Novel electrochemical deoxygenation reaction using diphenylphosphinates

Article abstract of DOI:10.1021/ol102714s

The electrochemical reduction of diphenylphosphinate esters leads smoothly and in high yields to the corresponding deoxygenated products. In comparison with the previously developed methodologies, the electrolysis could be performed at lower temperature and with a higher current density, resulting in a shorter reaction time.

Full text of DOI:10.1021/ol102714s

ORGANIC
LETTERS
2011
Vol. 13, No. 3
406-409
Novel Electrochemical Deoxygenation
Reaction Using Diphenylphosphinates
Kevin Lam and Istva´n E. Marko´*
UniVersite´ Catholique de LouVain, Baˆtiment LaVoisier, Place Louis Pasteur,
1, B-1348 LouVain-la-NeuVe, Belgium
IstVan.marko@uclouVain.be
Received November 9, 2010
ABSTRACT
The electrochemical reduction of diphenylphosphinate esters leads smoothly and in high yields to the corresponding deoxygenated products.
In comparison with the previously developed methodologies, the electrolysis could be performed at lower temperature and with a higher
current density, resulting in a shorter reaction time.
The removal of a hydroxyl group to form the corresponding
alkane is typically achieved by using the well-known
Barton-McCombie reaction1 or one of its less toxic vari-
ants.2 Unfortunately, this transformation suffers from a
serious drawback which is the need to prepare the heat and
light sensitive xanthate.3 One alternative to this procedure
is the direct deoxygenation of the hydroxyl group by using
a strong Lewis acid in combination with a hydride source.4
However, this protocol is only effective if the molecule does
not bear sensitive functionalities. On the other hand, growing
ecological and economical concerns are driving chemists
toward the discovery of new and nontoxic reactions that
employ inexpensive reagents. With this objective in mind,
we have recently reported some of our results on the
electrochemical reduction of toluates as an alternative to
classical deoxygenations. Indeed, electrochemical synthesis
usually avoids the use of toxic metallic reagents, solvents,
or additives, and it represents the cheapest and most readily
available source of electrons. Unfortunately, the reduction
of aromatic esters requires either the use of the toxic
samarium(II) iodide/HMPA system5 or that the electrore-
duction be carried out at high temperature with a low current
density. These conditions, while highly successful, tend to
require a long electrolysis time and give only modest yields
of deoxygenated products when primary alcohol derivatives
are employed.6
Diphenylphosphinates usually behave as leaving groups
when they are activated by a Lewis acid.7 They have also
been used as mild activating agents in peptide coupling
processes.8 Surprisingly, and to the best of our knowledge,
there are only a few records in the literature about the
electrochemical behavior of phosphorus esters and their use
in organic electrosynthesis.9 In this communication, we wish
to disclose that the electrochemical reduction of diphe-
(5) Lam, K.; Marko´, I. E. Org. Lett. 2008, 10, 2773.
(6) (a) Lam, K.; Marko´, I. E. Chem. Commun. 2009, 95. (b) Lam, K.;
Marko´, I. E. Tetrahedron. 2009, 65, 10930.
(1) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 16, 1574. (b) For a review, see: Hartwig, W. Tetrahedron 1983,
39, 2609.
(7) (a) Kobayashi, Y.; Minowa, T.; Mukaiyama, T. Chem. Lett. 2004,
33, 1362. (b) McCallum, J. S.; Sterbenz, J. T.; Liebeskind, L. S.
Organometallics 1993, 12, 927.
(2) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron
Lett. 1992, 33, 5709. (b) Spiegel, D. A.; Wiberg, K.; Schacherer, L.;
Medeiros, M.; Wood, J. J. Am. Chem. Soc. 2005, 127, 12513. (c) Postigo,
A.; Kopsov, S.; Ferreri, C.; Chatgilialoglu, C. Org. Lett. 2007, 9, 5159.
(3) Zard, Z. S. Angew. Chem., Int. Ed. Engl. 1997, 36, 672.
(4) Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem.
2001, 66, 7741.
(8) Ramage, R.; Hopton, D.; Parrott, M. J.; Richardson, R. S.; Kenner,
G. W.; Moore, G. A. J. Chem. Soc., Perkin Trans. 1 1985, 461.
(9) (a) For an excellent review, see: Kargin, Y. M.; Budnikova, Y. G.
Russ. J. Gen. Chem. 2001, 71, 1393. (b) Ohmori, H.; Maeda, H.; Kikuoaka,
M.; Maki, T.; Masui, M. Tetrahedron 1991, 47, 767. (c) Maeda, H.; Maki,
T.; Ohmori, H. Tetrahedron Lett. 1992, 33, 1347. (d) Maeda, H.; Ohmori,
H. Acc. Chem. Res. 1999, 32, 72.
10.1021/ol102714s  2011 American Chemical Society
Published on Web 12/21/2010

nylphosphinic esters leads to major improvements in our
previously reported electrochemical methodology for the
deoxygenation of alcohols.
At the onset of our studies, it was decided that the
mechanism of reduction of phosphinic esters would be
investigated by using cyclic voltammetry (Figure 1).
phosphorus(IV) intermediate 2 decomposes into the phos-
phorus(V) species 3. With the reduction process being
reversible, we were able to use the Shain and Nicholson’s
technique,10 refined with DigitalSimulation,11 to determine
the rate of decomposition of the radical-anion 2 as a function
of the nature of the alkyl substituent R. Various diphe-
nylphosphinates were synthesized,12 and the rate constants
for the dissociation of their radical anions were determined.
These results are summarized in Table 1.
Table 1. Decomposition Rate of Toluate and
Phosphinate-Derived Radical Anions
entry
R
k, p-CH3C6H4CO
k, (Ph)2PO
1
2
3
4
Ethyl
0.091
0.097
0.20
0.19
0.33
0.70
Cyclohexyl
1-Adamantyl
Allyl
Figure 1. Cyclic voltammogram of ethyldiphenylphosphinate (plain
6460a
Too fast to be mesured.b
line) and ethyl toluate (dotted line). Glassy carbon working
electrode, Pt rod counter electrode, Ag/AgClsat in LiCl in EtOH as
reference electrode. 0.001 M in DMF containing 0.1 M in NBu4BF4.
Sweeping rate: 150 mV/s.
a All mesures were realized in DMF containing 0.1 M NBu4BF4 using
the same setup as mentioned previously5 except for allyl toluate which was
recorded at 4000 V/s using an ultramicroelectrode. b Even at 100 000 V/s,
reversible behavior could not be observed.
As in the case of the reduction of aromatic esters,13 the
nature of the alkyl group R has a dramatic effect. The
decomposition rate can be directly correlated to the
stability of the produced radical 4. Indeed, the more stable
the radical 4, the faster the decomposition of the radical-
anion 6. It is also noteworthy that the diphenylphosphinate
radical-anion 2 tends to decompose 2 to 3 times faster
than the corresponding toluate radical anion. From a
synthetic point of view, a high decomposition rate is a
much appreciated advantage, since it will help in minimiz-
ing undesired side reactions that could otherwise arise
from the radical-anion 2.
With this information in hand, 1-adamantyldiphenylphos-
phinate 8 was submitted to a preparative electrochemical
reduction. For our initial experiment, the electrolysis was
performed in a simple electrochemical system consisting of
an undivided cell fitted with carbon graphite electrodes.14
Several solvents like DMF, NMP, CH3CN, and various
supporting electrolytes such as LiClO4, NBu4BF4, and
NBu4PF6 were screened. Unfortunately, and despite all our
efforts, no trace of adamantane 9 could be detected in these
reactions. However, when the reduction was conducted in a
divided cell, moderate yields of adamantane could be
obtained.
An interesting observation, that could be extracted from
the cyclic voltammogram, is the reversible electrochemical
behavior of ethyldiphenylphosphinate, indicating that the
reduced product (most probably the corresponding radical
anion) does not decompose immediately but possesses a long
enough lifetime to enable its oxidation back to the starting
phosphinate. The reduction potential of ethyl diphenylphos-
phinate is only slightly more negative than the corresponding
toluate: -2.4 V vs Ag/AgCl. Next, the number of electrons
exchanged during this redox process has been determined
by using standard coulometric techniques. The number of
faradays consumed per mole of ethyldiphenylphosphinate
was found to be equal to one. These observations strongly
suggest that the reduction of diphenylphosphinates follows
an EC type mechanism. Hence, the diphenylphosphinate ester
1 is initially reduced into the corresponding radical-anion 2
(E, Electrochemical step) which decomposes subsequently
into diphenylphosphonic acid (3) and into the radical of the
alkyl part (4) (C, Chemical step) (Scheme 1).
Scheme 1. Probable Decomposition Pathway
(10) Nicholson, R. S.; Shain, I. Anal. Chem. 1964, 706.
(11) http://www.elchsoft.com.
(12) McCallum, J. S.; Liebeskind, L. S. Synthesis 1993, 8, 819.
(13) Wagenknecht, J. H.; Goodin, R.; Kinlen, P.; Woodard, F. E. J.
Electrochem. Soc. 1984, 131, 1559.
The main driving force of this reaction would be the
formation of the phosphorus-oxygen double bond when the
(14) Peltier, D.; Le Guyader, M.; Tacussel, J. Bull. Soc. Chim. Fr. 1963,
2609.
Org. Lett., Vol. 13, No. 3, 2011
407

In order to optimize this process, the influence of the
solvent was initially studied. Some relevant results are
collected in Table 2.
Table 4. Influence of the Current Density
Table 2. Influence of the Solvent
a All yields are for pure, isolated products.
electrodes, and formation of side products originating from
the electrodegradation of the solvent.15 Finally, the supporting
electrolytes and the nature of the electrodes were found to
have little influence on the reaction rate even though carbon
graphite electrodes offer the advantage of being cheap and
easily renewable.
Having delineated the best conditions to successfully
perform the electrochemically mediated removal of the
oxygen function present in 1-adamantanol, the scope and
limitations of our methodology for the reductive deoxygen-
ation of alcohols were explored. Some significant results are
collected in Table 5.
As can be seen from Table 5, primary, secondary, and
tertiary (1°, 2°, and 3°) phosphinates smoothly undergo the
reductive deoxygenation, leading to the corresponding
saturated products in good to excellent yields. Especially
noteworthy are the yields obtained for the primary phosphi-
nates (entries 3, 7, and 8). These results contrast sharply with
those reported previously for the corresponding toluates that
not only reacted at much higher temperature (130 °C) but
also provided the desired products in poorer yields (around
30%). It is interesting to note that, a wide variety of
functionalities are tolerated under those conditions, such as
alkenes (entry 7), amides (entry 6), ketones (entry 8),
silylated ethers (entry 9), esters (entry 10), and even free
alcohols (entry 5). This last experiment strongly suggested
a All yields are for pure, isolated products. b Decomposition of the
starting material.
As can be seen from Table 2, NMP and DMF are suitable
solvents for the electroreduction, while, in DMSO and
acetonitrile, numerous byproducts were formed which,
unfortunately, could not be easily identified.
Since the temperature of the electrolysis was playing a
crucial role in the electroreduction of toluates, it was decided
that its impact on the electrochemically mediated cleavage
of diphenylphosphinates would be investigated. Some per-
tinent results are collected in Table 3.
Table 3. Influence of the Temperature
(15) When the electrolysis was carried out at a constant potential of
-2.4 V vs Ag/AgCl, only traces of deoxygenated product were isolated.
(16) Standard electrolysis procedure: An H-type cell, fitted with two
compartments of 100 mL capacity, and separated by a sintered glass with
a porosity of 40 µm, was dried during one night at 200 °C. 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 DMF, freshly distilled
under argon, 600 mg (1.7 mmol) of 1-adamantyldiphenylphosphinate,
dissolved in a little DMF, were added to the cathodic compartment and the
solution was stirred at 60 °C. Then, the intensity of the current was fixed
at 600 mA by using a potentiostat in galvanostatic mode, and the mixture
was electrolyzed 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
and dried over sodium sulphate, and the solvent was removed under reduced
pressure. Finally, the crude product was purified by chromatography on
silica gel, using pentane as eluent, affording the title compound as a white
powder in 92% yield. This material proved to be identical to an authentic
sample of adamantane.
a All yields are for pure, isolated products.
As can be seen from Table 3, the optimal temperature
appears to lie around 60 °C. Lowering the temperature or
increasing it beyond 60 °C results in a dramatic reduction
in the yields of adamantane 9. It is interesting to note that
this behavior stands in sharp contrast to the reduction of the
corresponding toluates that required up to 130 °C to proceed
efficiently and in good yields. Next, the effect of the current
density was investigated (Table 4).
From Table 4, the optimal current density was found to
be 100 mA·cm-2; higher current densities result in lower
yields, fast degradation of the surface of the carbon graphite
408
Org. Lett., Vol. 13, No. 3, 2011

if the deoxygenation was going through a radical pathway,
compound 29 was synthesized and submitted to the electrolysis.
Gratifyingly, adduct 30, resulting from a radical-mediated five
exodig cyclization on the pendant alkyne side chain, could be
isolated in good yield, thus reinforcing our proposed radical-
based mechanism (Scheme 2).
Table 5. Electrochemical Deoxygenation of Alcohols through
Phosphinate Esters16
Scheme 2.
Radical Cyclizationa
a The compound was identified by NMR, but the yield was determined
by capillary gas chromatography due to the volatility of the product.
Interestingly, the final adduct 30 contains no silicon
substituent; desilylation takes place during the reaction by
an, as yet, unclear mechanism.17 More experiments are
currently being performed to understand the origin of the
desilylation.
In summary, we have developed a new, efficient, and
versatile methodology for the deoxygenation of 1°, 2°, and
3° alcohols that possesses a broad scope and proceeds under
mild conditions. The method uses simple, commercially
available diphenylphosphinoyl chloride and the cheapest
source of electrons: electricity. Ongoing efforts are now
directed toward a deeper understanding of the mechanism
of this reaction, its transposition to purely chemical reduction,
and its application to the total synthesis of relevant natural
products.
Acknowledgment. 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 Uni-
versite´ Catholique de Louvain, the FRFC (1.5.294.09F), and
the ARC (08/13-012) are gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization of new compounds, and references
to known compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
a All yields are for isolated, pure products.
OL102714S
that a radical pathway, rather than an ionic mechanism, was
operating. In order to strenghten this proposal and to determine
(17) The corresponding toluate led to the silylated cyclized product.
Org. Lett., Vol. 13, No. 3, 2011
409