = 10:1); mp 101−103 °C; 1H NMR (400 MHz, CDCl3)
δ 8.11 (t, J = 1.8 Hz, 1H), 7.92−7.90 (m, 1H), 7.70−7.68 (m, 1H),
7.40 (t, J = 8.0 Hz, 1H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
160.4, 159.5, 135.2, 131.9, 131.1, 130.3, 127.8, 127.8, 122.7, 115.1,
110.4, 108.8, 107.8, 53.2; HRMS (EI-TOF) calcd. for C14H7BrN2O3
[M]+ 329.9640, found 329.9642; IR (KBr) 3107, 2234, 1736, 1530,
1466, 1309, 1216, 1104, 1024, 779 cm−1.
4-Acetyl-5-methylfuran-2,3-dicarbonitrile (2l). A white solid
(32 mg, 93%, yield): Rf = 0.18 (petroleum ether/ethyl acetate = 10:1);
F
dx.doi.org/10.1021/jo4026034 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Methyl 2-(4-bromophenyl)-4,5-dicyanofuran-3-carboxylate
Methyl 4,5-dicyano-2-(pyridin-2-yl)furan-3-carboxylate (4o).
A white solid (46 mg, 90%, yield): Rf = 0.25 (petroleum ether/ethyl
acetate = 4:1); mp 97−99 °C; 1H NMR (400 MHz, CDCl3) δ 8.76 (d,
J = 4.3 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.47
(t, J = 6.1 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
159.6, 159.4, 150.3, 144.9, 136.9, 131.3, 126.0, 125.1, 116.7, 109.9,
108.7, 107.8, 53.2; HRMS (EI-TOF) calcd. for C13H7N3O3 [M]+
253.0487, found 253.0484; IR (KBr) 2955, 2242, 1747, 1534, 1218,
1116, 1026, 786 cm−1.
Methyl 4,5-dicyano-2-(dimethylamino)thiophene-3-carbox-
ylate (8a). A white solid (45 mg, 95%, yield): Rf = 0.20 (petroleum
ether/ethyl acetate = 3:1); mp 60−62 °C; 1H NMR (400 MHz,
CDCl3) δ 3.90 (s, 3H), 3.13 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
167.0, 160.9, 121.6, 112.3, 111.9, 108.4, 100.6, 52.3, 45.6; HRMS (EI-
TOF) calcd. for C10H9N3O2S [M]+ 235.0415, found 235.0417.
Ethyl 4,5-dicyano-2-(dimethylamino)thiophene-3-carboxy-
late (8b). A white solid (47 mg, 94%, yield): Rf = 0.24 (petroleum
ether/dichloromethane = 1:1); mp 112−114 °C; 1H NMR (400 MHz,
CDCl3) δ 4.36 (q, J = 7.1 Hz, 2H), 3.13 (s, 6H), 1.39 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 160.5, 121.7, 112.3,
111.9, 108.7, 100.5, 61.9, 45.6, 14.0; HRMS (EI-TOF) calcd. for
C11H11N3O2S [M]+ 249.0572, found 249.0573.
(4g). A white solid (56 mg, 85%, yield): Rf = 0.25 (petroleum
1
ether/ethyl acetate = 20:1); mp 151−153 °C; H NMR (400 MHz,
CDCl3) δ 7.85 (d, J = 7.6 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 3.97 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 159.6, 132.1, 130.9,
130.5, 127.3, 124.9, 114.7, 110.5, 108.9, 107.9, 53.1; HRMS (EI-TOF)
calcd. for C14H7BrN2O3 [M]+ 329.9640, found 329.9638; IR (KBr)
2961, 2239, 1727, 1542, 1485, 1314, 1231, 1101, 838, 782 cm−1.
Methyl 2-(4-chlorophenyl)-4,5-dicyanofuran-3-carboxylate
(4h). A white solid (51 mg, 89%, yield): Rf = 0.21 (petroleum
1
ether/ethyl acetate = 20:1); mp 141−143 °C; H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 3.97 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 161.2, 159.6, 138.8, 130.8,
130.5, 129.2, 124.5, 114.6, 110.5, 108.8, 107.9, 53.0; HRMS (EI-TOF)
calcd. for C14H7ClN2O3 [M]+ 286.0145, found 286.0146; IR (KBr)
2962, 2239, 1727, 1485, 1313, 1233, 1104, 1089, 846, 781 cm−1.
Methyl 4,5-dicyano-2-p-tolylfuran-3-carboxylate (4i). A white
solid (40 mg, 76%, yield): Rf = 0.24 (petroleum ether/ethyl acetate =
1
10:1); mp 137−139 °C; H NMR (400 MHz, CDCl3) δ 7.84 (d, J =
8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 3.95 (s, 3H), 2.44(s, 3H); 13C
NMR (100 MHz, CDCl3) δ 162.7, 159.9, 143.2, 130.4, 129.5, 129.1,
123.3, 113.7, 110.4, 109.1, 108.1, 52.9, 21.7; HRMS (EI-TOF) calcd.
for C15H10N2O3 [M]+ 266.0691, found 266.0692; IR (KBr) 2956,
2924, 2233, 1739, 1499, 1308, 1214, 1095, 830, 780 cm−1.
tert-Butyl 4,5-dicyano-2-(dimethylamino)thiophene-3-car-
boxylate (8c). A white solid (51 mg, 92%, yield): Rf = 0.30
(petroleum ether/dichloromethane = 1:1); mp 121−123 °C; 1H NMR
(400 MHz, CDCl3) δ 3.11 (s, 6H), 1.59 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 166.3, 160.0, 121.6, 112.5, 112.1, 110.6, 100.0, 83.7, 45.4,
28.0; HRMS (EI-TOF) calcd. for C13H15N3O2S [M]+ 277.0885, found
277.0887.
Methyl 4,5-dicyano-2-(4-methoxyphenyl)furan-3-carboxy-
late (4j). A white solid (23 mg, 41%, yield): Rf = 0.22 (petroleum
1
ether/ethyl acetate = 10:1); mp 112−114 °C; H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 3.96 (s,
3H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8, 162.7,
160.0, 131.0, 130.0, 118.5, 114.2, 112.7, 110.5, 109.2, 108.2, 55.6, 52.8;
HRMS (EI-TOF) calcd. for C15H10N2O4 [M]+ 282.0641, found
282.0644; IR (KBr) 2956, 2845, 2230, 1741, 1607, 1499, 1308, 1264,
1180, 1095, 812, 781 cm−1.
Benzyl 4,5-dicyano-2-(dimethylamino)thiophene-3-carbox-
ylate (8d). A white solid (54 mg, 86%, yield): Rf = 0.30 (petroleum
1
ether/dichloromethane = 1:1.5); mp 120−122 °C; H NMR (400
MHz, CDCl3) δ 7.48 (d, J = 7.1 Hz, 2H), 7.39−7.31 (m, 3H), 5.35 (s,
2H), 3.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 167.2, 160.3,
135.0, 129.0, 128.6, 121.5, 112.4, 111.9, 108.3, 100.7, 67.6, 45.6;
HRMS (EI-TOF) calcd. for C16H13N3O2S [M]+ 311.0728, found
311.0727.
Methyl 4,5-dicyano-2-(2-(4-methylbenzyloxy)phenyl)furan-
3-carboxylate (4k). A white solid (57 mg, 77%, yield): Rf = 0.18
1
(petroleum ether/ethyl acetate = 10:1); mp 137−139 °C; H NMR
(400 MHz, CDCl3) δ 7.55−7.47 (m, 2H), 7.20−7.15 (m, 4H), 7.12−
7.08 (m, 2H), 5.05 (s, 2H), 3.72 (s, 3H), 2.37 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.2, 159.5, 157.1, 138.2, 133.6, 132.8, 131.1, 130.8,
129.3, 127.3, 120.9, 116.7, 116.2, 113.4, 109.3, 109.0, 108.2, 71.0, 52.5,
21.2; HRMS (ESI-TOF) calcd. for C22H16N2O4Na [M + Na]+
395.1008, found 395.1013; IR (KBr) 2958, 2930, 2232, 1729, 1451,
1262, 1247, 1015, 809, 755 cm−1.
Methyl 4,5-dicyano-2-(diethylamino)thiophene-3-carboxy-
late (8e). A white solid (45 mg, 85%, yield): Rf = 0.27 (petroleum
1
ether/dichloromethane = 1:1); mp 80−82 °C; H NMR (400 MHz,
CDCl3) δ 3.89 (s, 3H), 3.46 (q, J = 7.1 Hz, 4H), 1.24 (t, J = 7.1 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 165.2, 161.3, 121.5, 112.4,
111.9, 109.7, 100.9, 52.4, 50.2, 12.0; HRMS (EI-TOF) calcd. for
C12H13N3O2S [M]+ 263.0728, found 263.0729.
Methyl 4,5-dicyano-2-(naphthalen-2-yl)furan-3-carboxylate
(4l). A white solid (54 mg, 89%, yield): Rf = 0.21 (petroleum ether/
ethyl acetate = 10:1); mp 181−183 °C; 1H NMR (400 MHz, CDCl3)
δ 8.57 (s, 1H), 7.97−7.89 (m, 4H), 7.65−7.57 (m, 2H), 3.99 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 162.5, 159.9, 134.7, 132.4, 130.7,
130.6, 129.2, 128.8, 128.5, 127.8, 127.3, 124.5, 123.3, 114.4, 110.5,
109.1, 108.1, 53.0; HRMS (EI-TOF) calcd. for C18H10N2O3 [M]+
302.0691, found 302.0693; IR (KBr) 2952, 2232, 1740, 1535, 1200,
1094, 825, 784 cm−1.
Methyl 4,5-dicyano-2,2′-bifuran-3-carboxylate (4m). Recrys-
tallization of the crude product afforded a white solid (17 mg, 35%,
yield): Rf = 0.20 (petroleum ether/ethyl acetate = 20:1); mp 134−136
°C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 3.7 Hz, 1H), 7.70 (d, J
= 1.2 Hz, 1H), 6.66 (dd, J = 3.7, 1.7 Hz, 1H), 4.00 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.3, 152.8, 146.7, 141.5, 130.0, 119.3, 113.0,
111.6, 110.0, 108.8, 108.0, 52.9; HRMS (EI-TOF) calcd. for
C12H6N2O4 [M]+ 242.0328, found 242.0329; IR (KBr) 3148, 2233,
1718, 1597, 1533, 1318, 1250, 1011, 782 cm−1.
Methyl 2-(5-chlorothiophen-2-yl)-4,5-dicyanofuran-3-car-
boxylate (4n). Recrystallization of the crude product afforded a
yellowish solid (44 mg, 75%, yield): Rf = 0.29 (petroleum ether/ethyl
acetate = 20:1); mp 160−162 °C; 1H NMR (400 MHz, CDCl3) δ 7.92
(d, J = 4.2 Hz, 1H), 7.03 (d, J = 4.2 Hz, 1H), 4.00 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.9, 156.4, 138.9, 132.5, 129.8, 127.4, 125.8,
111.4, 110.1, 108.7, 107.9, 53.1; HRMS (EI-TOF) calcd. for
C12H5ClN2O3S [M]+ 291.9709, found 291.9711; IR (KBr) 3098,
2231, 1719, 1555, 1494, 1443, 1238, 1219, 1069, 815, 785 cm−1.
Methyl 4,5-dicyano-2-morpholinothiophene-3-carboxylate
(8f). A light yellow solid (29 mg, 53%, yield): Rf = 0.33 (petroleum
ether/dichloromethane = 1:2); mp 144−146 °C; 1H NMR (400 MHz,
CDCl3) δ 3.91 (s, 3H), 3.89 (t, J = 4.7 Hz, 4H), 3.35 (t, J = 4.7 Hz,
4H); 13C NMR (100 MHz, CDCl3) δ 168.2, 160.3, 121.5, 112.5,
112.1, 111.3, 104.5, 65.9, 53.4, 52.5; HRMS (EI-TOF) calcd. for
C12H11N3O3S [M]+ 277.0521, found 277.0511.
Methyl 4,5-dicyano-2-(methylamino)thiophene-3-carboxy-
late (8g). A white solid (19 mg, 43%, yield): Rf = 0.32 (petroleum
ether/dichloromethane = 1:1); mp 211−213 °C; 1H NMR (400 MHz,
CDCl3) δ 8.26 (s, 1H), 3.91 (s, 3H), 3.09 (d, J = 5.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.8, 163.6, 120.0, 112.0, 112.0, 103.3,
98.6, 52.2, 33.9; HRMS (EI-TOF) calcd. for C9H7N3O2S [M]+
221.0259, found 221.0261.
4-Acetyl-5-(dimethylamino)thiophene-2,3-dicarbonitrile
(8h). A white solid (34 mg, 77%, yield): Rf = 0.25 (petroleum ether/
dichloromethane = 1:2); mp 118−120 °C; 1H NMR (400 MHz,
CDCl3) δ 3.06 (s, 6H), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
191.0, 166.7, 119.9, 119.4, 112.9, 111.9, 101.0, 46.0, 30.3; HRMS (EI-
TOF) calcd. for C10H9N3OS [M]+ 219.0466, found 219.0463.
5-(Dimethylamino)-4-propionylthiophene-2,3-dicarbonitrile
(8i). A white solid (32 mg, 68%, yield): Rf = 0.30 (petroleum ether/
dichloromethane = 1:2); mp 140−142 °C; 1H NMR (400 MHz,
CDCl3) δ 3.04 (s, 6H), 2.99 (q, J = 7.3 Hz, 2H), 1.21 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 195.4, 166.1, 119.5, 119.0,
112.9, 112.0, 100.7, 45.8, 36.0, 8.8; HRMS (EI-TOF) calcd. for
C11H11N3OS [M]+ 233.0623, found 233.0625.
G
dx.doi.org/10.1021/jo4026034 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4-Benzoyl-5-(dimethylamino)thiophene-2,3-dicarbonitrile
= 20:1); 1H NMR (400 MHz, CDCl3) δ 2.68 (t, J = 6.1 Hz, 2H), 2.56
(t, J = 5.6 Hz, 2H), 1.95−1.89 (m, 2H), 1.85−1.79 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 158.9, 128.8, 121.1, 110.1, 109.3, 108.8, 23.3,
21.9, 21.7, 20.5; HRMS (EI-TOF) calcd. for C10H8N2O [M]+
172.0637, found 172.0640; IR (KBr) 2949, 2863, 2230, 1616, 1540,
1444, 1425, 1279, 1170, 1099, 955, 938 cm−1.
(8j). A light yellow solid (41 mg, 73%, yield): Rf = 0.21 (petroleum
1
ether/ethyl acetate = 3:1); mp 176−178 °C; H NMR (400 MHz,
CDCl3) δ 7.82 (d, J = 7.4 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.51 (t, J =
7.7 Hz, 2H), 3.00 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 188.7,
164.5, 137.6, 134.3, 129.8, 129.0, 121.2, 116.5, 112.0, 111.6, 99.3, 45.2;
HRMS (EI-TOF) calcd. for C15H11N3OS [M]+ 281.0623, found
281.0620; IR (KBr) 2928, 2604, 2496, 2205, 1644, 1544, 1410, 1397,
1352, 1035, 804 cm−1.
5,6,7,8-Tetrahydro-4H-cyclohepta[b]furan-2,3-dicarbonitrile
(6d). A colorless oil (31 mg, 82%, yield): Rf = 0.33 (petroleum ether/
1
ethyl acetate = 30:1); H NMR (400 MHz, CDCl3) δ 2.84 (t, J = 5.8
Hz, 2H), 2.59 (t, J = 5.7 Hz, 2H), 1.87−1.81 (m, 2H), 1.77−1.70 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 160.4, 126.1, 123.7, 109.6,
109.1, 108.1, 29.0, 28.1, 26.3, 24.3, 23.1; HRMS (EI-TOF) calcd. for
C11H10N2O [M]+ 186.0793, found 186.0794; IR (KBr) 2932, 2854,
2241, 2226, 1602, 1539, 1446, 1281, 1209, 1070, 962, 810 cm−1.
6,7-Dihydro-4H-thiopyrano[4,3-b]furan-2,3-dicarbonitrile
(6e). A white solid (13 mg, 34%, yield): Rf = 0.16 (petroleum ether/
4-(4-Bromobenzoyl)-5-(diethylamino)thiophene-2,3-dicar-
bonitrile (8k). A light yellow solid (47 mg, 61%, yield): Rf = 0.32
1
(petroleum ether/dichloromethane = 1:2); mp 90−92 °C; H NMR
(400 MHz, CDCl3) δ 7.69 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz,
2H), 3.27 (q, J = 7.1 Hz, 4H), 1.09 (t, J = 7.1 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 187.8, 162.9, 135.6, 132.4, 131.3, 129.7, 120.8, 117.0,
112.0, 111.7, 99.9, 50.1, 11.7; HRMS (EI-TOF) calcd. for
C17H14BrN3OS [M]+ 387.0041, found 387.0042.
1
ethyl acetate = 6:1); mp 80−82 °C; H NMR (400 MHz, CDCl3) δ
3.63 (s, 2H), 2.99 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 158.0,
128.7, 118.4, 109.3, 108.7, 108.2, 25.7, 25.1, 22.0; HRMS (EI-TOF)
calcd. for C9H6N2OS [M]+ 190.0201, found 190.0203; IR (KBr) 2935,
2923, 2907, 2227, 1606, 1538, 1437, 1415, 1330, 1196, 1083, 719
cm−1.
5-(Dimethylamino)thiophene-2,3,4-tricarbonitrile (8l). A
white solid (18 mg, 45%, yield): Rf = 0.20 (petroleum ether/ethyl
acetate = 2:1); mp 170−172 °C; 1H NMR (400 MHz, CDCl3) δ 3.37
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.9, 122.4, 113.3, 110.8,
110.5, 99.3, 85.1, 44.0; HRMS (EI-TOF) calcd. for C9H6N4S [M]+
202.0313, found 202.0314.
6,7-Dihydro-4H-furo[3,2-c]pyran-2,3-dicarbonitrile (6f). A
white solid (20 mg, 58%, yield): Rf = 0.23 (petroleum ether/ethyl
acetate = 5:1); mp 88−90 °C; 1H NMR (400 MHz, CDCl3) δ 4.66 (t,
J = 1.7 Hz, 2H), 4.03 (t, J = 5.5 Hz, 2H), 2.86 (tt, J = 1.7, 5.5 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 155.7, 129.8, 119.5, 109.2, 108.8,
105.9, 64.1, 62.0, 24.8; HRMS (EI-TOF) calcd. for C9H6N2O2 [M]+
174.0429, found 174.0427; IR (KBr) 2997, 2928, 2877, 2242, 2227,
1613, 1534, 1462, 1443, 1428, 1325, 1287, 1110, 1083, 961, 938, 843,
755 cm−1.
5-(2-Methoxyphenyl)furan-2,3-dicarbonitrile (6g). A white
solid (11 mg, 25%, yield): Rf = 0.21 (petroleum ether/ethyl acetate
= 20:1); mp 136−138 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J =
7.8 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.22 (s, 1H), 7.09 (t, J = 7.6 Hz,
1H), 7.04 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 156.6, 156.5, 132.1, 128.7, 127.0, 121.2, 115.8, 111.5, 111.4,
110.4, 109.9, 109.1, 55.7; HRMS (EI-TOF) calcd. for C13H8N2O2
[M]+ 224.0586, found 224.0587; IR (KBr) 3153, 2944, 2230, 1603,
1529, 1491, 1453, 1282, 1254, 1165, 1017, 756 cm−1.
General Procedure for Synthesis of Polysubstituted Furans
6a−6g. Carbonyl compounds (0.2 mmol) were added to a solution of
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (137 mg, 0.6 mmol) in
dry CH3CN (2 mL) at room temperature under an atmosphere of N2.
The resulting mixture was stirred under reflux until the reaction was
complete, as judged by TLC. Then the solvent was evaporated to
dryness, and the residue was purified by column chromatography on
100−200 mesh silica gel to afford pure polysubstituted furans 6a−6g.
4,5-Dihydronaphtho[1,2-b]furan-2,3-dicarbonitrile (6a). A
white solid (27 mg, 61%, yield): Rf = 0.21 (petroleum ether/ethyl
1
acetate = 10:1); mp 167−169 °C; H NMR (400 MHz, CDCl3) δ
7.58−7.56 (m, 1H), 7.37−7.31 (m, 2H), 7.30−7.27 (m, 1H), 3.09 (t, J
= 7.9 Hz, 2H), 2.90 (t, J = 7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 155.9, 136.0, 130.4, 128.9, 128.7, 127.6, 124.5, 121.3, 120.6, 109.7,
109.3, 109.0, 27.8, 19.3; HRMS (EI-TOF) calcd. for C14H8N2O [M]+
220.0637, found 220.0639; IR (KBr) 2950, 2925, 2241, 2223, 1620,
1530, 1447, 1432, 766, 714 cm−1.
Naphtho[1,2-b]furan-2,3-dicarbonitrile (6aa). A white solid (4
Preparation of Compound 3bb. A solution of carbonyl
compound 3b (39 mg, 0.2 mmol) and TEMPO (95 mg, 0.6 mmol)
in dry CH3CN (2 mL) was treated with 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) (137 mg, 0.6 mmol) at room
temperature under an atmosphere of N2. Then the resulting mixture
was stirred until the reaction was complete, as judged by TLC. The
solvent was evaporated to dryness to give 3bb (38 mg, ratio = 1:3,
mg, 10%, yield): Rf = 0.22 (petroleum ether/ethyl acetate = 10:1); mp
1
198−200 °C; H NMR (400 MHz, CDCl3) δ 8.35−8.33 (m, 1H),
8.04−8.02 (m, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.79−7.71 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 152.4, 133.8, 131.2, 128.8, 128.8, 128.4,
128.0, 120.6, 120.5, 120.4, 116.8, 109.6, 109.1, 105.4; HRMS (ESI-
TOF) calcd. for C14H7N2O [M + H]+ 219.0558, found 219.0556; IR
(KBr) 2922, 2852, 2232, 1556, 1459, 1379, 1261, 1147, 810, 756 cm−1.
7-Methoxy-4,5-dihydronaphtho[1,2-b]furan-2,3-dicarboni-
trile (6b). A white solid (20 mg, 40%, yield): Rf = 0.22 (petroleum
1
determined by H NMR spectroscopy) as a light yellow oil in 91%
yield after column chromatography (100−200 mesh silica gel,
petroleum ether/ethyl acetate = 5:1 as eluent). The observed
characterization data (1H and 13C NMR spectra, HRMS, and IR)
are consistent with that previously reported in the literature.24 Ketone:
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.7 Hz, 2H), 7.68 (t, J =
7.4 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.35 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 190.3, 183.8,
1
ether/ethyl acetate = 15:1); mp 150−152 °C; H NMR (400 MHz,
CDCl3) δ 7.51 (d, J = 8.3 Hz, 1H), 6.85−6.82 (m, 2H), 3.85 (s, 3H),
3.05 (t, J = 7.8 Hz, 2H), 2.89−2.85 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 161.4, 156.2, 138.4, 128.1, 123.0, 118.5, 117.6, 114.8, 112.5,
110.0, 109.7, 109.0, 55.5, 28.2, 19.3; HRMS (EI-TOF) calcd. for
C15H10N2O2 [M]+ 250.0742, found 250.0744; IR (KBr) 2963, 2913,
2243, 2219, 1618, 1595, 1498, 1448, 1431, 1272, 1248, 1035, 827
cm−1.
1
160.5,135.6, 131.5, 130.0, 129.2, 63.4, 13.9. Hydrate: H NMR (400
MHz, CDCl3) δ 8.07 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.44
(t, J = 7.5 Hz, 2H), 5.54 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.04 (t, J =
7.1 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 191.7, 169.9, 134.6,
131.4, 130.2, 128.8, 91.8, 63.1, 13.6; HRMS (EI-TOF) calcd. for
C11H10O4 [M]+ 206.0579, found 206.0580; IR (KBr) 3443, 2986,
1752, 1700, 1233, 1130 cm−1.
7-Methoxynaphtho[1,2-b]furan-2,3-dicarbonitrile (6bb). A
white solid (14 mg, 28%, yield): Rf = 0.23 (petroleum ether/ethyl
acetate = 15:1); mp 176−178 °C; 1H NMR (400 MHz, CDCl3) δ 8.14
(d, J = 8.9 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H),
7.35 (dd, J = 8.9, 2.3 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 3.99 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.9, 152.5, 135.7, 130.3, 126.9,
122.2, 120.4, 118.6, 117.4, 115.0, 109.7, 109.3, 107.7, 105.3, 55.6;
HRMS (EI-TOF) calcd. for C15H8N2O2 [M]+ 248.0586, found
248.0589; IR (KBr) 2937, 2229, 1634, 1598, 1474, 1461, 1370,
1266, 1249, 1169, 1028, 854, 814 cm−1.
Preparation of Methyl 4-cyano-5-(imino(methoxy)methyl)-
2-methylfuran-3-carboxylate (9). NaOMe (0.1 mL, 0.6 mmol, 30%
solution in MeOH) was added dropwise to a solution of 2,3-
dicyanofuran 2a (96 mg, 0.5 mmol) in MeOH (10 mL) at room
temperature. The mixture was stirred for 5 min. Then the solvent was
evaporated to dryness, giving 9 as a white solid after flash
chromatography 100−200 mesh silica gel (25%, ethyl acetate/
4,5,6,7-Tetrahydrobenzofuran-2,3-dicarbonitrile (6c). A col-
orless oil (9 mg, 25%, yield): Rf = 0.25 (petroleum ether/ethyl acetate
1
petroleum ether) (110 mg, 99% yield): mp 137−139 °C; H NMR
H
dx.doi.org/10.1021/jo4026034 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(400 MHz, CDCl3) δ 8.18 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 2.66 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 161.4, 157.5, 148.3,
115.3, 111.2, 97.7, 53.7, 52.3, 13.9; HRMS (EI-TOF) calcd. for
C10H10N2O4 [M]+ 222.0641, found 222.0640; IR (KBr) 3290, 2245,
1720, 1658, 1554, 1444, 1273, 1130, 1102, 979 cm−1.
Procedure for NMR Experiments. 1a (12.0 mg, 0.1 mmol) was
added to a solution of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)
(70.0 mg, 0.3 mmol) in dry CD3CN (1.0 mL) at room temperature
under an atmosphere of N2. Then the resulting mixture was stirred and
monitored by NMR spectroscopy with time.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of 1H, 13C NMR spectra of compounds 2, 4, 6, 8, 9, and
3bb, crystal data for compounds 4k (CCDC 943604), 8j
(CCDC 943606), and 9 (CCDC 943605), NMR and EPR
experiment details. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Chem., Int. Ed. 2008, 47, 7075. (e) Tu, W.; Liu, L.; Floreancig, P. E.
Angew. Chem. 2008, 120, 4252; Angew. Chem., Int. Ed. 2008, 47, 4184.
(f) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: xyluo@ecust.edu.cn.
*E-mail: weiping_deng@ecust.edu.cn.
■
́
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Fundamental Research Funds for the Central Universities,
the Shanghai Committee of Science and Technology (No.
11DZ2260600), and the National Natural Science Foundation
of China (No. 21172068) are thanked for support. W.P.D. and
J.S.F. also thank the Catalysis and Sensing for our Environment
(CASE) network and the Natural Science Foundation of China
for young foreign scientists (No. 21050110426).
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The Journal of Organic Chemistry
Article
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(14) (a) The initial results for the synthesis of 2,3-dicyanofurans has
been filed as Chinese patent application with limited substrate scope:
Deng, W.-P.; Wang, Z.-L.; Zhang, Z.-G.; Li, H.-C. CN 102516210 A,
2012. (b) One example has been reported on the formation of 2,3-
dicyanofuran as byproduct in 8% yield in the presence of DDQ:
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T.; White, A. J. P.; Witty, D.; Williams, D. J. J. Org. Chem. 2002, 67,
2735. (c) An example of similar reaction but with very limited
substrates scope from other group was just reported after our patent
application: Li, J.-S.; Xue, Y.; Li, Z.-W.; Liu, W.-D.; Lu, C.-H.; Zhao,
P.-X. Synlett 2013, 24, 2003.
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dx.doi.org/10.1021/jo4026034 | J. Org. Chem. XXXX, XXX, XXX−XXX