Electrochemically induced cross-dehydrogenative coupling (CDC) reaction. An efficient electrochemical method for the synthesis of dicoumarols

Article abstract of DOI:10.1039/c4ra08181a

Electrochemical synthesis of dicoumarols as anticoagulant drugs was carried out by the electrochemical oxidation of N,N,N′,N′-tetramethyl-1,4-phenylenediamine in the presence of 4-hydroxycoumarin derivatives. Electrochemically generated radical cation par

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Electrochemically induced cross-
dehydrogenative coupling (CDC) reaction. An
efficient electrochemical method for the
synthesis of dicoumarols
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
*
Bita Dadpou and Davood Nematollahi
DOI: 10.1039/x0xx00000x
Electrochemical synthesis of dicoumarols was carried out by the electrochemical oxidation of
N,N,N’,N’-tetramethyl-1,4-phenylenediamine in the presence of 4-hydroxycoumarin
derivatives.
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Electrochemically induced cross-
dehydrogenative coupling (CDC) reaction. An
efficient electrochemical method for the
synthesis of dicoumarols†
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Bita Dadpou and Davood Nematollahi*
DOI: 10.1039/x0xx00000x
Electrochemical synthesis of dicoumarols as anticoagulant drugs was carried out by the
electrochemical oxidation of N,N,N’,N’-tetramethyl-1,4-phenylenediamine in the presence of 4-
hydroxycoumarin derivatives. Electrochemically generated radical cation participates in cross-
dehydrogenative coupling (CDC) reaction with 4-hydroxycoumarins. The present work has led to
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the development of a facile catalyst-less, one-pot and environmentally friendly method under
ambient conditions using a carbon electrode.
This
mechanism
was
characterized
as
cross-
Introduction
6
dehydrogenative-coupling (CDC). The biological importance of
this drug prompted us to develop a facile and one-pot
electrochemical method for the synthesis of dicoumarols.
Therefore, the development of an efficient method for the
synthesis of dicoumarol derivatives, that overcome the
drawbacks of reported methods, would be appreciable. To the
best of our knowledge, there is only two reports on
electrochemical synthesis of dicoumarol.7 These objects
prompted us to investigate the electrochemical oxidation of
Dicoumarol is an anticoagulant drug that functions as a
1
vitamin K antagonist. It is metabolized from coumarin in the
sweet clover by molds, such as penicillium nigricans and
penicillium jensi and is considered to be a fermentation product
2
and mycotoxin. Coumarin was used as early as 1000 A.D as
3
medicinal plant extract according to Persian literature. After
that, numerous reports were published about anti-proliferative
and antitumor activities of coumarin and its derivatives such as
7
-hydroxycumarin by interfering with mitotic spindle
N,N,N’,N’-tetramethyl-1,4-phenylenediamine
Wurster's reagent) in the presence of 4-hydroxycoumarin (1a),
-hydroxy-6-methylcoumarin 1b and 4-hydroxy-6-
(TMPD)
microtubule function.4 Dicoumarol was synthesized via a
Knoevenagel-Michael reaction between 4-hydroxycoumarin and
formaldehyde or aromatic aldehydes, which allows attachment
of a second 4-hydroxycoumarin molecule through the linking
carbon of the aldehyde, to the 3-position of the first 4-
hydroxycoumarin molecule, to give the semi-dimer the motif of
the drug class.5
(
4
(
)
methylpyron (1c). Finally, we have discovered an easy and one-
pot electrochemical method for the synthesis of dicoumarol
derivatives (3a-3c) in the high yield and purity, using an
environmentally friendly method. From green chemistry and
waste management viewpoints, dicoumarol was synthesized via
catalyst-less electrochemically CDC mechanism. Therefore, this
method minimizes metallic catalyst consumption as a great
pollutant and on the other hand, catalyst recycling cost decreases
particularly.
Formation of C-C bonds is one of the most important
reactions in organic synthesis. The direct coupling of two C-H
bonds is the most efficient method for constructing C-C bonds.10
Transition metals, iron, Li and other alkali metals made a
significant contribution to develop a series of synthetic method
to form C-C bond directly from two C-H bonds under oxidative
conditions.
Results and discussion
Cyclic voltammogram of TMPD in water (phosphate buffer, c =
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran, Zip Code: 0.2 M, pH = 3.0)/ethanol mixture (70/30, v/v) is shown in Fig. 1
6
†
5178-38683. E-mail: nemat@basu.ac.ir; Fax: +98-811-8257407.
Electronic Supplementary Information (ESI) available: H NMR , C NMR,
curve a. In this condition, voltammogram exhibits two anodic
1
13
(
(
A
1
and A
and C
2
) in the positive-going scan and two cathodic peaks
FT-IR, MS of 3a-3c. See DOI: 10.1039/b000000x/
C
1
2
) in the negative-going scan. Anodic peaks A and A
1
2
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are correspond to the transformation of TMPD to radical cation product (3a). This work has been extended with the use of 1b
TMPD.+) and TMPD.+ to dication (TMPD++), respectively, and 1c as a substrate and related semi-dimer products have been
within two successive quasi-reversible one-electron processes reported.
(
(
2 1
Scheme 1). Obviously, cathodic peaks C and C are related to
the reduction of TMPD++ to TMPD.+ and TMPD.+ to TMPD
,
H
H
respectively.8
H C
3
CH3
H C
CH2
H C
3
C
3
OH
O
N
N
N
H
R
-
e-
-
H
+
O
1a,1b
N
N
N
H3C
CH3
H C
CH3
H3C
CH3
3
OH
O
TMPD
TMPD
TMPD
Or
O
CH3
R
1c
OH
OH
O
R
H2
C
H3C
H3C
R = H
+
NH
R = CH3
O
O
O
Fig. 1. Cyclic voltammograms of TMPD at a glassy carbon electrode in water
phosphate buffer, c = 0.2 M, pH = 3.0)/ethanol (70/30) mixture. Scan rate from a
1a,1b
(
-
1
o
to f are 1000, 500, 250, 100, 25 and 5 mV s . t = 25 ± 1 C.
N
CH3
2a,2b
The effect of potential scan rate on the cyclic voltammogram
of TMPD was also studied. It is seen that, upon decreasing the
H3C
OH
HO
OH
NH
OH
R
R
potential scan rate, the peak current ratios IpC1/IpA1 and IpC2/IpA2
)
Or
+
decrease, which is indicative of the presence of a following
chemical reaction (such as hydroxylation) after the electron
O
O
O
O
O
O
O
O
N
3
a,3b
3c
H3C
CH3
9
transfer step. It also should be noted that, the effect of potential
scan rate on the IpC2/IpA2 is more than IpC1/IpA1. These data is
consistent with the higher reactivity of TMPD++ compared with Scheme 2. Proposed Mechanism for the Electrochemical Oxidation of TMPD in the
that of TMPD.+. The peak current ratios (IpC1/IpA1 and IpC2/IpA2
are also dependent to pH of the solution. Our data show that,
pC1/IpA1 and IpC2/IpA2 decrease with increasing pH. These data
also indicate that IpC2/IpA2 is more sensitive to pH than IpC1/IpA1
Presence of 1a-1c.
)
I
Galvanostatic Studies
so that, the cathodic peak C
confirms instability of TMPD++ compared with that of TMPD.+
2
disappears in basic solutions. This
Constant current electrolysis was performed for improving
applicability of the procedure. To take the high product yield,
some affecting electrosynthesis factors must be optimized. In
this direction, applied current density, charge passed and
electrode material were investigated by setting all parameters to
be constant and optimizing one each time. Among the
electrochemical parameters for the synthesis of organic
compounds, the current density is one of the most important
factors influencing the yield and purity. This factor can also play
an important role in determining the dominant reaction at the
.
H3C
CH3
H3C
CH3
H3C
CH3
N
N
N
N
N
e-
-e-
-
N
H3C
CH3
H3C
CH3
H3C
CH3
TMPD
TMPD
TMPD
Scheme 1. Electrochemical Oxidation of TMPD
.
surface of electrode. In this work, the current density varied from
2
0
2
.05 to 1.20 mA/cm , while the other parameters (temperature =
98 K, charge passed = 50 C, TMPD, 0.5 mmol and 1a 1.0
Preparative scale electrolyses were performed in a mixture of
phosphate bu er (c = 0.2 M, pH = 3.0)/ethanol (70/30, v/v),
ff
mmol) are kept constant. The highest product yield was obtained
at current density of 1.0 mA/cm (Fig. 2, part I.). The formation
of TMPD++ (two electron oxidation) at higher current densities
and its participation in Michael addition reaction cause a
decrease in the product yield. The product yield also depends on
the amount of charge passed, as shown in Figure 2, part II. The
effect of charge passed was studied in the range of 10-60 C
containing TMPD (0.5 mmol) and 1a (1.0 mmol) in an
undivided cell at the first peak potential. The reaction product
was isolated and identified as dicoumarol (3a) (yield 95%)
2
(
Scheme 2). The formation of this compound is explained as
follows: oxidation of TMPD at 0.25 V (vs. Ag/AgCl), by loss of
an electron, affords the corresponding radical cation (TMPD.+),
which further converts to hydrogen radical and the cation
TMPD+. Subsequent intramolecular attack of 1a to TMPD+
(
theoretical amount is 50 C). As is shown, the product yield
decreases with increasing charge passed from theoretical
amount. This may be due to the over-oxidation of 3a after
gives intermediate 2a. In acidic media, 2a undergoes direct S
N
2
substitution11 by the second molecule of 1a to afford the final
2
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consumption of
1
F mol-1. All variables (anode = carbon, current or 1c (1.0 mmol), was electrolyzed in an undivided cell by
2
density = 1.0 mA/cm , temperature = 298 K, TMPD, 0.5 mmol potentiostatic method at first peak potential or galvanostatic
and 1a, 1.0 mmol), except the amount of charge passed, were method at current density 1.0 mA/cm . The electrolysis was
2
kept constant. The effect of anode material (carbon, platinum and terminated when the consumed charge equals to 52 C. At the end
gold) on the yield of 3a was also studied. Our data show that of the electrolysis, the precipitated solid was collected by
carbon is a suitable anode for the synthesis of 1a. The similar filtration and washed with water/ethanol mixture (50/50 v/v).
1
results are obtained by repeating the same experiments for 1b The products were characterized by: MS, FTIR, H NMR and
and 1c
.
13C NMR (see ESI†).
3,3'-Methylenebis(4-hydroxy-2H-chromen-2-
one) or dicoumarol (3a)
Creamy–white crystalline powder (yield 95%). mp = 286−289
°
3
2
C (dec) (Lit. 289-292).11a 1H NMR (400 MHz, DMSO-d
6
) 
.79 (s, 2H, methylene), 7.34 (m, 4H, aromatic), 7.59 (t, J =7.6,
H, aromatic), 7.91 (d, J =7.6, 2H, aromatic); 13C NMR (100
): δ 19.3, 102.2, 116.0, 116.8, 123.3, 123.8,
MHz, DMSO-d
1
1
6
−
1
31.6, 151.8, 162.4, 163.6; IR (KBr, cm ): 770, 1110, 1309,
349, 1454, 1601, 1628, 1651, 2612, 2729, 3067, 3436; MS (EI)
+
(
(
m/z) (relative intensity): 336 [M] (83), 290 (7), 215 (67), 187
44), 175 (27), 162 (82), 121 (100), 65(63).
Fig. 2. Effect of current density and charge passed on the yield of 3a
.
4
-Hydroxy-3-((4-hydroxy-6-methyl-2-oxo-2H-
chromen-3-yl) methyl)-6-methyl-2H-chromen-
-one (3b)
Conclusion
2
The results of this work show that TMPD is oxidized to its
respective radical cation. The formed radical cation via the cross-
dehydrogenative-coupling (CDC) converts to dicoumarol (3a) in
good yield and high purity without any metal catalysts. The
prominent features of this paper, the synthesis of valuable
compounds in aqueous/ethanol mixture instead of toxic solvents,
room temperature conditions, high energy efficiency and using
the electrode as an electron source instead of toxic reagents, are
in accord with the principle of green chemistry.
Creamy–white powder (yield 90%). mp = 273–275 °C (dec.)
Lit. 273-275).11a,11b 1H NMR (400 MHz, DMSO-d
): δ 2.38 (s,
H, methyl), 3.77 (s, 2H, methylene), 7.24 (d, J = 8.4, 2H,
aromatic), 7.39 (d, J = 8.4, 2H, aromatic), 7.71 (s, 2H,aromatic);
13C NMR (100 MHz, DMSO-d
): δ 19.3, 20.4, 102.2, 115.8,
(
6
6
6
−
1
1
1
3
2
16.4, 120.3, 132.6, 133.1, 1ꢀ3.3, 164; IR (KBr, cm ): 816, 916,
106, 1211, 1282, 1332, 1447, 1504, 1581, 1659, 292ꢀ, 3061,
+
432; MS (EI) m/z (relative intensity): 364 [M] (85), 318 (11),
90 (3), 255 (3), 229 (58), 202 (32), 176 (69), 135 (100), 106
(
16 6
30), 72 (32), 51 (15). Anal. calcd for C21H O : C, 69.23; H,
4
.43%. Found: C, 69.16; H, 4.60.
Experimental
4
-Hydroxy-3-((4-hydroxy-6-methyl-2-oxo-2H-
The working electrode used in the voltammetry experiments was
pyran-3-yl)methyl)-6-methyl-2H-pyran-2-one
2
a glassy carbon disc (1.8 mm area) and platinum wire was used
as counter electrode. The working electrode used in controlled- (3c)
potential coulometry and macro-scale electrolysis was carbon
plate (148 cm ) and large steel gauze constitutes the counter
electrode. The working electrode potential was measured versus
Ag/AgCl. The electrochemical oxidations were performed under
constant-current condition in a simple cell equipped with a
magnetic stirrer. N,N,N’,N’-tetramethyl-1,4-phenylenediamine,
Black crystalline powder (yield 80%). mp = 245-247 °C (dec.)
Lit. 250-251).11c 1H NMR (400 MHz, DMSO-d
): δ 2.13 (s, 6H,
methyl), 3.33 (s, 2H, methylene), 5.96 (s, 2H, aromatic), 11.1 (s,
2
(
6
H, OH). 13C NMR (100 MHz, DMSO-d
1
1
1
6
): δ 17.2, 19.1, 99.0,
00.0, 159.7, 165.0, 165.6. IR (KBr, cm ): 52ꢀ, 991, 1076,
17ꢀ, 1238, 1578, 1681, 2672, 2926, 3087, 3439. MS (EI) m/z
−1
4-hydroxycoumarin, ethanol, phosphoric acid and phosphate
+
(
relative intensity): 264 [M] (100), 221 (14), 179 (85), 151 (50),
salts were reagent-grade materials and obtained from
commercial sources. These chemicals were used without further
purification. The glassy carbon electrode was polished using
alumina slurry (from Iran Alumina Co.). Reaction equipment is
described in an earlier article.10 For more details see ESI†.
1
12 6
11 (21), 85 (42), 55 (18). Anal. calcd for C13H O : C, 59.09;
H, 4.58%. Found: C, 58.93; H, 4.67.
Acknowledgements
We acknowledge the Bu-Ali Sina University Research
Council and Centre of Excellence in Development of
Environmentally Friendly Methods for Chemical Synthesis
Electroorganic synthesis of 3a-3c
A solution of phosphate bu
ff
er (c = 0.2 M, pH = 3.0)/ethanol
(
70/30 v/v) mixture, containing TMPD (0.5 mmol) and 1a
,
1b
(
CEDEFMCS) for their support of this work.
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