A Facile Synthesis of α-aryl α-oxoheterocyclic ketene N,N-acetals bearing an electron-rich catechol subunit-An electrochemical oxidative approach

Article abstract of DOI:10.1002/ejoc.200900733

Heterocyclic ketene N, N-acetals are versatile building blocks for the synthesis of nitrogen-containing heterocyclic compounds. In the present work, the anodic oxidation of catechols 2a-f in the presence of α- oxoheterocyclic ketene N, Nacetals la-d has b

Full text of DOI:10.1002/ejoc.200900733

FULL PAPER
DOI: 10.1002/ejoc.200900733
A Facile Synthesis of α-Aryl α-Oxoheterocyclic Ketene N,N-Acetals Bearing
an Electron-Rich Catechol Subunit–An Electrochemical Oxidative Approach
Cheng-Chu Zeng,*[a] Da-Wei Ping,[a] Yi-Sheng Xu,[b] Li-Ming Hu,[a] and Ru-Gang Zhong[a]
Keywords: Green chemistry / Electrochemistry / Heterocycles / Ketene N,N-acetals / Arylation reaction / Catechols /
Density functional calculations
Heterocyclic ketene N,N-acetals are versatile building
blocks for the synthesis of nitrogen-containing heterocyclic
compounds. In the present work, the anodic oxidation of cat-
echols 2a–f in the presence of α-oxoheterocyclic ketene N,N-
acetals 1a–d has been investigated using cyclic voltammetry
and controlled-potential electrolysis methods. These results
indicate that α-oxoheterocyclic ketene N,N-acetals could un-
quinones and produce α-carbon-arylated products in good
yields. This approach provides effective and “green“ access
to the synthesis of α-aryl α-oxoheterocyclic ketene N,N-ace-
tals containing an electron-rich aromatic ring. In addition,
density functional theory calculations were performed to ex-
plain the exclusive formation of α-carbon-arylated products.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
dergo Michael addition to the anodically generated o-benzo- Germany, 2009)
and amino groups. Furthermore, one molecule with two
electrophilic sites can be used to assemble a fused hetero-
Introduction
During the past decades, much attention has been paid cyclic ring in one pot. For example, α-oxoheterocyclic ket-
to the α-oxoheterocyclic ketene N,N-acetals (I, Scheme 1) ene N,N-acetals can react smoothly with alkyl halides,[3]
due to their unique structure and various applications in activated acetylenes,[4] electrophilic olefins[4] and 1,3-di-
the synthesis of nitrogen-containing heterocyclic com- poles[5] to obtain various α-carbon-alkylated products.
pounds, especially the fused heterocyclic ones.[1] Structur-
Compared to the α-carbon alkylation of α-oxohetero-
ally, α-oxoheterocyclic ketene N,N-acetals function as en- cyclic ketene N,N-acetal derivatives, few studies involving
aminones,[2] in which the electron-donating amino groups their α-carbon arylation have been carried out.[6] To the
and electron-withdrawing carbonyl groups are conjugated best of our understanding, only one successful example was
and thus, the double bond is highly polarized, leading to reported on the synthesis of a 2,4-dinitrobenzene derivative
the nucleophilicity of the α-carbon and the amino groups of an α-oxoheterocyclic ketene N,N-acetal using NaH as a
(the α- and β-carbons of the heterocyclic ketene N,N-ace- base and 2,4-dinitrohalobenzenes as the reactants
tals are marked in Scheme 1). Accordingly, two different (Scheme 1, left). In this example, two nitro groups played a
electrophiles may be introduced at the same time through key role in achieving substitution, and no other aryl groups
the respective substitution at or addition to the α-carbon with moderate electron-withdrawing or electron-donating
Scheme 1. Synthetic approach toward electron-poor (left) and electron-rich (right) α-aryl α-oxoheterocyclic ketene N,N-acetals.
[a] College of Life Science & Bioengineering, Beijing University of
Technology,
Beijing 100124, P. R. China
groups succeeded. Therefore, it is highly desirable to seek a
complementary approach to obtain some α-aryl α-oxo-
heterocyclic ketene N,N-acetals bearing electron-rich
groups, such as catechol analogues (Scheme 1, right).
Fax: +86-10-67392001
E-mail: zengcc@bjut.edu.cn
[b] Atmospheric Chemistry & Aerosol Research Department, Chi-
nese Research Academy of Environmental Sciences,
Beijing 100012, P. R. China
5832
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α-Aryl α-Oxoheterocyclic Ketene N,N-Acetals
As part of our continuous efforts towards the electro- chol to the corresponding o-benzoquinone and vice versa.
chemical synthesis of polyhydroxylated aromatics as poten- The ratio of the current amplitudes between the oxidation
tial HIV-1 integrase inhibitors, we have investigated the and reduction processes was equal to unity (Ipox/Ipred), indi-
electrochemical oxidation of catechols in the presence of cating that the o-benzoquinone produced at the surface of
nucleophiles and synthesized a variety of heterocyclic sub- the electrode was stable in pH = 7 acetate buffer and that
stituted catechols.[7] With this rationale in mind and in view side reactions such as hydroxylation or dimerization were
of the nucleophilicity of the α-carbon of α-oxoheterocyclic too slow to be observed on the time scale of the cyclic vol-
ketene N,N-acetals, we hypothesized that the electrochemi- tammetry.[9] When we added 1 equiv. of α-oxoheterocyclic
cally in-situ-generated o-benzoquinones may be used as ketene N,N-acetal 1a, the voltammogram of 4-methylcat-
Michael addition acceptors and react with α-oxohetero- echol exhibited one anodic peak (A1) at +0.36 V vs. Ag/
cyclic ketene N,N-acetals to synthesize α-aryl α-oxohetero- AgCl (3 ), whereas the cathodic counterpart of the anodic
cyclic ketene N,N-acetals containing an electron-rich aro- peak A1 decreased (curve c, Figure 1). Moreover, the ratio
matic ring. The present work demonstrates that α-aryl α- of the anodic current to the cathodic current (Ipox/Ipred) of
oxoheterocyclic ketene N,N-acetals incorporating a cate- the mixture of 4-methylcatechol and 1a decreased with in-
chol subunit can be synthesized in good to high yields using creasing potential sweep rate (Figure 2). Curve b in Figure 1
this electrochemical approach. This protocol provides an ef- is the CV of α-oxoheterocyclic ketene N,N-acetal 1a, where
ficient way to obtain α-aryl α-oxoheterocyclic ketene N,N- two irreversible anodic waves at 0.70 V and 1.17 V were ob-
acetals containing electron-rich aromatic rings.
served. In addition, the positive anodic shifts of the anodic
It is worth noting that the reaction between p-benzoqui- A1 peak (0.36 V vs. 0.30 V) in the presence of 1a we attrib-
none and an α-oxoheterocyclic ketene N,N-acetal was pre- uted to the formation of a thin film of product at the sur-
viously reported using a conventional chemical approach. face of the electrode, inhibiting to a certain extent the per-
However, a 5-hydroxyindole derivative was formed in 9% formance of the electrode process.[9a–9d]
yield, instead of the expected Michael addition product
(Scheme 2).[8]
Scheme 2. Reaction of α-oxoheterocyclic ketene N,N-acetals and p-
benzoquinone.
Results and Discussion
Electrochemical Investigation of Catechols in the Absence
Figure 1. CVs of a) 2 m 4-methylcatechol (2a), b) 2 m α-oxo-
or Presence of α-Oxoheterocyclic Ketene N,N-Acetals by
heterocyclic ketene N,N-acetal 1a and c) a mixture of 2 m 2a and
Cyclic Voltammetry
2 m 1a with a glassy carbon working electrode, a platinum wire
counter and Ag/AgCl reference electrodes in 2:1 (v/v) acetate
buffer/acetonitrile (0.2 , pH = 7) at a scan rate of 50 mV/s.
Before we performed the electrochemical coupling reac-
tion of electron-rich aromatics and α-oxoheterocyclic ketene
N,N-acetals, we needed to first study the electrochemical
properties of the starting materials. Taking 4-methylcate-
On the basis of the CVs described above for catechols in
chol (2a) as a example, we investigated the electrochemical the absence or presence of α-oxoheterocyclic ketene N,N-
behavior of catechols 2 by cyclic voltammetry (CV) in the acetals, we assumed that a chemical step occurred between
absence or presence of α-oxoheterocyclic ketene N,N-ace- the electrochemically generated o-benzoquinone (at A) and
tals 1 at room temperature in water containing 0.2  acetate the α-oxoheterocyclic ketene N,N-acetals 1, and therefore,
buffer (pH = 7.0) as the supporting electrolyte. Due to the Michael addition products may be synthesized upon the an-
poor solubility of α-oxoheterocyclic ketene N,N-acetals in odic oxidation of a mixture of a catechol and a α-oxohetero-
water, we added acetonitrile as a cosolvent.
cyclic ketene N,N-acetal 1 when the electrolysis potential
As shown in Figure 1, upon scanning anodically, 4-meth- is controlled by modulating the anodic potentials of the
ylcatechol exhibited a well-defined quasireversible oxi- corresponding catechols. We hypothesized that the unde-
dation wave (peak A) at +0.30 V vs. Ag/AgCl (3 ) and a sired oxidation of α-oxoheterocyclic ketene N,N-acetals
corresponding cathodic peak (C) at +0.08 V vs. Ag/AgCl would not take place due to their significantly higher an-
(3 ), which we attributed to the oxidation of 4-methylcate- odic potentials.
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C.-C. Zeng, D.-W. Ping, Y.-S. Xu, L.-M. Hu, R.-G. Zhong
FULL PAPER
Scheme 3. Anodic oxidation of catechols 2 and α-oxoheterocyclic
ketene N,N-acetals 1.
Subsequently, we applied the reaction to 3-substituted
catechols such as 3-methoxycatechol (2d), 3-methylcatechol
(2e) and catechol (2f) with a view to investigate the scope of
the reaction. In a similar way, we performed electrochemical
oxidation of 2d and 2e in the presence of 1a and obtained
the expected products 3d and 3e in 36 and 27% yield,
respectively (Table 1, Entries 4 and 5). In the case of cate-
chol itself, no solid precipitated, although TLC showed a
major product formed in the electrolytic solution. Upon
modification of the electrolytic component (the volume ra-
tio of acetate buffer to acetonitrile), the desired 3f precipi-
tated, and we isolated a 21% yield after simple filtration.
Obviously, the chemical yields in the cases of 2d–f were a
little lower than those of 4-substituted catechols 2a–c.
In order to demonstrate the versatility of the reaction, we
turned our studies to other α-oxoheterocyclic ketene N,N-
acetals. Thus, the electrochemical oxidation of 4-methylcat-
echol (2a) in the presence of 2-(p-methylbenzoylmethylene)-
imidazolidine (1b), 2-(p-methoxybenzoylmethylene)imid-
azolidine (1c) and 2-(p-chlorobenzoylmethylene)imidazolid-
ine (1d) also proceeded smoothly under the previously de-
scribed conditions, yielding the desired 3g–i in respective
73%, 50% and 79% yields (Table 1, Entries 7–9). We also
obtained similar results when we electrochemically oxidized
caffeic acid (2c), 3-methoxycatechol (2d) or 4-tert-butylcat-
echol in the presence of 1b–d, and we isolated the corre-
sponding α-arylated heterocyclic ketene N,N-acetals 3j–o in
moderate to high yields (Table 1, Entries 10–15).
Figure 2. Top: CVs of a mixture of 2 m 2a and 2 m 1a at a scan
rate of: a) 20 mV/s, b) 50 mV/s, c) 100 mV/s, d) 300 mV/s and e)
500 mV/s. Bottom: variation of peak current ratio Ipox/Ipred vs. scan
rate.
Electrochemical Synthesis of 3a–o
We determined the structures of 3a–o by using 1H NMR,
13C NMR, IR and ESI-MS. Taking 3a as an example, its
1H NMR spectrum exhibited one singlet at δ = 1.85 ppm,
which we attributed to the methyl group. The two singlets
at δ = 6.37 and 6.45 ppm are the signals of the two aromatic
protons of the catechol unit. The two OH proton signals of
the catechol unit were located at δ = 8.40 and 8.47 ppm,
respectively. Interestingly, the two N–H groups were quite
different, as one N–H resonated at δ = 5.97 ppm, while the
other resonated at δ = 10.05 ppm due to its intramolecular
H-bonding with the neighboring carbonyl group. The 13C
NMR spectrum of 3a exhibited 18 signals.
We employed controlled-potential electrolysis (CPE) in a
divided cell to perform the α-carbon arylation of α-oxohet-
erocyclic ketene N,N-acetals, and the results are summa-
rized in Table 1. As shown in Table 1 and Scheme 3, accord-
ing to our reported conditions,[7] we electrolyzed an equiva-
lent amount of 4-methylcatechol (2a) and α-oxoheterocyclic
ketene N,N-acetal 1a at a controlled potential of 0.3 V vs.
Ag wire in acetate buffer. During the reaction, the solution
turned from yellow to brown, and a white powder precipi-
tated. After 4-methylcatechol was consumed (the passed
charge was approximately 2.5 F/mol), we filtered the re-
sulting powder, washed it with water and characterized it
as the desired 3a in 79% yield on the basis of its spectral
and analytical data (Table 1, Entry 1).
Reaction Mechanism
When we subjected 4-tert-butylcatechol (2b) and caffeic
As the reaction mechanism is concerned, it is well docu-
acid (2c) to anodic oxidation in the presence of 1a under mented[9] that the anodic oxidation of catechol and its de-
the same conditions, we achieved the desired products 3b rivatives in an aqueous medium leads to the formation of
and 3c in 50% and 48% yield, respectively (Table 1, Entries the corresponding o-benzoquinone intermediates. These in-
2 and 3).
termediates are converted to other intermediates or prod-
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α-Aryl α-Oxoheterocyclic Ketene N,N-Acetals
Table 1. Electrochemical synthesis of α-aryl α-oxoheterocyclic ketene N,N-acetals containing a catechol subunit.
[a] The yield increased to 82% after 2.24 F/mol of charge was passed through the mixture when the CPE was carried out at 0 °C instead
of room temperature (about 25 °C).
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C.-C. Zeng, D.-W. Ping, Y.-S. Xu, L.-M. Hu, R.-G. Zhong
We note that very recently, we electrolyzed a mixture of
FULL PAPER
ucts, following a pattern of an EC or an ECEC mechanism,
depending on the nature of the nucleophiles and structures catechol derivatives 2 and α-oxoheterocyclic ketene N,O-
of the starting catechols. Accordingly, it is safe to speculate acetals 6 (the analogues of N,N-acetals 1) and achieved the
that the α-arylation of α-oxoheterocyclic ketene N,N-acetals one-pot electrochemical synthesis of fused indole deriva-
to generate products 3 also follows a similar mechanism. As tives 7 and 8 in the range of 37–71% yields (Scheme 5).[10]
illustrated in Scheme 4, the initial step is an electrochemical This reaction may involve the over oxidation of the initially
process that involves the oxidation of catechols 1 on the formed intermediates followed by enamine-imine tauto-
anodic electrode surface and generates the corresponding o- merization, imine-enamine tautomerization, intramolecular
benzoquinones. Subsequently, a chemical reaction in the Michael addition and aromatization. Similarly, compounds
bulk electrolytic solution occurs, wherein the active o- of type 3 are typical catechol derivatives, with oxidation po-
benzoquinone intermediates undergo a Michael addition to tentials close to that of the starting catechols 2, (such as
the α-carbon of the α-oxoheterocyclic ketene N,N-acetals 1 0.30 V for 1a and 0.35 V for 3a vs. Ag/AgCl, Figure 3).
followed by aromatization, leading to products 3.
Therefore, over oxidation and further intramolecular
Michael addition may also occur and cause the formation
of corresponding indole derivatives. However, we observed
the exclusive formation of α-aryl α-oxoheterocyclic ketene
N,N-acetals 3. Their selective formation may have resulted
from the poor solubility of products 3a–o in the given elec-
trolytic system, which prevented their over oxidation, al-
though the nature of the starting α-oxoheterocyclic ketene
acetals (N,N-acetal or N,O-acetal) may also have played a
key role.[11]
Figure 3. CVs of (a) 2 m 4-methylcatechol (2a) and (b) 2 m 3a
with a glassy carbon working electrode, a platinum wire counter
and Ag/AgCl reference electrodes in 1:1 (v/v) acetate buffer/aceto-
nitrile (0.2 , pH = 7) at a scan rate of 50 mV/s.
Scheme 4. A plausible mechanism for the reaction between cat-
echols 2 and heterocyclic ketene N,N-acetals 1.
Scheme 5. One-pot synthesis of fused indole derivatives from catechols and α-oxoheterocyclic ketene N,O-acetals.
5836 Eur. J. Org. Chem. 2009, 5832–5840
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α-Aryl α-Oxoheterocyclic Ketene N,N-Acetals
Scheme 6. The possible reaction products of 1a in the presence of 2.
We noted that the asymmetry of 3-substituted catechols, Table 2. APT charges of selected atoms in 1a–d, 2dЈ and 2eЈ.
such as 3-methoxycatechol and 3-methylcatechol, may
En-
try
C-4
C-5
C-6
N-1
N-2
C-7
cause the formation of two isomers because the nucleophilic
attack of the α-carbon of α-oxoheterocyclic ketene N,N-
acetals upon the electrochemically generated 3-substituted
o-benzoquinone may take place at the C-5 or C-4 of the
benzene ring, leading to 3 or their isomers 4, respectively
(Scheme 6).[10] In our case, we introduced the α-oxohetero-
cyclic ketene N,N-acetal subunits in the C-5 position of the
catechol scaffold, which led exclusively to products 3d and
3e.
1
2
3
4
5
6
2dЈ
2eЈ
1a
1b
1c
–0.275 0.351 –0.313
–0.018 0.166 –0.217
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–0.793 –0.801
–0.805 –0.811
–0.224 –0.198
–0.803 –0.814
–1.020
–1.041
–0.396
–1.052
1d
In order to further elucidate these results, we performed
density functional theory (DFT) calculations [using B3LYP/
6-311+g(d,p) base] of atomic polar tensor (APT) charges of
1a–d and electro-generated intermediates 2dЈ and 2eЈ (Fig-
ure 4). As shown in Table 2, the APT charge of C-5 in 2dЈ
and 2eЈ were 0.351 and 0.166, respectively. These values
were higher than those of C-4 (–0.275 for 2dЈ and –0.018
for 2eЈ), which indicated that α-oxoheterocyclic ketene N,N-
acetals 1a–d were easily introduced at the C-5 position of
the catechol scaffolds by nucleophilic attack. The steric hin-
drance of C-4 may also have played a key role in controlling
the generation of regioisomers 4d and 4e. Both factors led
to the exclusive formation of 3 instead of 4.
in Table 2, the α-carbon of heterocyclic ketene N,N-acetals
exhibited a higher atomic charge than that of the two amino
groups (N-1 and N-2). For example, the APT charge of C-
7 of 1a was –1.020; however, the APT charges of N-1 and
N-2 were –0.793 and –0.801, respectively. Therefore, we ex-
clusively formed C-substituted compounds.
Conclusion
In summary, the electrochemical behavior of catechols 2
in the absence or presence of α-oxoheterocyclic ketene N,N-
acetals 1 have been investigated by CV. The CVs of the cate-
chols exhibited one well-defined oxidation wave and a cor-
responding cathodic peak. However, when 1 equiv. of 1 was
added, the cathodic wave disappeared or decreased de-
pending on the nature of the initial substituent on the cat-
echol ring. Based on relative CVs data, the anodic oxidation
of catechols 2 in the presence of α-oxoheterocyclic ketene
N,N-acetals 1 were conducted to synthesize α-aryl ketene
N,N-acetals 3 in moderate to good yields. Thus, this process
provides an alternative access to α-aryl α-oxoheterocyclic
ketene N,N-acetals containing a catechol subunit. The poor
solubility of the products may have been responsible for
their selective formation. In addition, DFT calculations
were performed to explain the exclusive formation of α-car-
Figure 4. Atomic labeling of selective atoms.
The DFT calculation results also shed light on the for- bon-arylated products. Such reactions further demonstrates
mation of α-carbon-substituted derivatives of α-oxohetero- that the anodic oxidation of catechol derivatives and their
cyclic ketene N,N-acetals 1, forming C-substituted 3 instead in-situ transformation can be utilized to synthesize a library
of the corresponding N-substituted 5 (Scheme 6). As shown of polyhydroxylated aromatics.
Eur. J. Org. Chem. 2009, 5832–5840
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C.-C. Zeng, D.-W. Ping, Y.-S. Xu, L.-M. Hu, R.-G. Zhong
FULL PAPER
2-[Benzoyl(4,5-dihydroxy-2-tert-butylphenyl)methylene]imidazolid-
ine (3b): Yield 50 % (352 mg); m.p. 256 °C (dec.). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.02 [s, 9 H, C(CH3)3], 3.28–3.36 (m,
2 H, CH2), 3.62–3.66 (m, 2 H, CH2), 5.78 (br. s, 1 H, NH), 6.45 (s,
1 H, ArH), 6.74 (s, 1 H, ArH), 7.02–7.20 (m, 3 H, ArH), 7.22 (dd,
J = 8.4, 1.2 Hz, 2 H, ArH), 8.55 (s, 1 H, OH), 8.60 (s, 1 H, OH),
10.22 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 32.5, 36.0, 42.8, 44.2, 94.1, 116.3, 123.8, 126.7, 127.1, 128.0,
Experimental Section
Instruments and Reagents: CVs were measured with a 273A po-
tentiostat/galvanostat equipped with electrochemical analysis soft-
ware and a conventional three-electrode cell. The working electrode
was a glassy carbon disk electrode (Ø ≈ 3 mm). The auxiliary and
reference electrodes in these studies were Pt wire and saturated Ag/
AgCl, respectively. The glassy carbon was polished with polishing
cloth before each measurement. All electrodes for CV experiments
were from CH Instruments, Inc., USA. Acetate buffer was prepared
with NaAc and HOAc and monitored by a digital pH meter. The
scan rate was 50 mV/s. The concentration of 1 and 2 were 2 m,
while that of the supporting electrolyte was 0.2 .
128.9, 140.9, 143.0, 143.8, 144.3, 165.9, 182.2 ppm. IR (KBr): ν =
˜
3456, 3961, 1587, 1574, 1525, 1476 cm–1. ESI-MS: m/z = 353.1 [M
+ 1]+, 350.8 [M – 1]–, 702.4 [2M – 1]–.
(E)-3-[4,5-Dihydroxy-2-(1-imidazolidin-2-ylidene)-2-oxo-2-phenyl-
ethyl]phenylacrylic Acid (3c): Yield 48% (351 mg); m.p. 196–197 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 3.35–3.68 (m, 4 H,
NCH2CH2N), 5.87 (d, J = 16.0 Hz, 1 H, CH=CH), 6.19 (br. s, 1
H, NH), 6.48 (s, 1 H, ArH), 6.95–7.07 (m, 6 H, ArH), 7.54 (d, J =
16.0 Hz, 1 H, CH=CH), 10.04 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 42.8, 44.1, 88.8, 113.1, 114.8, 121.1,
126.5, 127.3, 127.8, 132.4, 143.8, 144.0, 144.9, 148.3, 165.2, 168.6,
For controlled-potential electrolysis (CPE), a 100 mL, H-type cell
was equipped with a medium glass frit as a membrane. The anode
compartment contained an assembly of seven graphite rods as the
anode; the upper rims of the rods were wrapped with a copper wire,
and a polished silver wire was the quasireference electrode, which
was immersed in electrolyte solution in a glass cylinder with a fine
glass frit at its end. A platinum plate (2 cm2) as the counter elec-
trode was immersed in the cathode compartment. The applied po-
tential throughout CPE was 0.30 V vs. Ag wire and controlled by
the 273A potentiostat/galvanostat. The passed charge for each ex-
periment was recorded on a computer. During electrolysis, the mix-
ture was stirred magnetically.
185.2 ppm. IR (KBr): ν = 3520, 3429, 3298, 1591, 1529, 1474 cm–1.
˜
ESI-MS: m/z = 366.9 [M + 1]+, 388.8 [M + Na]+, 405.0 [M +
K]+, 364.8 [M – 1]–, 730.9 [2M – 1]–.
2-[Benzoyl(3,4-dihydroxy-5-methoxyphenyl)methylene]imidazolidine
1
(3d): Yield 36% (234 mg); m.p. 210–211 °C. H NMR (400 MHz,
[D6]DMSO): δ = 3.32–3.63 (m, 4 H, NCH2CH2N), 3.51 (s, 3 H,
OCH3), 6.01 (d, J = 2.0 Hz, 1 H, ArH), 6.07 (d, J = 2.0 Hz, 1 H,
ArH), 6.30 (br. s, 1 H, NH), 7.06–7.08 (m, 5 H, ArH), 7.91 (br. s,
1 H, OH), 8.53 (br. s, 1 H, OH), 10.05 (br. s, 1 H, NH) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 39.9, 40.6, 56.0, 92.7, 108.7,
113.5, 127.3, 127.7, 128.2, 129.1, 132.5, 144.4, 145.7, 148.3, 165.4,
All melting points were measured with a XT4A Electrothermal
melting point apparatus and are uncorrected. IR spectra were re-
corded as KBr pellets. 1H and 13C NMR spectra were recorded
with an AV 400M Bruker spectrometer (400 MHz 1H frequency
and 100 MHz 13C frequency). Chemical shifts are given as δ values
(internal standard: TMS). The MS spectra (ESI) were recorded
with a Bruker esquire 6000 mass spectrometer.
185.2 ppm. IR (KBr): ν = 3373, 2963, 2934, 1585, 1573, 1543, 1519,
˜
1460 cm–1. ESI-MS: m/z = 326.9 [M + 1]+, 348.9 [M + Na]+, 324.7
[M – 1]–, 650.8 [2M – 1]–.
Catechols 2a–e were of reagent-grade, purchased from Alfa Aesar,
China (Tianjin) Co., Ltd. Compounds 1a–d were synthesized ac-
cording to ref.[12] Other chemicals and solvents were from Beijing
Chemicals Co. and used without further purification. Doubly dis-
tilled deionized water was used for the preparation of the acetate
buffer. All experiments were performed at room temperature and
ambient pressure.
2-[Benzoyl(3,4-dihydroxy-5-methylphenyl)methylene]imidazolidine
(3e): Yield 27% (167 mg); m.p. 247 °C (dec.). 1H NMR (400 MHz,
[D6]DMSO): δ = 1.92 (s, 3 H, CH3), 3.40–3.59 (br. m, 4 H,
NCH2CH2N), 6.17 (br. s, 1 H, NH), 6.23 (d, J = 1.6 Hz, 1 H,
ArH), 6.25 (d, J = 1.6 Hz, 1 H, ArH), 7.04–7.13 (m, 5 H, ArH),
7.89 (br. s, 1 H, OH), 8.84 (br. s, 1 H, OH), 10.07 (br. s, 1 H, NH)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 16.6, 39.9, 40.6, 92.5,
117.8, 124.3, 125.7, 127.3, 127.7, 128.4, 129.2, 141.7, 144.2, 144.8,
General Procedure for the Synthesis of 3a–o: In a typical procedure,
a mixture of acetate buffer (50 mL, pH = 6) and acetonitrile
(12 mL) was pre-electrolyzed at the chosen potential (0.30 V vs. Ag
wire) in the H-type divided cell, which was kept in water at room
temperature for 10 min (to remove impurities present in the electro-
lytic system). Subsequently, a catechol 2 (2 mmol) and a α-oxohet-
erocyclic ketene N,N-acetal 1 (2 mmol) were added to the anodic
compartment, and electrolysis was continued. The electrolysis was
terminated when the starting 2 was consumed (as determined by
TLC). The passed charge was in the range of 2.3–3.5 F/mol. After
electrolysis, the pH was adjusted to 7 with a few drops of acetic
acid, and the precipitate was filtered and washed with water.
165.6, 184.7 ppm. IR (KBr): ν = 3439, 1585, 1541, 1476 cm–1. ESI-
˜
MS: m/z = 310.9 [M + 1]+, 332.8 [M + Na]+, 308.7 [M – 1]–, 619.0
[2M – 1]–.
2-[Benzoyl(3,4-dihydroxyphenyl)methylene]imidazolidine (3f): Yield
21 % (124 mg); m.p. 247 °C (dec.). 1H NMR (400 MHz, [D6]-
DMSO): δ = 3.42–3.57 (br. m, 4 H, NCH2CH2N), 6.22 (br. s, 1 H,
NH), 6.25 (d, J = 8.0 Hz, 2 H, ArH), 6.40 (s, J = 1.2 Hz, 1 H,
ArH), 6.50 (d, J = 8.0 Hz, 2 H, ArH), 7.07 (s, 5 H, ArH), 8.57 (br.
s, 2 H, OH), 10.06 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 39.9, 40.6, 92.4, 115.9, 120.3, 124.0, 127.3, 127.7,
128.4, 130.0, 143.6, 144.2, 145.1, 165.5, 184.9 ppm. IR (KBr): ν =
˜
3435, 1584, 1538, 1478 cm–1. ESI-MS: m/z = 296.8 [M + 1]+, 318.8
[M + Na]+, 294.6 [M – 1]–, 590.9 [2M – 1]–.
2-[Benzoyl(4,5-dihydroxy-2-methylphenyl)methylene]imidazolidine
1
(3a): Yield 79% (489 mg); m.p. 245 °C (dec.). H NMR (400 MHz,
[D6]DMSO): δ = 1.85 (s, 3 H, CH3), 3.33 (t, J = 7.6 Hz, 2 H, CH2),
2-[(4-Methylbenzoyl)(4,5-dihydroxy-2-methylphenyl)methylene]imid-
3.67 (s, J = 7.6 Hz, 2 H, CH2), 5.97 (br. s, 1 H, NH), 6.37 (s, 1 H, azolidine (3g): Yield 73 % (473 mg); m.p. 192–193 °C. 1H NMR
ArH), 6.45 (s, 1 H, ArH), 7.06–7.08 (m, 5 H, ArH), 8.40 (s, 1 H, (400 MHz, [D6]DMSO): δ = 1.84 (s, 3 H, CH3), 2.18 (s, 3 H, CH3),
OH), 8.47 (s, 1 H, OH), 10.05 (br. s, 1 H, NH) ppm. 13C NMR 3.34 (t, J = 7.6 Hz, 2 H, CH2), 3.65 (t, J = 7.6 Hz, 2 H, CH2), 5.91
(100 MHz, [D6]DMSO): δ = 19.6, 39.4, 39.8, 90.5, 117.6, 121.0,
(br. s, 1 H, NH), 6.37 (s, 1 H, ArH), 6.46 (s, 1 H, ArH), 6.85 (d, J
= 8.0 Hz, 2 H, ArH), 6.98 (d, J = 8.0 Hz, 2 H, ArH), 8.40 (s, 1 H,
127.2, 127.8, 127.9, 128.5, 129.2, 143.1, 144.2, 165.4, 184.43 ppm.
IR (KBr): ν = 3404, 3107, 2899, 1590, 1575, 1526, 1477 cm–1. ESI- OH), 8.47 (s, 1 H, OH), 10.06 (br. s, 1 H, NH) ppm. 13C NMR
˜
MS: m/z = 311.0 [M + 1]+, 308.7 [M – 1]–.
(100 MHz, [D6]DMSO): δ = 19.6, 21.2, 42.8, 44.1, 90.4, 117.7,
5838
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5832–5840

α-Aryl α-Oxoheterocyclic Ketene N,N-Acetals
121.0, 127.8, 128.0, 128.7, 129.1, 137.1, 141.4, 143.1, 144.2, 165.3,
NMR (400 MHz, [D6]DMSO): δ = 3.58 (s, 3 H, OCH3), 3.67 (s, 3
184.4 ppm. IR (KBr): ν = 3430, 2920, 1587, 1522, 1475, 1454 cm–1. H, OCH3), 3.33–3.67 (br. m, 4 H, NCH2CH2N), 6.08 (s, 1 H, ArH),
˜
ESI-MS: m/z = 325.1 [M + 1]+, 347.0 [M + Na]+, 322.7 [M – 1]–.
6.09 (s, 1 H, ArH), 6.22 (br. s, 1 H, NH), 6.64 (d, J = 8.8 Hz, 2 H,
ArH), 7.10 (d, J = 8.8 Hz, 2 H, ArH), 7.97 (br. s, 1 H, OH), 8.59
(br. s, 1 H, OH), 10.09 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 39.9, 40.6, 55.4, 56.1, 92.5, 108.5, 112.5, 113.6,
129.5, 130.1, 132.6, 136.5, 145.8, 148.4, 159.1, 165.4, 184.2 ppm.
2-[(4-Methoxybenzoyl)(4,5-dihydroxy-2-methylphenyl)methylene]-
imidazolidine (3h): Yield 50 % (340 mg); m.p. 200 °C (dec.). 1H
NMR (400 MHz, [D6]DMSO): δ = 1.85 (s, 3 H, CH3), 3.66 (s, 3
H, OCH3), 3.48–3.83 (br. m, 4 H, NCH2CH2N), 5.97 (br. s, 1 H,
NH), 6.39 (s, 1 H, ArH), 6.49 (s, 1 H, ArH), 6.61 (d, J = 8.8 Hz,
2 H, ArH), 7.07 (d, J = 8.8 Hz, 2 H, ArH), 8.45 (br. s, 1 H, OH),
8.50 (br. s, 1 H, OH), 10.08 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 19.6, 39.9, 40.6, 55.3, 90.3, 112.5,
117.8, 120.9, 128.8, 129.1, 129.7, 136.4, 143.2, 144.2, 159.2, 165.4,
IR (KBr): ν = 3439, 3386, 2964, 2934, 1605, 1590, 1573, 1522, 1480
˜
cm–1. ESI-MS: m/z = 356.9 [M + 1]+, 354.8 [M – 1]–, 710.9 [2M –
1]–.
2-[(4-Chlorobenzoyl)(3,4-dihydroxy-5-methoxyphenyl)methylene]-
imidazolidine (3n): Yield 81% (583 mg); m.p. 243–244 °C (dec.). 1H
NMR (400 MHz, [D6]DMSO): δ = 3.56 (s, 3 H, OCH3), 3.51–3.61
(br. m, 4 H, NCH2CH2N), 6.05 (d, J = 2.0 Hz, 1 H, ArH), 6.07 (d,
J = 2.0 Hz, 1 H, ArH), 6.40 (br. s, 1 H, NH), 7.11 (d, J = 8.8 Hz,
2 H, ArH), 7.15 (d, J = 8.8 Hz, 2 H, ArH), 7.98 (br. s, 1 H, OH),
8.59 (br. s, 1 H, OH), 10.02 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 39.9, 40.6, 56.1, 92.8, 108.6, 113.6,
127.3, 128.7, 130.1, 132.3, 132.7, 143.1, 145.8, 148.4, 165.4, 183.4
183.5 ppm. IR (KBr): ν = 3435, 2966, 1583, 1535, 1475 cm–1. ESI-
˜
MS: m/z = 340.9 [M + 1]+, 338.8 [M – 1]–, 678.9 [2M – 1]–.
2-[(4-Chlorobenzoyl)(4,5-dihydroxy-2-methylphenyl)methylene]imid-
azolidine (3i): Yield 79 % (543 mg); m.p. 242–244 °C (dec.). 1H
NMR (400 MHz, [D6]DMSO): δ = 1.85 (s, 3 H, CH3), 3.35 (s, 3
H, OCH3), 3.35 (br. s, 2 H, NCH2CH2N), 3.69 (br. s, 2 H,
NCH2CH2N), 6.07 (br. s, 1 H, NH), 6.37 (s, 1 H, ArH), 6.48 (s, 1
H, ArH), 7.06 (d, J = 8.8 Hz, 2 H, ArH), 7.12 (d, J = 8.8 Hz, 2 H,
ArH), 8.45 (br. s, 1 H, OH), 8.54 (br. s, 1 H, OH), 10.00 (br. s, 1
H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 19.6, 39.9,
40.6, 90.6, 117.7, 121.0, 127.3, 128.1, 129.1, 129.8, 132.4, 143.0,
ppm. IR (KBr): ν = 3514, 3365, 1586, 1583 cm–1. ESI-MS: m/z =
˜
360.9 [M + 1]+, 358.6 [M – 1]–.
2-[(4-Methylbenzoyl)(4,5-dihydroxy-5-tert-butylphenyl)methylene]-
imidazolidine (3o): Yield 25% (183 mg); m.p. 244–246 °C (dec.). 1H
NMR (400 MHz, [D6]DMSO): δ = 1.03 [s, 9 H, (CH3)3], 2.17 (s, 3
H, CH3), 3.27–3.67 (m, 4 H, NCH2CH2N), 5.72 (br. s, 1 H, NH),
6.43 (s, 1 H, ArH), 6.75 (s, 1 H, ArH), 6.85 (d, J = 8.8 Hz, 2 H,
ArH), 7.11 (d, J = 8.8 Hz, 2 H, ArH), 8.54 (br. s, 1 H, OH), 8.59
(br. s, 1 H, OH), 10.22 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 21.1, 32.4, 36.0, 39.9, 40.6, 94.0, 116.3, 123.8,
127.0, 127.7, 129.0, 137.3, 140.9, 1401.0, 143.0, 144.2, 165.84, 182.1
143.3, 144.4, 165.4, 182.8 ppm. IR (KBr): ν = 3248, 1638, 1582
˜
cm–1. ESI-MS: m/z = 344.7 [M + 1]+, 342.7 [M – 1]–.
(E)-3-{4,5-Dihydroxy-2-[1-(imidazolidin-2-ylidene)-2-oxo-2-p-
tolylethyl]phenyl}acrylic Acid (3j): Yield 52% (395 mg); m.p. 195–
1
196 °C. H NMR (400 MHz, [D6]DMSO): δ = 2.13 (s, 3 H, CH3),
3.31–3.64 (m, 4 H, NCH2CH2N), 5.86 (d, J = 15.6 Hz, 1 H,
CH=CH), 6.12 (br. s, 1 H, NH), 6.44 (s, 1 H, ArH), 6.81 (d, J =
8.0 Hz, 2 H, ArH), 6.87 (d, J = 8.0 Hz, 2 H, ArH), 6.99 (s, 1 H,
ArH), 7.51 (d, J = 16.0 Hz, 1 H, CH=CH), 10.02 (br. s, 1 H, NH)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 21.2, 42.8, 44.1, 88.7,
113.2, 114.9, 121.1, 126.5, 126.6, 127.9, 128.9, 132.6, 137.1, 141.2,
ppm. IR (KBr): ν = 3435, 2955, 1706, 1582, 1532 cm–1. ESI-MS:
˜
m/z = 367.0 [M + 1]+, 364.9 [M – 1]–.
Acknowledgments
143.8, 144.9, 148.3, 165.2, 168.6 ppm. IR (KBr): ν = 3419, 1586,
˜
1529, 1474 cm–1. ESI-MS: m/z = 380.7 [M + 1]+, 379.0 [M – 1]–,
759.0 [2M – 1]–.
The authors thank Drs. L.-J. Huang and H.-W. Zhao for reviewing
the manuscript. This work was supported by Grants from the
National Natural Science Foundation of China (No. 20772010), the
National Basic Research Program of China (No. 2009CB930200)
and the Beijing Novel Project (No. 2005B10).
(E)-3-{4,5-Dihydroxy-2-[1-(imidazolidin-2-ylidene)-2-(4-methoxy-
phenyl)-2-oxoethyl]phenyl}acrylic Acid (3k): Yield 52% (411 mg);
1
m.p. 198–200 °C. H NMR (400 MHz, [D6]DMSO): δ = 3.33–3.67
(m, 4 H, NCH2CH2N), 3.65 (s, 3 H, OCH3), 5.90 (d, J = 16.0 Hz,
1 H, CH=CH), 6.08 (br. s, 1 H, NH), 6.48 (s, 1 H, ArH), 6.59 (d,
J = 8.8 Hz, 2 H, ArH), 6.98 (d, J = 8.8 Hz, 2 H, ArH), 7.52 (d, J
= 16.0 Hz, 1 H, CH=CH), 10.07 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 42.8, 44.1, 55.3, 88.6, 112.6, 113.3,
115.0, 121.0, 126.5, 129.7, 132.7, 136.2, 143.8, 144.9, 148.4, 159.1,
[1] For a review of the synthesis and application of heterocyclic
ketene N,N-acetals, see: a) H. Junjappa, H. ILa, C. V. Asokan,
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165.2, 168.6, 184.3 ppm. IR (KBr): ν = 3427, 1601, 1574, 1525,
˜
1475 cm–1. ESI-MS: m/z = 396.9 [M + 1]+, 418.9 [M + Na]+, 435.0
[M + K]+, 394.7 [M – 1]–, 790.9 [2M – 1]–.
2-[(4-Methylbenzoyl)(3,4-dihydroxy-5-methoxyphenyl)methylene]-
imidazolidine (3l): Yield 75 % (510 mg); m.p. 245 °C (dec.). 1H
NMR (400 MHz, [D6]DMSO): δ = 2.18 (s, 3 H, CH3), 3.40–3.61
(m, 4 H, NCH2CH2N), 3.56 (s, 3 H, OCH3), 6.06 (s, 2 H, ArH),
6.25 (br. s, 1 H, NH), 6.88 (d, J = 8.0 Hz, 2 H, ArH), 7.02 (d, J =
8.0 Hz, 2 H, ArH), 7.93 (br. s, 1 H, OH), 8.55 (br. s, 1 H, OH),
10.08 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 21.2, 39.9, 40.6, 56.0, 92.7, 108.7, 113.6, 127.8, 128.3, 129.3,
132.6, 137.0, 141.5, 145.7, 148.3, 165.3, 185.0 ppm. IR (KBr): ν =
˜
3397, 2962, 1588, 1528 cm–1. ESI-MS: m/z = 341.0 [M + 1]+, 363
[M + Na]+, 338.7 [M – 1]–.
2-[(4-Methoxybenzoyl)(3,4-dihydroxy-5-methoxyphenyl)methylene]-
[8] V. Aggarwai, A. Kumar, H. Ila, H. Junjappa, Synthesis 1981,
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imidazolidine (3m): Yield 40 % (284 mg); m.p. 229 °C (dec.). 1H
Eur. J. Org. Chem. 2009, 5832–5840
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5839

C.-C. Zeng, D.-W. Ping, Y.-S. Xu, L.-M. Hu, R.-G. Zhong
FULL PAPER
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Received: July 2, 2009
Published Online: October 5, 2009
5840
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Eur. J. Org. Chem. 2009, 5832–5840