Electroorganic synthesis using a fluoride ion mediator under ultrasonic irradiation: Synthesis of oxindole and 3-oxotetrahydroisoquinoline derivatives

Article abstract of DOI:10.1021/ol049152f

(Equation Presented) Anodic intramolecular cyclization of α-(phenylthio)acetamides using a fluoride ion mediator was realized. Under ultrasonic irradiation, cyclization was accelerated markedly to give desired cyclized products in moderate to good yields.

Full text of DOI:10.1021/ol049152f

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ORGANIC
LETTERS
2004
Vol. 6, No. 14
2441-2444
Electroorganic Synthesis Using a
Fluoride Ion Mediator under Ultrasonic
Irradiation:1 Synthesis of Oxindole and
3-Oxotetrahydroisoquinoline Derivatives
Yi Shen, Mahito Atobe, and Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, 4259 Nagatsuta,
Midori-ku, Yokohama 226-8502, Japan
fuchi@echem.titech.ac.jp
Received May 10, 2004
ABSTRACT
Anodic intramolecular cyclization of r-(phenylthio)acetamides using a fluoride ion mediator was realized. Under ultrasonic irradiation, cyclization
was accelerated markedly to give desired cyclized products in moderate to good yields. The local heating effect of ultrasonic irradiation
seems to be more advantageous than usual heating.
Electroorganic synthesis has developed remarkably because
it offers unique selectivity and the high possibility of realizing
specific reactions that cannot be accomplished by other
chemical synthetic procedures.2 One great advantage of the
electrochemistry associated with mediators is that it carries
out reactions under mild conditions and achieves high yields
and selectivities.3-6 To date, electroorganic synthetic efforts
have specifically addressed carbon-carbon bond formation
reactions; a wide variety of methods have been developed.7,8
Recently, Motherwell et al. demonstrated that the cyclization
reaction of N-phenyl- and N-benzyl-R-(phenylthio)acetamides
proceeded with a fluoro-Pummerer-type mechanism using
difluoroiodotoluene as an oxidizing reagent.9 Nevertheless,
those cyclization product yields were moderate. Difluor-
oiodotoluene is unstable. Moreover, preparation of the
oxidant requires hazardous fluorine gas or costly XeF2. On
the other hand, we have shown that anodic generation of
carbocations on the R-position to the sulfur atom occurs using
a fluoride ion mediator. Methanol successfully trapped these
intermediates to give R-methoxylated products (Scheme 1).10
Presumably, the cation intermediates generated in these
reactions can also be directly trapped with an aromatic ring.
In addition, applying ultrasonic irradiation in electrochemical
systems may cause various interesting and beneficial effects
and can act as a probe of the reaction mechanism.11-14 We
(1) Electroorganic Synthesis Using a Fluoride Ion Mediator. 6.
(2) Moeller, K. D. Tetrahedron 2000, 56, 9527.
(3) Simonet, J.; Pilard, J.-F. Organic Electrochemistry, 4th ed.; Lund,
H., Hammerich, O., Eds.; Marcel Dekker: New York, 2001; Chapter 29.
(4) Steckhan, E. Angew. Chem. 1986, 98, 681.
(9) Motherwell, W. B.; Greaney, M. F.; Edmunds, J. J.; Steed, J. W. J.
Chem. Soc., Perkin Trans. 1 2002, 2816.
(5) Torii, S. Synthesis 1986, 893.
(6) Shen, Y.; Suzuki, K.; Atobe, M.; Fuchigami, T. J. Electroanal. Chem.
2003, 540, 189.
(7) (a) Reddy, S. H. K.; Chiba, K.; Sun, Y.; Moeller, K. D. Tetrahedron
2001, 57, 5183. (b) Sun, Y.; Liu, B.; Kao, J.; d’Avignon, D. A.; Moeller,
K. D. Org. Lett. 2001, 3, 1729. (c) Sun, Y.; Moeller, K. D. Tetrahedron
Lett. 2002, 43, 7159.
(10) (a) Fuchigami, T.; Yano, H.; Konno, A. J. Org. Chem. 1991, 56,
6731. (b) Furuta, S.; Fuchigami, T. Electrochim. Acta 1998, 43, 3153. (c)
Furuta, S.; Saito, Y.; Fuchigami, T. J. Fluorine Chem. 1998, 87, 209.
(11) Walton, D. J.; Phull, S. S. AdVances in Sonochemistry; Mason, T.
J., Ed.; JAI: London, 1996; Vol. 4, p 248 and references therein.
(12) Compton, R. G.; Eklund, J. C.; Marken, F.; Rebbitt, T. O.;
Akkermans, R. P.; Waller, D. N. Electrochim. Acta 1997, 42, 2919.
(8) Mihelcic, J.; Moeller, K. D. J. Am. Chem. Soc. 2003, 125, 36.
10.1021/ol049152f CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/17/2004

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with the increase of the passed charge, and the best yield
was obtained at 6 F mol-1 (entry 4). The yield decreased
when more than 6 F mol-1 was passed. A considerable
amount of substrate 1a was recovered at less than 6 F mol-1
(entries 2 and 3), whereas the overoxidization of 2a and 3a
occurred, thereby engendering lower yields at more than 6
F mol-1(entry 5). Next, the charge was fixed at 6 F mol-1
and the amount of a fluoride ion mediator was varied (Table
1, entries 4, 6, and 7). As shown in entry 6, the low yields
of 2a and 3a indicated that 0.1 mmol of Et3N‚3HF was not
sufficient for the oxidation of 1a because of its lower
conductivity. The use of 0.5 mmol of Et3N‚3HF accelerated
the further fluorination of 2a and 3a so that the yields of 2a
and 3a were decreased (entry 7). Consequently, 0.2 mmol
of Et3N‚3HF was found to be the most suitable concentration
of the mediator. Furthermore, current density was obviously
important for the oxidation of 1a. In addition, Table 1 shows
that the yields of products changed greatly depending on the
current density (entries 4, 8, and 9). At 20 mA cm-2 of
current density, the highest yields of 2a (41%) and 3a (42%)
were obtained (entry 8).
Scheme 1
were interested in proving how the ultrasonic irradiation
might influence a fluoride ion mediated reaction.
With these facts in mind, the anodic cyclization of N-aryl-
and N-benzyl-R-(phenylthio)acetamides 1 using a fluoride
ion mediator was attempted using 1 mmol of R-(phenylthio)-
N-methyl-N-phenylacetamide (1a) as a model substrate in
15 mL of acetonitrile containing Et3N‚3HF as both a
supporting electrolyte and mediator in an undivided cell
equipped with platinum plates (2 × 2 cm2) as an anode and
a cathode under various conditions, as shown in Table 1.
Under these consequent optimum conditions (Table 1,
entry 8), the anodic oxidation of other derivatives 1b-d was
carried out using fluoride ions as a mediator (Table 2). All
Table 1. Effect of Electrolytic Conditions on the Anodic
Oxidation of 1a Using a Fluoride Ion Mediator
Table 2. Anodic Oxidation of 1 Using a Fluoride Ion
Mediatora
mediator
yield (%)
(Et3N‚3HF) charge passed current density
(mmol)
substrate
yield (%)
entry
(F mol-1
)
(mA cm-2
)
2a
3a
ox b
entry
no.
R
R′
n
Ep
(V vs SCE)
2
3
1
2
3
4
5
6
7
8
9
0a
6
3
4
6
8
6
6
6
6
10
10
10
10
10
10
10
20
40
0
2
9
24
20
5
8
41
26
0
10
23
30
21
10
28
42
38
1
2
3
4
1a
2a
3a
4a
Me
Et
H
H
0
0
1
0
1.59
1.59
1.57
1.55
41
14
13
16
42
32
31
11
0.2
0.2
0.2
0.2
0.1
0.5
0.2
0.2
Me
Me
H
Me
a Electrolytic conditions: 0.2 mmol of Et3N‚3HF and 1 mmol of substrate
in 15 mL of MeCN, current density, 20 mA cm-2; charge passed, 6 F mol-1
T, 20 °C. b Substrate 3 mM in 0.1 M Bu4NBF4/MeCN; Pt disk anode (Φ
) 1 mm); scan rate, 100 mV s-1
;
.
a 0.1 M Bu4NBF4 was used as a supporting electrolyte.
reactions gave both corresponding cyclized products 2 and
fluorinated products 3 in reasonable yields, which supported
the proposed mechanism, as shown in Scheme 2. One-
electron oxidation of starting amides 1a-d generates radical
cation A, which is trapped by a fluoride ion to give the
corresponding radical B. Further oxidation of the radical B
was followed by elimination of HF to afford intermediate
C. At this stage, two pathways are possible as follows: an
intramolecular Friedel-Crafts-type reaction gives desired
cyclized products 2 (path 1), whereas C reacts with a fluoride
ion to give R-fluorinated compounds 3. In both cases, the
fluoride ion works as a mediator for formation of the
intermediate C.
Although anodic oxidation did not proceed at all in the
absence of fluoride ions (entry 1), fluoride ion mediated
anodic oxidation proceeded to provide the desired product
2a and fluorinated products 3a regardless of electrolytic
conditions.
First, we investigated the effect of a passed charge on the
yield of 2a (Table 1, entries 2-5). The yield of 2a increased
(13) Walton, D. J.; Mason, T. J. Synthetic Organic Sonochemistry; Luche,
J.-L., Ed.; Plenum: New York, 1998; Chapter 7 and references therein.
(14) (a) Atobe, M.; Nonaka, T. J. Chem. Soc. Jpn. 1998, 219. (b) Atobe,
M.; Kado, Y.; Nonaka, T. Ultrason. Sonochem. 2000, 7, 97. (c) Atobe, M.;
Sasahira, M.; Nonaka, T. Ultrason. Sonochem. 2000, 7, 103.
2442
Org. Lett., Vol. 6, No. 14, 2004

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Electrooxidation under ultrasonic irradiation was attempted
using 1c as a model substrate. As shown in Figure 2, the
Scheme 2. Proposed Mechanism for the Anodic Oxidation of
1 in the Presence of Fluoride Ions
Figure 2. Effect of ultrasonic irradiation power on anodic
cyclization using a fluoride ion mediator: b, yield of 2c; 2, yield
of 3c; 9, total yield.
yield of 2c increased markedly with increased ultrasonic
irradiation power. The yield achieved the maximum 68%
yield at 43 W cm-2 of the ultrasonic power. On the other
hand, the yield of fluorinated product 3c decreased ap-
preciably from 31% (non irradiation) to 15%. Encouraged
by this good result, electrolysis of other derivatives 1a,b,d
was carried out under the same conditions. Table 3 lists the
However, the yields of the desired cyclized products 2
were not satisfactory under the above electrolytic conditions.
Our experience in sonoelectrochemistry prompted us to apply
ultrasonic irradiation to this anodic oxidative cyclization.
Figure 1 shows the apparatus for electrolysis under ultrasonic
Table 3. Anodic Oxidation of 1 Using a Fluoride Ion Mediator
under Ultrasonic Irradiationa
substrate
yield (%)
entry
no.
R
R′
n
2
3
1
2
3
4
1a
1b
1c
1d
Me
Et
Me
Me
H
H
H
Me
0
0
1
0
72
58
68
47
12
9
15
7
a Conditions: 0.2 mmol of Et3N‚3HF and 1 mmol of substrate 1 in 15
mL of MeCN; current density, 20 mA cm-2; charge passed, 6 F mol-1; T,
20 °C; ultrasonic irradiation power, 43 W cm-2
.
Figure 1. Apparatus for electrosynthesis under ultrasonic irradia-
tion. Sonoelectrochemical system using a stepped horn: (1) working
electrode (Pt 2 × 2 cm2), (2) counter electrode (Pt 2 × 2 cm2), (3)
ultrasonic horn, (4) heater, (5) pipe-type cooler, (6) stirring bar.
yields of cyclized products 2 and fluorinated products 3. The
desired cyclization was promoted markedly under ultrasonic
irradiation to provide cyclized products 2 in much higher
yields compared with the electrolysis under nonsonication
(Table 2). The highest yield of 2a reached 72% (Table 3,
entry 1), whereas the corresponding fluorinated product 3a
was decreased radically to 12%, which indicates the strong
effect of ultrasonic irradiation on product selectivity control.
However, we wondered why the ultrasound irradiation
affected the reaction pathways so drastically. Ultrasound
irradiation. The working electrode is located on the bottom
of the cell and an ultrasonic stepped horn is set vertically
1.5 cm apart from the work electrode.
The water bath temperature is maintained automatically
at 20 °C using a heater and a pipe-type cooler to maintain
the temperature inside cell under ultrasonic irradiation.
Org. Lett., Vol. 6, No. 14, 2004
2443

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exerts myriad effects upon electrochemical reactions.14
Herein, it is important to understand which is the main effect
of ultrasound on the electrolytic reactions. The following
experiments were designed to disclose the effect. First, we
investigated the effect of stirring speed using 1c as a model
substrate under electrolytic conditions similar to Table 3.
Figure 3 shows that the yields of both 2c and 3c increase
Figure 4. Effect of temperature on electrolysis of 1c: b, yield of
2c; 2, yield of 3c; 9, total yield.
bond formation was reported by Moeller et al.15 From results
obtained under ultrasonication, the effect of ultrasound on
the selectivity of 2c seems to be attributable to its local
heating action, which increases the temperature sufficiently
for cyclization. On the other hand, such a high temperature
is not available through usual heating because of the limited
boiling points of organic solvents such as acetonitrile.
In conclusion, an intramolecular carbon-carbon bond
formation was realized by anodic oxidation of sulfides using
a fluoride ion mediator. Under ultrasonic irradiation, the
cyclization is markedly accelerated to give the desired cyclic
products in moderate to good yields. The local heating effect
by ultrasonic irradiation seems to be more advantageous than
usual heating. Further efforts to utilize this unique ultrasound-
aided anodic cyclization synthetic method are in progress.
Figure 3. Effect of stirring speed on electrolysis of 1c: b, yield
of 2c; 2, yield of 3c; 9, total yield.
simultaneously. No change of selectivity was observed,
which indicates that the acceleration of mass transport was
not obviously allied with the selectivity. In the next experi-
ment, the stirring speed was fixed at 1000 rpm. The
temperature was varied from 20 to 70 °C. As shown in Figure
4, the yield of 2c increased with an increase of temperature.
In addition, the yield of 2c became higher than that of 3c at
around 55 °C, indicating that high temperature is suitable
for selective formation of 2c. Because the intramolecular
reaction pathway would involve smaller activation entropy,
it would become more favorable than the intermolecular
pathway as the reaction temperature increases. A similar
temperature effect on anodic cyclization caused by C-O
Supporting Information Available: A sample experi-
ment for the electrochemical procedure and characterization
data for electrochemical substrates and corresponding prod-
ucts are included along with copies of proton NMR spectra
for 1b, 2b, and 3a,b,d. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL049152F
(15) Duan, S.; Moeller, K. D. J. Am. Chem. Soc. 2002, 124, 9368.
2444
Org. Lett., Vol. 6, No. 14, 2004