Anodic oxidation of catechols in the presence of α-oxoketene N,N-acetals with a tetrahydropyrimidine ring: Selective α-arylation reaction

Article abstract of DOI:10.1039/c001847c

The electrochemical oxidation of catechols leads to the formation of o-benzoquinones. This property has been applied to effectively synthesize α-arylated products of α-oxoketene N,N-acetals with a tetrahydropyrimidine ring.

Full text of DOI:10.1039/c001847c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Anodic oxidation of catechols in the presence of a-oxoketene N,N-acetals
with a tetrahydropyrimidine ring: selective a-arylation reaction†
Cheng-Chu Zeng,* Da-Wei Ping, Li-Ming Hu, Xiu-Qing Song and Ru-Gang Zhong
Received 1st February 2010, Accepted 12th March 2010
First published as an Advance Article on the web 24th March 2010
DOI: 10.1039/c001847c
The electrochemical oxidation of catechols leads to the formation of o-benzoquinones. This property
has been applied to effectively synthesize a-arylated products of a-oxoketene N,N-acetals with a
tetrahydropyrimidine ring.
1. Introduction
Functionalized o-benzoquinones and their benzo-fused analogues
have attracted a great deal of attention as a class of important
intermediates for the synthesis of various biologically active
products. Interest in the synthesis of these compounds leads to the
development of numerous methods. Chemical oxidants, such as sil-
ver oxide,1 potassium ferricyanide2 or nonmetal organic catalysts3
have been used to transfer catechols or 2-methoxyphenols to o-
benzoquinones. Recently, periodate salt4 or polymer supported
periodate oxidant (ps-IO4)5 have also been used for the in situ
generation of the o-benzoquinone intermediates. However, most
of the conventional chemical oxidation approaches involve toxic
oxidizing agents and/or metal additive, as well as stoichiometric
oxidants, and are therefore regarded as non-environmentally
benign processes.
Organic electrochemical synthesis in aqueous medium provides
an alternative strategy for the synthesis and transformation of
o-benzoquinones. Tabakovic´,6 Nematollahi7 and others8 have
studied the anodic oxidation of catechols in the presence of
nucleophiles and observed that electrochemically-generated o-
benzoquinones undergo Michael addition reaction to form var-
ious substituted catechols through an EC mechanism or benzofu-
ran derivatives with diketo reagents through an ECEC mechanism.
These electrochemical processes use electrons as oxidants and
thus avoid the utilization of toxic metal-based reagents. From
the viewpoint of green chemistry, it would be more attractive9
to produce o-benzoquinones through an electrochemical method.
In order to discover polyhydroxylated aromatics as potential
HIV-1 integrase inhibitors, we have also investigated the elec-
trochemical oxidation of catechols in the presence of mercapto
heterocycles and synthesized a variety of heterocyclic substituted
catechols.10 In view of the dinucleophilic property of enamines,11
very recently, we have also explored the electrochemical oxidation
of 4-tert-butylcatechol in the presence of a-oxoketene N,O-
acetals12 and developed a one pot electrochemical approach to the
synthesis of fused indole derivatives containing active hydroxyl
groups13 (Scheme 1). This reaction may involve successive anodic
Scheme
1 A one-pot synthesis of fused indole derivatives from
4-tert-butylcatechol and a-oxoketene N,O-acetals with an oxazolidine
ring.
oxidation, intermolecular Michael addition, anodic oxidation,
enamine–imine tautomerization, imine–enamine tautomerization,
intramolecular Michael addition and final aromatization process.
In the present study, we further study the anodic oxidation of
catechols in the presence of a-oxoketene acetals in which a-
oxoketene N,N-acetals with a tetrahydropyrimidine ring have
been used in place of a-oxoketene N,O-acetals. Results of this
study indicate that a-aryl a-oxoketene N,N-acetals are obtained
in moderate to good yields, instead of the corresponding fused
indole derivatives. To the best of our knowledge, there is only one
example involving the a-arylation reaction of a-oxoheterocyclic
ketene N,N-acetals using 2,4-dinitrohalobenzenes as reactants
by a radical nucleophilic substitution pathway.14 Therefore, this
protocol provides an efficient and complementary way to obtain
a-aryl a-oxoketene N,N-acetals containing an electron-rich aro-
matic ring.
2. Results and discussion
2.1 Electrochemical investigation of catechols in the absence and
presence of a-oxoketene N,N-acetals by cyclic voltammetry
To conduct the electrochemical coupling reaction between cate-
chols and a-oxoketene N,N-acetals with a tetrapyrimidine ring,
the electrochemical properties of the starting materials need to
be studied first. Taking 4-methylcatechol (1b) as an example, the
electrochemical behavior of 2 mM catechols 1 in the absence and
presence of a-oxoketene N,N-acetals 2 in 0.2 M acetate buffer at
pH 7.0 were studied using cyclic voltammetry (CV) at a scan rate
of 50 mV s-1 (Fig. 1). Due to the poor solubility of a-oxoketene
N,N-acetals in water, acetonitrile was added as a co-solvent.
As shown in Fig. 1, in the absence of a-oxoketene N,N-acetal
2a, the cyclic voltammogram of 4-methylcatechol consists of a
well defined anodic peak (peak A0) at +0.56 V, which is due to
the two-electron oxidation of 1b to its corresponding 4-methyl o-
benzoquinone, and a corresponding cathodic peak (C0) at +0.22 V
College of Life Science & Bioengineering, Beijing University of Technology,
Beijing, 100124, China. E-mail: zengcc@bjut.edu.cn; Fax: 00 86 10-
67392001
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of 3a–n, and quantum calculation of o-benzoquinone. See DOI:
10.1039/c001847c
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reversible anodic peak at 0.52 V and cathodic peak at 0.24 V,
which move respectively to 0.54 V and 0.22 V in the presence
of 2a. Interestingly, no obvious changes of anodic and cathodic
currents were observed when 2a was added, which implied that
the chemical reaction between electrogenerated 4-tert-butyl o-
benzoquinone and 2a occurred slowly.
2.2 Electrochemical synthesis of compounds 3a–3n
On the basis of above CVs behavior of catechols in the absence
and presence of a-oxoketene N,N-acetals, which is similar to that
in the presence of a-oxoketene N,O-acetals, we can assume that
a chemical step occurs between the electrochemically generated
o-benzoquinones and the a-oxoketene N,N-acetals 2, and then
Michael addition products may be produced upon anodic oxida-
tion of catechols and a-oxoketene N,N-acetals 2. Thus, similar
to our previous reaction conditions for a one-pot electrochemical
synthesis of fused indole derivatives containing active hydroxyl
groups,13 the anodic oxidation of 4-tert-butylcatechol (1a) was
performed in the presence of a-oxoketene N,N-acetal 2a at
controlled-potential at 0.3 V versus Ag wire15 in acetate buffer
using a divided cell. After 4-tert-butylcatechol was consumed,
the formed precipitate was filtered, washed by water, dried and
finally compound 3a was isolated in 27% yield. However, the
structure of 3a was characterized to be a direct Michael addition
and aromatization product, different from our previous results
where indole derivatives were produced selectively from the anodic
oxidation of the mixture of 4-tert-butyl catechol and a-oxoketene
N,O-acetals with an oxazolidine ring. This observation indicates
that the structure of a-oxoketene acetals (N,O-acetals or N,N-
acetal) play a key role in the formation of either indoles or a-aryl
a-oxoketene acetals.
Since electrochemical parameters, such as electrode materials,
quantity of electric charge passed, solvents, supporting elec-
trolytes, types of cell (divided cell or undivided cell) and mode of
electrolysis (controlled potential or constant current), significantly
affect the electrochemical results, 4-methylcatechol (1b) was then
chosen as a model compound to investigate the appropriate
conditions and then applied the optimized conditions to other
catechols. Here, the mode of electrolysis (controlled potential or
constant current) and types of cell (divided cell or undivided cell)
were studied respectively (on the basis of our previous results, it
is preferable to perform this type of reaction in buffer solution
in the pH range of 6.0 to 8.0, using carbon rod as working
electrode; therefore, other electrochemical parameters were not
investigated). As shown in Table 2, the anodic oxidation of 1b
in the presence of 2a was conducted at controlled-potential at
0.3 V vs. Ag wire15 in a divided cell, affording 3b in 52% yield. It
decreased slightly to 50% when the same reaction was repeated in
an undivided cell (beaker type cell). Next, the mode of electrolysis
was investigated. As shown in Table 2, the yield of 3b was 57%
when the reaction was performed by using constant current
technique in a divided cell, whereas it decreased to 43% in an
undivided cell. This observation indicates that cell type seems
to play a predominant role and the divided cell is preferable in
the present coupling reaction.16 In addition, controlled potential
electrolysis gives a comparable yield versus that using constant
current technique. One of the plausible reasons is a big differ-
ence in oxidizing potential between catechols and a-oxoketene
Fig. 1 Cyclic voltammograms of 1b in the absence and presence of
a-oxoketene N,N-acetal 2a. I: 2 mM of 1b; II: a mixture of 2 mM of
1b and 2 mM of a-oxoketene N,N-acetal 2a; III: 2 mM of a-oxoketene
N,N-acetal 2a at a glassy carbon working electrode, platinum wire counter,
and Ag/AgCl (in 3 M KCl) reference electrode, in 1 : 1 (v/v) acetate buffer
solution/acetonitrile (0.2 M, pH 7); scan rate 50 mV s-1.
attributed to the reduction of 4-methyl o-benzoquinone back to
4-methylcatechol (curve I). The ratio of the current amplitudes
between the oxidation and reduction processes is equal to unity
(Ipox/Ipred), indicating that the o-benzoquinone produced at the
surface of the electrode is stable under pH 7 acetate buffer and
that side-reactions such as hydroxylation or dimerization reactions
are too slow to be observed on the time scale of the cyclic
voltammetry.7,8
When one equivalent amount of a-oxoketene N,N-acetal 2a
was added, the height of the anodic peak A1 for the oxidation of
4-methylcatechol increased, whereas that of the cathodic peak C1
for the reduction of 4-methyl o-benzoquinone decreased (Fig. 1,
curve II). Moreover, the anodic peak (A1) of 4-methylcatechol in
the presence of 2a shifts slightly positive to 0.59 V compared to
that in the absence of 2a. Curve III in Fig. 1 is the CV of a-
oxoketene N,N-acetal 2a, where two irreversible anodic waves at
1.00 V and 1.25 V are observed. The observation that the anodic
peak increased and cathodic peak decreased when 2a was present
indicates that the electrogenerated o-benzoquinone intermediate
undergoes follow-up chemical reaction with 2a.
The electrochemical behavior of other catechols in the absence
and presence of a-oxoketene N,N-acetal 2a were also investigated.
The corresponding peak potentials were summarized in Table 1.
As shown in Table 1, all of other catechols exhibit similar
electrochemical pattern. For example, CV of 1a itself gives a
Table 1 Peak potentials of catechols in the absence and presence of 2a
Peak potentials at GCa,b
Peak potentials at GCa,c
Epred1
Catechol
Epox
Epred Epox
Epred2
1a
1b
1c
1d
0.52
0.56
0.52
0.45
0.24
0.22
0.30
0.26
0.54
0.59
0.57
0.51
0.22
0.21
0.29
0.27
—
—
—
0.10
a Cyclic voltammetry measurements were performed in 0.2 M acetate buffer
solution (pH 7); glassy carbon (GC) working electrode; scan rate 50 mV s-1.
Reference electrode: Ag/AgCl. b 2 mM of 1 in the absence of 2a. c 2 mM
of 1 in the presence of 2 mM of 2a.
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Table 2 Electrolysis of mixture of 1b and 2a under different conditionsa
Entry
Current/mA
Electrolytic time/h
Electrolysis mode
Cell type
Yield of 3b
1
2
3
4
15.9–17.4
15.0
34.7–24.8
15.0
1.6
1.5
1.1
1.5
Controlled potentialb
Constant current
Divided cell
Divided cell
Undivided cell
Undivided cell
52.0
57.0
50.0
43.0
Controlled potentialb
Constant current
a Acetate buffer: acetonitrile = 51.5 mL: 12.5 mL, 0.5 mmol 1b and 0.5 mmol 2a; passed charge: 2.24 F mol-1; room temperature. b Controlled potential
at 0.3 V vs. Ag wire.
N,N-acetals, which mean a-oxoketene N,N-acetals were not
oxidized or were difficult to oxidize when the mixture of catechols
and a-oxoketene N,N-acetals was electrolysized using either
constant current or controlled-potential techniques.
Considering that a potentiostat is considerably more expensive
and not always available in organic synthesis laboratory. Moreover,
comparable yields can afford when using either constant current
electrolysis or controlled-potential electrolysis mode. Therefore,
constant current electrolysis in divided cell seems to be preferable
and then is employed for the electrochemical oxidation of other
catechols in the presence of a-oxoketene N,N-acetals with a
tetrahydropyrimidine ring 2 (Scheme 2).
and 3g in 68%, 39% and 46% yields, respectively (Table 3, entries
5–7).
Similarly, when 4-methylcatechol was subjected to anodic
oxidation in the presence of 2b, 2c or 2d under same conditions,
desired a-aryl a-oxoketene N,N-acetals 3h–3j were afforded in
49%, 82% and 40% yields, respectively (Table 3, entries 8–10).
In addition, when caffeic acid was anodically oxidized in the
presence of 2b, 2c or 2d, the corresponding a-aryl a-oxoketene
N,N-acetals 3k–3m were afforded in reasonable yield. (Table 1,
entries 11–13).
Finally, compound 3n was produced in 59% yield from the
constant current electrolysis of a mixture of 1d and 2c (Table 3,
entry 14).
It is worth noting that compounds 3 appear not stable and
could not survive from column chromatography isolation. The
only way to purify is to make the products precipitate and then
recrystallize. Therefore, the exact yields of compounds 3 should
be higher than that reported in Table 3, which is based on the
precipitated amounts.
On the basis of above results, we can conclude that the nature of
dinucleophile plays a key role in the formation of products. When
the dinucleophiles are a-oxoketene N,O-acetals, indole derivatives
are produced. However, it affords exclusively a-arylation products
when the dinucleophiles are N,N-acetals. Therefore, our present
work provides an efficient method to obtain a-aryl a-oxoketene
N,N-acetals containing electron-rich aromatic ring.
Scheme 2 Anodic oxidation of a mixture of catechols 1 and a-oxoketene
N,N-acetals 2.
Thus, anodic oxidation of 4-tert-butylcatechol (1a) in the
presence of 2a was repeated at a constant current of 15 mA
(~3 mA cm-2) in the divided cell. The corresponding product 3a
was achieved in 25%. (Table 3, entry 1). Similarly, compound 3c
was produced in 32% yield upon constant current electrolysis
of the mixture of caffeic acid and 2a in the phosphate buffer
solution.17 It is worth noting that, in this case, 3c did not precipitate
directly from the electrolytic mixture. Moreover, it was observed
that compound 3c decomposed when flash chromatography was
used to isolate the reaction mixture. Then, the reaction solutions
(water and acetonitrile) were first removed partially under reduced
pressure and solid precipitated. The desired compound 3c was
finally obtained after filtering and recrystallizing from a mixed
solution of methanol and water.
Subsequently, the reaction was applied to 3-substituted cate-
chols such as 3-methoxycatechol (1d) with a view to investigate the
scope of the reaction. In a similar way, electrochemical oxidation of
1d in the presence of 2a was performed and the expected products
3d were accomplished in 54% yield (Table 3, entry 4).
In order to evaluate the versatility of the reaction further,
a series of a-oxoketene N,N-acetals were also investigated by
a similar procedure. As shown in Table 3, the electrochemical
oxidations of 4-tert-butylcatechol (1a) in the presence of 1-phenyl-
2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (2b), 1-(p-me-
thylphenyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (2c),
or 1-(p-methoxyphenyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)-
ethanone (2d) also proceeded smoothly, yielding the desired 3e, 3f
The structures of 3a–n were characterized by using 1H NMR, 13C
NMR, IR and ESI-MS. First of all, ESI-MS results strongly sug-
gests that compounds 3 are the coupling products of a-oxoketene
N,N-acetal moieties and catechol scaffolds. The structures of these
compounds were then elucidated by NMR spectroscopy. The 1H
NMR spectra of products from the reaction of 4-substituted
catechols and 2 displays two singlets of aromatic protons. The
1H NMR spectrum of the compounds from the reaction of 3-
substituted catechols and 2 exhibits two meta-oriented aromatic
proton signals (doublets, J = 2.0 Hz). These results are consistent
with the 1,4-addition products, which indicates that the a-carbon
atom of a-oxoketene N,N-acetal moieties always attack selectively
the carbon atom of the catechol scaffold that is the para-position
(rather than the ortho-position) of one of the two OH groups of
the benzene ring (Fig. 2).
2.3. Mechanism
On the basis of the above results and related work by others,7,8 an
EC mechanism can be speculated for the formation of compounds
3. As described in Scheme 3, the initial step is an electrochemical
process that involves the oxidation of catechols 1 on the anodic
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Table 3 Electrochemical synthesis of a-aryl a-oxoketene N,N-acetals 3
Table 3 (Contd.)
containing the catechol subunita
Entry Catechol 1
Ketene N,N-acetal 2 Product
Yield
59c
Entry Catechol 1
Ketene N,N-acetal 2 Product
Yield
14
1
27b,f
25b
a Reaction conditions: constant current at 15 mA (3 mA cm-1), graphite rod
anode, Pt wire cathode and divided cell. b The product precipitated from the
electrolytic solution, which was filtered and washed by water to give a high
quality product. c The products did not precipitate from the electrolytic
solution. After removal of the mixed solution under reduced pressure, the
residue was re-dissolved in methanol and acidified with hydrochloride to
pH 1. The mixture was kept in refrigerator overnight. The formed solid
(NaCl) was removed and the filtrate was recrystallized in a mixed solution
of methanol and water. d Phosphate buffer was used as the electrolyte. In
this case, the products did not precipitate from the electrolytic solution.
After removal of partial solution under reduced pressure, the desired
products precipitated and were obtained after filtering and recrystallizing
from mixed solution of methanol and water. e The reaction was performed
at 0 ◦C. f The reaction was performed under controlled-potential at 0.3 V
vs. Ag wire in divided cell.
2
57b
79b,e
3
4
32d
54b
5
6
68b
39b
7
8
46b
49b
9
82c
Fig. 2 Partial 1H NMR spectra of compound 3b and 3d showing
regioselective products from 1,4-addition.
10
11
40d
20d
electrode surface, generating the corresponding o-benzoquinones,
which diffuses to the bulk electrolytic solution. Subsequently,
a chemical reaction occurs between the active o-benzoquinone
intermediates and the a-carbon atom of the a-oxoketene N,N-
acetals 2 through a Michael addition reaction followed by an
aromatization process leading to products 3.
It is worth mentioning that the electrochemical oxidation of
4-tert-butylcatechol and 3-substituted catechols in the presence
of a-oxoketene N,O-acetals (the analogues of N,N-acetals 2) can
achieve a one-pot electrochemical synthesis of fused indole deriva-
tives in the range of 37–71% yields.13 In addition, it was reported
that the putative o-benzoquinone derivatives stemmed from the
anodic oxidation of dopamine undergoes rapid intramolecular
cyclization, leading to a redox active indoline derivative, which,
after subsequent oxidation, rapidly affords insoluble melanin-like
polymer.18 In view of the facts that compounds of type 3 were
also typical catechol derivatives, and therefore over-oxidation of
compounds 3 followed by further intramolecular Michael addition
12
13
76d
25d
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generated o-benzoquinones undergo 1,4-Michael addition with a-
oxoketene N,N-acetals 2 following an EC mechanism to afford
exclusively a-aryl a-oxoketene N,N-acetals 3 in moderate to good
yield, which provides an electrochemical oxidization approach
for the arylation reaction of a-oxoketene N,N-acetals. Further
studies towards the synthetic application (for example, further
transformation to indoles) are current under way in our group.
4. Experimentals
4.1 Instruments and reagents
All melting points were measured with a XT4A Electrothermal
melting point apparatus and are uncorrected. IR spectra were
recorded as KBr pellets. 1H and 13C NMR spectra were recorded
1
with an AV 400M Bruker spectrometer (400 MHz H frequency,
100 MHz 13C frequency). Chemical shifts are given as d values
(internal standard: TMS). The MS spectra (ESI) were recorded
on a Bruker esquire 6000 mass spectrometer.
Catechols 1a–d were reagent-grade from Alfa Aesar China
(Tianjin) Co. Ltd. Compounds 2a–d were synthesized according
to the known procedure.19 Other chemicals and solvents were from
Beijing Chemicals Co. and used without further purification. All
electrodes for CV experiments were from CH Instruments, Inc.
USA. Doubly distilled de-ionized water was used for preparation
of aqueous acetate buffer. All experiments were performed at room
temperature and ambient pressure.
Scheme 3 A plausible mechanism between catechols 1 and ketene
N,N-acetals 2 under the anodic oxidation conditions.
was expected to occur and cause the formation of corresponding
indole derivatives. However, it is observed that a-arylated a-
oxoketene N,N-acetals 3 were produced exclusively. The reason
behind this is not clear, although the nature of the starting a-
oxoketene N,N-acetals may play a predominant role.
In addition, principally, o-benzoquinone derivatives may un-
dergo 1,4-addition and 1,6-addition with nucleophiles and there-
fore a couple of regioisomers may generate (Scheme 4). More-
over, it was reported that 1,6-addition products have been
obtained as predominant products from reaction of various o-
benzoquinones with SH-containing nucleophiles such as cysteine,
N-acetylcysteine and glutathione at physiological pH, due to
intramolecular base catalysis and greater softness of the sulfur
atom.8 However, in our cases, only 1,4-addition adducts were
obtained. We have calculated the distribution of the coefficients
of the LUMO of o-benzoquinone (see the ESI†), and the result
shows that there is no obvious difference between C3 and C4
atoms. Therefore, the regioselective outcome may be rationalized
in the terms of the greater hardness of the a-carbon atom of ketene
N,N-acetals 2, which prefers attacking the more electropositive C
position of the quinone ring.
4.2 Cyclic voltammetry
Cyclic voltammograms were measured by a 273A Potentio-
stat/Galvanostat equipped with an electrochemical analysis soft-
ware, using a conventional three-electrode cell. The working
electrode was a glassy carbon disk electrode (ca. f = 3 mm). The
auxiliary and reference electrodes in these studies were Pt wire and
saturated Ag/AgCl (in 3 M KCl), respectively. Glassy carbon was
polished with polishing cloth before each measurement. Acetate
buffer solution was prepared by NaAc and HAc monitored by a
digital pH meter. Scan rate was 50 mV s-1. The concentration of
1 and 2 were 2 mmol L-1, while that of the supporting electrolyte
was 0.2 mol L-1.
4.3 General procedure for the synthesis of compounds 3a–3n by
constant current electrolysis
A 100 mL of H-type cell was equipped with a medium glass frit
as a membrane. The anode compartment contained an assembly
of 7 graphite rods as the anode, whose upper rims were wrapped
by a copper wire, and a platinum wire as the counter electrode
was immersed in the cathode compartment. The applied current
throughout electrolysis was 15 mA and was controlled by a D.C.
regulated power supply. During electrolysis, a magnetic stirrer
stirred the mixture.
Scheme 4 Possible regioselective reaction of o-benzoquinones 1 and
ketene N,N-acetals 2.
In a typical procedure, to the anode compartment which is
kept in water at room temperature (in the range of 23–25 ◦C)
was added a mixture of 52 mL acetate buffer solution (pH 6)
(or phosphate buffer solution) and 12 mL of acetonitrile. Subse-
quently, 1 mmol catechols 1 and 1 mmol 1-(substituted)-phenyl-
2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone 2 were added to
the anodic compartment and electrolyzed. The electrolysis was
3. Conclusion
In summary, anodic oxidation of catechols 1 in the presence of
a-oxoketene N,N-acetals with a tetrahydropyrimidine ring 2 have
been investigated by cyclic voltammetry and constant current elec-
trolysis methods. The results indicate that the electrochemically
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terminated when the starting 1 was consumed by TLC following
the reaction process. After electrolysis, the anolyte was worked
up by one of the methods as indicated below to obtain desired
compounds 3.
The product precipitated from the electrolytic solution, then the
reaction mixture was filtered and the solid was washed with water
to give high quality of products.
The product did not precipitate from the electrolytic solution.
Then, after removal of the anolyte under reduced pressure,
the residue was re-dissolved in methanol and acidified with
hydrochloride to pH 1. The mixture was maintained in refrigerator
overnight. The formed solid (NaCl) was removed and the filtrate
was recrystallized in methanol–water to afford products.
Phosphate buffer solution was used as electrolyte. In these cases,
the product did not precipitate from the electrolytic solution.
Then, after partial removal of the solution under reduced pressure,
the desired products precipitated, which were purified using
recrystallization from mixed solution of methanol and water.
7.10 (d, J = 8.4 Hz, 2H, ArH), 8.03 (s, 1H, OH), 8.64 (s, 1H,
OH), 12.28 (s, br, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d 25.0, 43.3, 60.9, 99.7, 114.6, 119.4, 131.9, 132.2, 134.6, 136.2,
137.9, 148.6, 150.7, 153.3, 164.2, 185.3; IR (KBr): n 3417, 2975,
2942, 2870, 1607, 1574, 1464; ESI-MS: m/z 374.9 (M++1), 372.6
(M--1).
4.3.5. 2-(2-tert-Butyl-4,5-dihydroxyphenyl)-1-phenyl-2-(tetra-
hydropyrimidin-2(1H)-ylidene)ethanone (3e). Yield: 68%; mp:
◦
1
243 C (dec); H NMR (400 MHz, DMSO-d6): d 1.04 (s, 9H,
C(CH3)3), 1.74-1.81 (m, 2H, CH2), 3.16 (s, 2H, CH2), 3.37 (s, 2H,
CH2), 5.32 (s, br, 1H, NH), 6.42 (s, 1H, Ar–H), 6.74 (s, 1H, Ar–H),
7.01-7.016 (m, 5H, Ar–H), 8.62 (s, 2H, OH), 12.81 (s, br, 1H, NH);
13C NMR (100 MHz, DMSO-d6): d 20.6, 32.5, 36.2, 39.6, 96.1,
116.7, 118.5, 124.3, 125.3, 127.0, 127.3, 128.8, 141.6, 143.1, 144.5,
160.0, 179.1; IR (KBr): n 3415, 2959, 2870, 1602, 1582, 1501, 1485;
ESI-MS: m/z 366.9 (M++1), 733.1 (2M++1), 364.8 (M--1), 731.0
(2M--1).
4.3.6. 2-(2-tert-Butyl-4,5-dihydroxyphenyl)-2-(tetrahydropyri-
midin-2(1H)-ylidene)-1-p-tolylethanone (3f). Yield: 39%; mp:
247–249 ◦C; 1H NMR (400 MHz, DMSO-d6): d 1.05 (s, 9H,
C(CH3)3), 1.72-1.81 (m, 2H, CH2), 2.16 (s, 3H, CH3), 3.16 (s,
2H, CH2), 3.33-3.37 (m, 2H, CH2), 5.26 (s, br, 1H, NH), 6.39 (s,
1H, Ar–H), 6.75 (s, 1H, Ar–H), 6.82 (d, 2H, J = 8.0 Hz, Ar–H),
7.04 (d, J = 8.4 Hz, 2H, Ar–H), 8.61 (s, 2H, OH), 12.85 (s, br, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d 20.6, 21.1, 32.5, 36.2,
38.1, 95.8, 116.7, 124.3, 125.5, 127.6, 128.8, 136.5, 141.5, 141.7,
143.1, 144.5, 159.9, 179.0; IR (KBr): n 3382, 2947, 1595, 1523,
1494, 1416; ESI-MS: m/z 380.8 (M++1), 761.1 (2M++1), 378.8
(M--1), 759.1 (2M--1).
4.3.1. 2-(2-tert-Butyl-4,5-dihydroxyphenyl)-1-(4-chlorophenyl)-
2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone
(3a). Yield:
◦
1
25%; mp: 225–226 C; H NMR (400 MHz, DMSO-d6): d 1.04
(s, 9H, C(CH3)3), 1.72-1.82 (m, 2H, CH2), 3.16 (s, br, 2H, CH2),
3.33-3.37 (m, 2H, CH2), 5.42 (s, br, 1H, NH), 6.40 (s, 1H, Ar–H),
6.76 (s, 1H, Ar–H), 7.07 (d, 2H, J = 8.4 Hz, Ar–H), 7.14 (d, J =
8.4 Hz, 2H, Ar–H), 8.66 (s, 2H, OH), 12.72 (s, br, 1H, NH); 13C
NMR (100 MHz, DMSO-d6): d 20.5, 32.5, 36.2, 38.1, 96.2, 116.8,
124.2, 124.9, 127.0, 130.6, 132.0, 141.6, 143.2, 143.3, 144.7, 160.1,
177.3; IR (KBr): n 3413, 3001, 2958, 2874, 1603, 1584, 1522,
1504, 1483; ESI-MS: m/z 400.9 (M++1), 801.1 (2M++1), 398.8
(M--1), 799.0 (2M--1).
4.3.7. 2-(2-tert-Butyl-4,5-dihydroxyphenyl)-1-(4-methoxyphe-
nyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (3g). Yield:
46%; mp: 232–233 ◦C; 1H NMR (400 MHz, DMSO-d6): d 1.06 (s,
9H, C(CH3)3), 1.72-1.81 (m, 2H, CH2), 3.16 (s, br, 2H, CH2), 3.31-
3.37 (m, 2H, CH2), 3.65 (s, 3H, OCH3), 5.21 (s, br, 1H, NH), 6.40
(s, 1H, Ar–H), 6.56 (d, 2H, J = 8.8 Hz, Ar–H), 6.79 (s, 1H, Ar–H),
7.12 (d, J = 8.8 Hz, 2H, Ar–H), 8.62 (s, 2H, OH), 12.91 (s, br, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d 20.7, 32.4, 36.2, 38.1,
55.3, 95.5, 112.2, 116.7, 124.2, 125.8, 130.4, 136.9, 141.6, 143.2,
144.5, 158.8, 159.9, 178.3; IR (KBr): n 3416, 2965, 1600, 1511,
1490; ESI-MS: m/z 396.8 (M++1), 793.1 (2M++1), 394.8 (M--1),
791.0 (2M--1).
4.3.2. 1-(4-Chlorophenyl)-2-(4,5-dihydroxy-2-methylphenyl)-
2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (3b). Yield: 57%;
mp: 222–223 ◦C; 1H NMR (400 MHz, DMSO-d6): d 1.79 (s, 2H,
CH2), 1.86 (s, 3H, CH3), 3.26-3.34 (m, 4H, CH2), 5.56 (s, br, 1H,
NH), 6.33 (s, 1H, Ar–H), 6.48 (s, 1H, Ar–H), 7.00 (d, 2H, J =
8.4 Hz, Ar–H), 7.08 (d, 2H, J = 8.4 Hz, Ar–H), 8.47 (s, 1H, OH),
8.58 (s, 1H, OH), 12.38 (s, br, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d 19.6, 20.4, 38.6, 92.7, 117.8, 121.8, 126.9, 127.2,
129.5, 130.0, 131.7, 143.4, 143.7, 144.6, 159.3, 179.9; IR (KBr):
n 3468, 3287, 2936, 2879, 1642, 1600, 1500, 1483; ESI-MS: m/z
358.7 (M++1), 716.7 (2M++1), 356.7 (M--1), 714.9 (2M--1).
4.3.3. (E)-3-{4,5-Dihydroxy-2-[2-oxo-2-(4-chlorophenyl)-1-
(tetrahydropyrimidin-2(1H)-ylidene)]ethyl}phenylacrylic acid (3c).
Yield: 32%; mp: 186–188 ◦C; 1H NMR (400 MHz, DMSO-d6): d
1.77 (t, J = 5.2 Hz, 2H, CH2), 3.15-3.24 (m, 4H, CH2), 5.75 (s, br,
4.3.8. 2-(4,5-Dihydroxy-2-methylphenyl)-1-phenyl-2-(tetra-
hydropyrimidin-2(1H)-ylidene)ethanone (3h). Yield: 49%; mp:
◦
1
247 C (dec); H NMR (400 MHz, DMSO-d6): d 1.79-1.80 (m,
2H, CH2), 1.88 (s, 3H, CH3), 3.26-3.34 (m, 4H, CH2), 5.50 (s, br,
1H, NH), 6.34 (s, 1H, Ar–H), 6.45 (s, 1H, Ar–H), 7.00-7.04 (m,
5H, Ar–H), 8.43 (s, br, 1H, OH), 8.50 (s, br, 1H, OH), 12.48 (s,
br, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d 19.6, 20.5, 38.5,
92.61, 117.8, 121.9, 127.1, 127.3, 127.7, 130.0, 143.3, 144.4, 144.9,
159.3, 181.6; IR (KBr): n 3393, 1595, 1524, 1500; ESI-MS: m/z
324.8 (M++1), 649.0 (2M++1), 322.6 (M--1), 646.8 (2M--1).
=
1H, NH), 5.89 (d, J = 16.0 Hz, 1H, CH CH), 6.40 (s, 1H, Ar–H),
6.89 (d, J = 8.8 Hz, 2H, ArH), 6.94 (s, 1H, Ar–H), 7.02 (d, J =
=
8.8 Hz, 2H, ArH), 7.44 (d, J = 16.0 Hz, 1H, CH CH), 12.30 (s,
br, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d 20.3, 90.9, 113.5,
115.3, 121.9, 127.2, 127.4, 129.4, 130.7, 131.7, 143.5, 145.3, 148.4,
159.3, 168.6, 180.9; IR (KBr): n 3435, 1636, 1510; ESI-MS: m/z
414.9 (M++1), 828.2 (2M++1), 412.6 (M--1).
4.3.4. 1-(4-Chlorophenyl)-2-(3,4-dihydroxy-5-methoxyphenyl)-
4.3.9. 2-(4,5-Dihydroxy-2-methylphenyl)-2-(tetrahydropyri-
2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone
(3d). Yield:
midin-2(1◦H)-ylidene)-1-p-tolylethanone (3i). Yield: 82%; mp:
◦
1
1
54%; mp: 245 C (dec); H NMR (400 MHz, DMSO-d6): d 1.80
(s, 2H, CH2), 3.27-3.33 (m, 4H, CH2), 3.56 (s, 3H, OCH3), 6.05 (s,
1H, Ar–H), 6.07 (s, 1H, Ar–H), 7.05 (d, J = 8.0 Hz, 2H, ArH),
208–209 C; H NMR (400 MHz, DMSO-d6): d 1.85 (t, J =
5.6 Hz, 2H, CH2), 2.23 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.31-3.38
(m, 4H, CH2), 6.21 (s, 1H, NH), 6.27 (s, 1H, Ar–H), 6.73 (s, 1H,
2470 | Org. Biomol. Chem., 2010, 8, 2465–2472
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◦
1
Ar–H), 7.30 (d, 2H, J = 8.0 Hz, Ar–H), 7.72 (d, 2H, J = 8.0 Hz,
Ar–H), 8.90 (s, 1H, OH), 9.23 (s, 1H, OH), 9.46 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6): d 18.2, 19.1, 21.6, 53.9, 117.4,
119.2, 120.0, 128.0, 129.4, 129.9, 132.8, 143.9, 145.1, 146.2, 160.9,
194.4; IR (KBr): n 3499, 3139, 3026, 1686, 1663, 1609, 1530, 1463;
ESI-MS: m/z 338.8 (M++1), 676.9 (2M++1), 336.8 (M--1), 675.0
(2M--1).
59%; mp: 194–195 C; H NMR (400 MHz, DMSO-d6): d 1.84
(s, 2H, CH2), 2.33 (s, 3H, CH3), 3.34-3.36 (d, 4H, CH2), 3.72 (s,
3H, OCH3), 6.32 (s, br, 1H, NH), 6.46 (s, 1H, Ar–H), 6.54 (s, 1H,
Ar–H), 7.30 (d, J = 7.6 Hz, 2H, Ar–H), 7.86 (d, J = 8.0 Hz, 2H,
Ar–H), 8.86 (s, br, 1H, OH), 9.18 (s, br,1H, OH), 9.57 (s, br, 1H,
NH) 13C NMR (100 MHz, DMSO-d6): d 18.2, 21.6, 39.2, 55.1,
56.4, 105.3, 110.8, 121.8, 129.5, 129.9, 132.9, 135.4, 145.0, 146.8,
149.5, 161.1, 193.5; IR (KBr): n 3453, 1683, 1662, 1616, 1536,
1456; ESI-MS: m/z 354.7 (M++1), 352.7 (M--1).
4.3.10. 2-(4,5-Dihydroxy-2-methylphenyl)-1-(4-methoxyphe-
nyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (3j). Yield:
40%; mp: 224–225 ◦C; 1H NMR (400 MHz, DMSO-d6): d 1.78 (t,
J = 4.4 Hz, 2H, CH2), 1.86 (s, 3H, CH3), 3.17-3.33 (m, 4H, CH2),
3.64 (s, 3H, OCH3), 5.27 (s, br, 1H, NH), 6.35 (s, 1H, Ar–H), 6.49
(s, 1H, Ar–H), 6.57 (d, 2H, J = 8.4 Hz, Ar–H), 6.98 (d, 2H, J =
8.8 Hz, Ar–H), 8.50 (s, 2H, OH), 12.59 (s, br, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): dd 19.6, 20.5, 38.6, 55.3, 92.2, 112.4, 117.9,
121.8, 127.6, 129.4, 130.0, 137.2, 143.4, 144.5, 158.6, 159.3, 180.8;
IR (KBr): n 3446, 3407, 2966, 2928, 2865, 1600, 1578, 1510, 1488;
ESI-MS: m/z 354.8 (M++1), 352.7 (M--1).
Acknowledgements
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
Fund to Zeng, C. C. from Beijing City Education Committee
(KM201010005009).
References
4.3.11. (E)-3-{4,5-Dihydroxy-2-[2-oxo-2-phenyl-1-(tetrahy-
dropyrimidin-2(1H)-ylidene]ethyl}phenylacrylic acid (3k). Yield:
1 (a) K. C. Nicolaou, J. Wang and Y. Tang, Angew. Chem., Int. Ed., 2008,
47, 1432; (b) D. Aebisher, E. M. Brzostowska, A. Mahendran and A.
Greer, J. Org. Chem., 2007, 72, 2951.
◦
1
20%; mp: 203–204 C; H NMR (400 MHz, DMSO-d6): d 1.80
(t, J = 5.2 Hz, 2H, CH2), 3.17-3.36 (m, 4H, CH2), 5.07 (s, br, 1H,
2 A. Alizadeh, D. Nematollahi, D. Hbibi and M. Hesari, Synthesis, 2007,
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=
NH), 5.89 (d, J = 15.6 Hz, 1H, CH CH), 6.43 (s, 1H, Ar–H),
3 W. Adam, C. R. Saha-Mo¨ller and P. A. Ganeshpure, Chem. Rev., 2001,
101, 3499.
6.90-6.93 (m, 2H, Ar–H), 6.94 (s, 1H, Ar–H), 6.98-7.01 (m, 3H,
=
4 V. Nair, D. Sethumadhavan, S. M. Nair, N. P. Rath and G. K. Eigendorf,
J. Org. Chem., 2002, 67, 7533.
5 K. M. Bogle, D. J. Hirst and D. J. Dixon, Org. Lett., 2007, 9,
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635.
Ar–H), 7.54 (d, J = 16.0 Hz, 1H, CH CH), 12.41 (s, br, 1H, NH);
13C NMR (100 MHz, DMSO-d6): d 20.3, 37.9, 39.4, 90.9, 113.3,
122.1, 126.2, 127.2, 127.5, 127.6, 128.3, 131.1, 144.7, 145.2, 148.3,
159.3, 168.7, 182.6; IR (KBr): n 3422, 1605, 1508, 1448; ESI-MS:
m/z 380.7 (M++1), 378.7 (M--1).
7 (a) D. Nematollahi and M. Rafiee, Green Chem., 2005, 7, 638; (b) D.
Nematollahi, D. Habibi, M. Rahmati and M. Rafiee, J. Org. Chem.,
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Tetrahedron, 2007, 63, 3894; (d) S. S. H. Davarani, D. Nematollahi,
M. Shamsipur, N. M. Najahi, L. Masoumi and S. Ramyar, J. Org.
Chem., 2006, 71, 2139; (e) D. Nematollahi, M. Alimoradi and S. Waqif
Husain, Electrochim. Acta, 2006, 51, 2620.
8 (a) F. Zhang and G. Dryhurst, J. Electroanal. Chem., 1995, 398, 117;
(b) X.-M. Shen and G. Dryhurst, J. Med. Chem., 1996, 39, 2018; (c) R.
Xu, X. Huang, K. J. Kramer and M. D. Hawley, Bioorg. Chem., 1996,
24, 110; (d) X. Huang, R. Xu, M. D. Hawley, T. L. Hopkins and K. J.
Kramer, Arch. Biochem. Biophys., 1998, 352, 19; (e) A. Felim, A. Urios,
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9 (a) E. Steckhan, T. Arns, W. R. Heineman, G. Hilt, D. Hoormann, J.
Jorissen, L. Kroner, B. Lewall and H. Putter, Chemosphere, 2001, 43,
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4.3.12. (E)-3-{4,5-Dihydroxy-2-[2-oxo-2-p-tolyl-1-(tetrahy-
dropyrimidin-2(1H)-ylidene)]ethyl}phenylacrylic acid (3l). Yield:
76%; mp: 209–210 ◦C; 1H NMR (400 MHz, DMSO-d6): d 1.78 (t,
J = 4.8 Hz, 2H, CH2), 2.14 (s, 3H, CH3), 3.15-3.33 (m, 4H, CH2),
=
5.69 (s, br, 1H, NH), 5.90 (d, J = 16.0 Hz, 1H, CH CH), 6.43 (s,
1H, Ar–H), 6.78-6.83 (m, 4H, Ar–H), 6.97 (s, 1H, Ar–H), 7.56 (d,
=
J = 16.0 Hz, 1H, CH CH), 9.37 (s, br, 2H, OH), 12.46 (s, br, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d 20.4, 21.1, 38.6, 90.8,
113.4, 115.1, 122.0, 127.4, 127.7, 127.8, 131.4, 136.3, 141.9, 143.8,
145.1, 148.3, 159.3, 168.6, 182.5; IR (KBr): n 3430, 3337, 1683,
1605, 1306; ESI-MS: m/z 394.8 (M++1), 416.8 (M++Na), 392.7
(M--1).
4.3.13. (E)-3-{4,5-Dihydroxy-2-[2-oxo-2-(4-methoxyphenyl)-
1-(tetrahydropyrimidin-2(1H)-ylidene)]ethyl}phenylacrylic
acid
(3m). Yield: 25%; mp: 216–217 ◦C; 1H NMR (400 MHz,
DMSO-d6): d 1.78 (t, J = 5.2 Hz, 2H, CH2), 3.20-3.32 (m, 4H,
CH2), 3.62 (s, 3H, OCH3), 5.60 (s, br, 1H, NH), 5.92 (d, J =
=
16.0 Hz, 1H, CH CH), 6.43 (s, 1H, Ar–H), 6.55 (d, J = 8.8 Hz,
2H, ArH), 6.89 (d, J = 8.8 Hz, 2H, ArH), 6.99 (s, 1H, Ar–H),
11 A. A. Elassar and A. A. El-Khair, Tetrahedron, 2003, 59, 8463.
12 (a) H. Junjappa, H. ILa and C. V. Asokan, Tetrahedron, 1990, 46, 5423;
(b) Z. T. Huang and M. X. Wang, Heterocycles, 1994, 37, 1233; (c) M. X.
Wang and Z. T. Huang, Prog. Nat. Sci., 2002, 12, 249.
13 C. C. Zeng, F. J. Liu, D. W. Ping, Y. L. Cai, L. M. Hu and R. G. Zhong,
J. Org. Chem., 2009, 74, 6386.
=
7.54 (d, J = 16.0 Hz, 1H, CH CH), 10.05 (s, br, 2H, OH), 12.50
(s, br, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d. 20.4, 38.0,
55.3, 90.6, 112.5, 113.5, 114.1, 115.4, 122.0, 127.4, 129.3, 131.5,
131.7, 137.1, 143.6, 145.2, 148.5, 158.5, 159.3, 168.8, 181.8; IR
(KBr): n 3551, 3414, 1663, 1637; ESI-MS: m/z 410.9 (M++1),
432.8 (M++Na), 4.8.8 (M--1).
14 W. Y. Zhao and Z. T. Huang, J. Chem. Soc., Perkin Trans. 2, 1991,
1967.
15 Here, the reference electrode was changed to Ag wire quasi-reference
electrode. In fact, the anodic potential of 1b is 0.55 V (vs. Ag/AgCl),
which is equal to 0.35 V (vs. Ag wire). To allow for the selective oxidation
4.3.14. 1-(4-methylphenyl)-2-(3,4-dihydroxy-5-methoxyphe-
nyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (3n). Yield:
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of catechol 1b, rather than compounds 2, we controlled potential at
0.30 V vs. Ag wire. See reference: C. C. Zeng and J. Y. Becker, J. Org.
Chem., 2004, 69, 1053–1059.
17 When acetate buffer solution was used to performed this reaction,
current efficiency and yield are lower than that in phosphate buffer,
therefore, phosphate buffer solution was used for this oxidation.
18 F. Zhang and G. Dryhurst, J. Med. Chem., 1994, 37,
1084.
16 This result is not surprising because more side-reactions may occur
using undivided cell compared with divided cell. In addition, in the
cases of caffeic acid, we even found that no product was isolated when
undivided cell was used.
19 Z. T. Huang and P. C. Zhang, Chem. Ber., 1989, 122,
2011.
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