Organic electrosynthesis using toluates as simple and versatile radical precursors

Article abstract of DOI:10.1039/b813545b

The electrolysis of toluate esters leads smoothly to the formation of the radical of the alkyl fragment. This property has been used to develop a new electrochemical deoxygenation reaction. The Royal Society of Chemistry.

Full text of DOI:10.1039/b813545b

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COMMUNICATION
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Organic electrosynthesis using toluates as simple and versatile
radical precursorsw
´ ´
Kevin Lam and Istvan E. Marko*
Received (in Cambridge, UK) 5th August 2008, Accepted 7th October 2008
First published as an Advance Article on the web 17th November 2008
DOI: 10.1039/b813545b
The electrolysis of toluate esters leads smoothly to the formation
of the radical of the alkyl fragment. This property has been used
to develop a new electrochemical deoxygenation reaction.
the produced radical 5: the more stable is 5, the faster will be
the breakdown of 3.
By recording cyclic voltammograms of aromatic esters such
as 1 and by using DigitalSimulation,9 we have been able to
measure the kinetics of decomposition of various radical
anions (See ESIw). The modulation of the aromatic substitu-
tion revealed that the toluate moiety displayed enhanced
reactivity.10 It was thus selected for the deoxygenation studies.
Our initial attempts to deoxygenate 9-fluorenyl toluate 6 were
performed in an undivided electrolysis cell (Table 1). Unfortu-
nately, using different sacrificial anodes or various solvents led
to none of the desired product 7. However, when the reaction
was conducted in a divided H-type cell, in N-methylpyrrolidone
(NMP) at 130 1C using tetrabutylammonium tetrafluoroborate
as supporting electrolyte,11 we were able to isolate the deoxyge-
nated product 7 in a yield of 50%.12 Surprisingly, when the
electrolysis was carried out in acetonitrile, only degradation
occurred, probably due to side reactions involving the solvent.
The yields in DMF and in NMP are comparable, but NMP is
more convenient to use for long electrolysis since it doesn’t suffer
degradation when heated. However, NMP is difficult to remove
(high boiling point) and we have tried to replace it by THF.
Although the electrochemical window of THF is too small to
allow the reduction of the toluate (À2.6 V vs. Ag/AgCl in EtOH
sat. LiCl), it is possible to use a mixture of THF/NMP (9/1 in
volume) if the electrochemical cell is modified to be compatible
with refluxing THF.
The transformation of an alcohol into the corresponding
alkane by removal of the OH function represents an important
and often delicate conversion in organic chemistry. Apart
from classical multistep sequences,1 the Barton–McCombie
reaction and its variants have been considered as the acme of
such transformations.2 Unfortunately, this procedure suffers
from a number of shortcomings, including the preparation of
sensitive xanthates and the use of toxic reagents, such as tin
derivatives. Growing ecological concerns have provided che-
mists with renewed impetus to offer environmentally friendlier
alternatives such as the use of hypophosphite3 or the trialkyl-
borane/water system.4 Electrochemistry is a particularly eco-
nomical and environmentally benign technology that possesses
enormous, though still under exploited, potential for the
development of eco-friendly transformations. For example,
only a few preparative electrochemical deoxygenation reac-
tions have been recounted in the literature. Usually, they
require either a rather negative potential,5 and hence, the use
of a lead or mercury cathode with high overvoltage, or they
are limited to primary and secondary alcohols.6 Recently, we
have described a method for generating radical species,
directly from simple toluate esters, using samarium(II) iodide.7
In this Communication, we wish to report the successful
application of electrochemistry to the efficient deoxygenation
of a large variety of toluate esters. In contrast to our previous
approach, no metals and no toxic co-solvents (e.g. HMPA) are
required.
The temperature of the electrolysis also plays a key role
(Table 2). The optimal temperature range lies between 70 1C
and 100 1C. When the electrolysis was performed below 70 1C,
only traces of the reduced compound were found among
numerous degradation products.
It has already been proposed that, under electrochemical
conditions, aromatic esters were initially reduced to the corre-
sponding radical anion 3, which partitions into the carboxy-
late 4 and the radical 5 (See Scheme 1).8 The rate of this
decomposition can be directly correlated with the stability of
Table 1 Influence of the solventa
Scheme 1 Decomposition pathway of the radical anion.
Entry
Solvent
Yield in fluorene
1
2
3
4
CH3CN
NMP
THF
THF/NMP (90/10)
0%
50%
0%
De´partement de Chimie, Baˆtiment Lavoisier, Universite´ catholique de
Louvain, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium.
E-mail: istvan.marko@uclouvain.be
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization of new compounds, references to known
compounds, an example of a cyclic voltammogram and kinetic rates
determined by DigitalSimulation. See DOI: 10.1039/b813545b
46%
a
All reactions were performed under argon, in dried and degassed
solvent, at 130 1C or under reflux.
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Table 2 Influence of the temperaturea
Table 4 Electroreduction of toluatesa
Entry Toluate
Product
Yield
Entry
Temperature
Yield in fluorene
1
2
12
14
13 85%
1
2
3
4
25 1C
70 1C
100 1C
130 1C
0%
32%
50%
50%
15 75%
a
All reactions were performed under argon in dried and degassed
NMP.
Finally, we have also investigated the influence of the
cathode’s composition on the yield of the final product. As
can be seen from Table 3, carbon graphite provides the best
yield (entry 1). Surprisingly, with copper and lead electrodes,
fluorenone was formed in 10% and 40% yields, respectively.13
3
4
16
18
17 38%
Table 3 Influence of the cathodea
19 72%
5
6
20
22
21 83%
23 64%
Entry
Cathode
Yield in fluorene
1
2
3
4
5
Cgraphite
Platinum
Iron
Copper
Lead
50%
42%
10%
0%b
0%b
7
8
24
25 70%
29 41%
28 n-C22H46
a
All reactions were performed under argon in dried and degassed
NMP with a 6 cm2 cathode, except for the platinum cathode which
was 9.5 cm2. See ref. 13.
b
9
6
7
50%
In order to demonstrate the formation of a radical, akin to
5, during the reduction process, it was decided to capture it by
a suitably positioned triple bond (See Scheme 2). Precursor 8
was thus assembled and subjected to the electrolytic condi-
tions. Delightfully, the expected tetrahydrofuran 9 could be
isolated in up to 60% yield.
10
30
31 67%
a
All reactions were performed under argon in dried and degassed
NMP at 130 1C.
With this information in hand, the scope and limitations of
this electrochemically-mediated deoxygenation methodology14
were investigated, with a special emphasis on functional group
compatibility. Some results are collected in Table 4.
Scheme 2 Radical cyclization.
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Table 5 Formation of radical or aniona
Notes and references
1 K. Kaikiuchi, M. Ue, M. Takeda, T. Tadaki, Y. Kato,
T. Nagashima, Y. Tobe, H. Koike, N. Ida and Y. Odaira, Chem.
Pharm. Bull., 1987, 35, 617; T. H. Haskell, P. W. K. Woo and
D. R. Watson, J. Org. Chem., 1977, 42, 1302; E. L. O. Sauer and
L. Barriault, Org. Lett., 2004, 6, 3329.
2 D. H. R. Barton and S. W. J. McCombie, J. Chem. Soc.,
Perkin Trans. 1, 1975, 1574; W. Hartwig, Tetrahedron, 1983, 39, 2609.
3 D. H. R. Barton, D. O. Jang and J. Cs. Jaszberenyi, Tetrahedron
Lett., 1992, 33, 5709; S. R. Graham, J. A. Murphy and D. Coates,
Tetrahedron Lett., 1999, 40, 2415.
4 D. A. Spiegel, K. Wiberg, L. Schacherer, M. Medeiros and
J. L. Wood, J. Am. Chem. Soc., 2005, 127, 12513.
5 T. Shono, Y. Matsumura, K. Tsubata and Y. Sugihara, Tetra-
hedron Lett., 1979, 20, 2157.
6 H. Ohmori, H. Maeda, M. Kikuoaka, T. Maki and M. Masui,
Tetrahedron, 1991, 47, 767; H. Maeda, T. Maki and H. Ohmori,
Tetrahedron Lett., 1992, 33, 1347; H. Maeda and H. Ohmori, Acc.
Chem. Res., 1999, 32, 72.
Entry R1
R2
R3
Yield in 33
32a 33%
32b 64%
Yield in 34
33a 0%
33b 0%
33c 0%
33d 62%
1
2
3
4
n-Bu
H
H
H
34a
34b
34c
34d
Me
Me
Me
n-Hex
Me
Ph
Me 32c 79%
32d 5%
H
a
All reaction were performed under argon in dry and degassed NMP.
7 K. Lam and I. E. Marko, Org. Lett., 2008, 10, 2773.
´
As can be seen from Table 4, a wide variety of functional
8 J. H. Wagenknecht, R. Goodin, P. Kinlen and F. E. Woodard,
J. Electrochem. Soc., 1984, 131, 1559; R. D. Webster, A. M.
Bond and R. G. Compton, J. Phys. Chem., 1996, 100,
10288; R. D. Webster and A. M. Bond, J. Org. Chem., 1997, 62, 1779.
9 DigitalSimulations were performed by using DigiElch Pro software.
10 The decomposition of the aromatic radical-anion is faster when the
aromatic nucleus bears an inductive electron substituent, such as a
methyl group. The methoxy-substituted benzoates are slightly
more difficult to reduce but the rate of decomposition of the
corresponding anion-radical is similar to that derived from the
toluate. Finally, in the case of the simple benzoate, competing
addition of the in situ generated radical to the para position of the
aromatic ring has been observed.
groups are compatible with the deoxygenation reaction.
The toluate ester could be selectively deoxygenated in the presence
of another ester (entry 4), an amide (entry 7) or a silyl ether
(entry 5). Even ketones or unprotected alcohols are tolerated
(entries 6 and 10). Only primary toluates tend to give moderate
yields.
The inertness of the ketone function under these reductive
conditions was rather puzzling and the deoxygenation of a
few carbonyl-containing derivatives was next attempted
(See Table 5).
11 We suspect the tetrabutylammonium cation to be the hydrogen
atom donor since only degradation occurred when lithium
perchlorate was used as the supporting electrolyte.
As can be seen from Table 5, the substitution of the carbon
atom bearing the toluate function by simple alkyl groups does
not influence the fate of the reduction, since deoxygenation
of primary, secondary and tertiary toluates gives only the
reduced, non cyclic product 33, though the yields increase in
the order 11o21o31 (entries 1, 2 and 3). On the other hand, if
there is an anion stabilizing group a to the toluate, the radical
could be rapidly reduced to the corresponding anion. This is
illustrated by the electrolysis of substrate 32d, bearing a
benzylic toluate (entry 4), which leads to the cyclic product
34d. In this case, the benzylic radical is rapidly reduced into
the corresponding benzylic anion.
12 Standard electrolysis procedure: An H-type cell, with two compart-
ments of 100 ml, separated by a sintered glass with a porosity of
40 mm, was dried during one night at 200 1C. Then, each cell was
equipped with a graphite electrode of 6 cm2 and a magnetic stir bar.
Both compartments were then flushed with argon during
10 min. After filling them with 5 g of NBu4BF4 and with 100 ml of
NMP, freshly distilled under argon, 600 mg (0.6 mmol) of 9-fluorenyl
toluate, dissolved in a little NMP, were added to the cathodic
compartment and the solution was stirred and heated up to 130 1C.
Then, the intensity of the current was fixed at 90 mA and the mixture
was electrolysed until completion of the reaction, as shown by TLC or
by GC. The cell was then cooled down to room temperature and the
catholyte was carefully diluted with 100 ml of 4 N HCl. The resulting
solution was extracted 4 times with 30 ml of ether. The organic phases
were pooled, dried over sodium sulfate and the solvent was removed
under reduced pressure. Finally, the crude product was purified by
chromatography on silica gel, using pentane as eluent (Rf = 0.7),
affording the title compound as a white powder in 50% yield. This
material proved to be identical to an authentic sample of fluorene.
13 A plausible explanation could be a reaction between the fluorenyl
radical and the oxide layer of the electrode. Indeed, copper and
lead electrodes are usually covered by a reactive oxide layer. In this
regard, we have obtained a similar result when using Cgraphite
electrodes in non-degassed NMP.
In summary, we have developed a novel, efficient and
economical methodology for the deoxygenation of alcohols
which tolerates a wide variety of functionalities. In contrast to
previous methods, noxious or unstable xanthates and deriva-
tives, expensive or sensitive metals and toxic co-solvents are no
longer required. In addition, this methodology can also be
useful for the electrogeneration of radicals or anions directly
from the corresponding toluates.
Financial support of this work by the F.R.I.A. (Fond pour
la formation a la Recherche dans l’Industrie et l’Agriculture,
studentship to K.L.), the Universite catholique de Louvain
´
14 No Kolbe-like dimers have been detected in this reaction. This
could originate from the rapid capture of the radical by the large
excess of tetra-alkylammonium salts or, as in the case of the
benzylic substrates, by the fast reduction of this radical into the
corresponding anion. (See Table 5, entry 4).
and Merck Sharp and Dohme (Merck Academic Development
Program Award to I.E.M.) is gratefully acknowledged.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 95–97 | 97