An innovative strategy for electrochemically-promoted addition reactions

Article abstract of DOI:10.1039/b406512c

A new strategy based on the catalytic release of the supporting electrolyte agent in the electrolysis medium proved to be effective for the direct electroactivation of suitable C-H acid-containing compounds vs. catalytic addition processes, under solvent-

Full text of DOI:10.1039/b406512c

An innovative strategy for electrochemically-promoted addition reactions
Laura Palombi,*a Marta Feroci,b Monica Orsinib and Achille Inesi*c
a Dip. di Chim., Università degli Studi, Via S. Allende, Salerno, 84081 Baronissi, Italy.
E-mail: lpalombi@unisa.it
b Dip. di ICMMPM, Università “La Sapienza”, Via C. Laurenziano 7, I-00161, Roma, Italy
c
Dip. di CICM, Università degli Studi, L’Aquila, I-67040 Monteluco di Roio, Italy.
E-mail: inesi@ing.univaq.it
Received (in Cambridge, UK) 5th May 2004, Accepted 23rd June 2004
First published as an Advance Article on the web 26th July 2004
A new strategy based on the catalytic release of the supporting
electrolyte agent in the electrolysis medium proved to be
effective for the direct electroactivation of suitable C–H acid-
containing compounds vs. catalytic addition processes, under
solvent-free conditions.
of chemical yield and chemoselectivity since, in this case, no
double addition product was detected by 1H NMR (as well as GC-
MS) analyses of the crude mixtures.
As an extension of the methodology to other synthetically
interesting b-dicarbonyl compounds, pure 1b–d were electrolysed
according to method B. At the end of the electrolysis (I = 10 mA
cm22, Q = 0.1 F mol21), the Michael acceptor 2a was added to the
cathode compartment and the reaction was prolonged at room
temperature for the time reported in Table 2. Surplus of starting
materials 1b–d was distilled under vacuum at room temperature
and recovered for recycling with a glass trap cooled to 278 °C.
Over the last decades, electrosynthesis has emerged as a convenient
tool to improve selectivity, cheapness and eco-friendliness of a
wide variety of synthetic constructions, including catalytic C–C
bond-forming processes. In this field, over a period of many years,
a number of helpful electrochemical methods have enabled
conjugate addition to activated unsaturated systems and nucleo-
phile addition to carbonyl compounds.1 Nevertheless, some
downsides related to electrochemical techniques (specialized
equipment for controlling the potential, trouble in scaling up the
reactions, massive use of supporting electrolyte agents etc.) have
resulted in little use of them to date in preparative organic
synthesis.
Table 1 Electrochemically-promoted Michael addition of 1a under different
electrolysis conditions
Current
intensity
(mA cm22
Current
quantity
Electrolysis
methoda
Yield
(%)c
Entry
)
(F mol21 b
)
To enhance the usefulness of the electrosynthetic methodology
increasing efforts are being devoted to develop as easy as possible
electrochemical reaction systems, mainly focused on the working
out of constant current procedures. Still, a variety of synthetic
targets have been conveniently obtained via electrogenerated bases
(EGBs) and acids (EGAs). In our recent reports, e.g., the EGB
cyanomethyl anion2 proved to be effective for a selective activation
of amidic and aminic N–H as well as C–H bonds, succesfully used
in N–C and C–C bond-forming processes.3 On the other hand, the
achievement of carb- and heteroanions by direct cathodic reduction
of appropriate organic acids, avoiding any use of chemical or
electrogenerated bases, certainly appears a much more attractive
approach.4
1
2
3
4
A
B
B
B
10
10
10
5
0.1
0.1
0.07
0.1
76 (5)
64
76
87
a Method A: Anolyte: 0.1 M TEAP/DMF. Catholyte: 15 ml of 0.03 M
TEAP/CH3CN solution. At the end of the electrolysis 1a (1 ml) and 2a were
added in sequence and the reaction was prolonged at room temperature for
2 h. Method B: electrolysis conditions being equal, except for the catholyte:
(5 ml of pure 1a). b The current quantity refers to the Michael acceptor 2a
(3 mmol scale), added to the catholyte at the end of the electrolysis. c The
yields refer to isolated, chromatographically pure 3a and are calculated on
the starting material 2a. Yield in brackets refers to double addition
product.
In line with the demand for simplification, we here report a new
strategy for the direct galvanostatic electrogeneration of carbon
nucleophiles under solvent-free conditions characterized by a
drastic slashing of the amount of supporting electrolyte in the
electrolysis medium.
With this in mind and according to our previous investigations on
electrochemically-promoted addition reactions,5 we checked for a
direct electroactivation of the representative methylene-active
compound 1a, under several different electrolysis conditions (Table
1). The efficiency of the electrochemical activation systems was
then tested in the conjugate addition to 2a, chosen as a typical
Michael acceptor (Scheme 1). As depicted in Fig. 1, all the
experiments were performed using a two compartment cell
equipped with a Pt anode and cathode, while a G3-glass diaphragm
fitted up with a layer of agar gel† was used as separator septum.
Furthermore, pure compound 1a was used as catholyte, avoiding
both the solvent and supporting electrolyte addition.
Scheme 1
As summarized in Table 1, a set of experiments was performed
to find the optimal electrochemical conditions by altering either the
current quantity or the current intensity. As shown, under the
optimised conditions (entry 4), Michael adduct 3a was obtained in
very good yield and selectivity. If compared to the electrogenerated
cyanomethyl anion-catalysed procedure (entry 1), solventless
electrolysis of 1a allowed a significant improvement both in terms
Fig. 1 Schematic depiction of the cell.
1846
C h e m . C o m m u n . , 2 0 0 4 , 1 8 4 6 – 1 8 4 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Table 3 Electrochemically-promoted nitroaldol reactions under solvent-
free conditions
Crude mixtures yielded pure adducts 3 after simple filtration over
silica gel.
As shown, the reaction proceeded with very satisfactory
efficiency and selectivity with b-diketones, b-keto esters or
malonate esters, affording the Michael adducts in good to excellent
yields, under mild conditions and in short reaction times (Table 2,
entries 1–3).
Finally, to test whether the method was applicable to different
kinds of Michael acceptors, we considered the reactivity of the
electrolysed compound 1d towards the mono- and di-substituted
olefins 2b–f, bearing different EWG in conjugation with the double
bond. The Michael addition again occurred with very good yields in
nearly all the cases, using a catalytic amount of current; it is
noteworthy that in spite of a slightly lower yield obtained for the
acceptor 2e, a total chemoselectivity in favour of the a-monoaddi-
tion products was always observed.
Current
quantity
(F mol21
)
Reaction
time (h)
Yield
(%)a
Entry
4
1
2
3
4
5
6
7
8
4a
4a
4b
4c
4c
4c
4d
4e
0.05
0.1
0.1
0.1
0.2
1
1
0.75
1
1.5
1.5
1.5
1.5
1
65
91
84 (12)
60 (34)
60 (36)
31 (33)
70
0.1
0.1
63
a The yields refer to isolated, chromatographically pure 2-nitroalcohols 5
and are calculated on the starting aldehyde 4. Yields in brackets refer to the
recovered starting materials 4.
To further broaden the scope of this electrochemical method-
ology, we decided to investigate its effectiveness vs. other classes
of catalytic nucleophilic additions. As a practical route to many
important building blocks, the nitroaldol reaction is a main topic in
this area. Concerning an electrosynthetic approach to the issue,
Evans and co-workers reported a catalytic activation of nitro-
methane vs. Michael addition6 as well as Henry reaction,7 via
superoxide anion as EGB. Actually, depending on the electrolysis
procedure, the authors showed two different processes targeted at
2-nitroalcohols or 1,3-dinitro compounds.8
We have now found that, under the electrolysis conditions
reported above (method B), the direct reduction of pure nitro-
methane, under an inert atmosphere, could be conveniently used for
a selective synthesis of the 2-nitroalcohols 5 by addition of an
aldehyde 4 to the cathode compartment at the end of the electrolysis
(Scheme 2). As shown in Table 3, very good yields and selectivity
were produced, for aromatic, heteroaromatic and aliphatic alde-
hydes. Thanks to the mild electrolysis conditions no by-products
due to a concurrent a-elimination step on the products 5 were
observed.
Unfortunately, attempts to improve the chemical yield for the
substrate 4c, by increasing the current quantity, the temperature or
the reaction time, gave unsatisfactory results. In particular, the use
of a stoichiometric amount of electricity (1 F mol21) compromised
both the yield and the selectivity of the reaction (Table 3, entry
6).
In summary, we have demonstrated a new, convenient electro-
chemical strategy to promote the activation of C–H acid-containing
compounds in a solventless environment, avoiding metal, basic or
EGB catalysts. With respect to the traditional chemical methods,
the electrochemical, metal-free conditions resulted in enhanced
reactivity of the electrogenerated bare carbon-anion, so that the
reactions with suitable acceptors were found to occur under mild
conditions and in short reaction times. Furthermore, easy set-up and
work-up procedures were established thanks to the minimised
amount of the supporting electrolyte used.
Table 2 Electrochemically-promoted Michael addition reactions under
solvent-free conditions
Reac-
tion
Yield
Entry Donor 1 Acceptor 2
Product 3
time (h) (%)a
The authors wish to thank MURST (Cofin 2002) for financial
support.
1
2
1b
1c
2a
2a
2
4
82
83
93
Notes and references
† Agar gel constituted methyl cellulose 0.5% vol. dissolved in 1 M TEAP/
3b
4b
5b
1d
1d
1d
2a
2
12
12
DMF solution.
2b
87
1 (a) M. M. Baizer, J. L. Chruma and D. A. White, Tetrahedron Lett., 1977,
52, 5209–5212; (b) T. Shono and M. Mitani, J. Am. Chem. Soc., 1971, 93,
5284.
2c
> 98
2 H. Lund, Organic Electrochemistry; H. Lund, O. Hammerich, Eds;
Marcel Dekker: New York, 2001; pp. 264 and references therein.
3 (a) M. Feroci, A. Inesi, L. Palombi and G. Sotgiu, J. Org. Chem., 2002,
67, 1719–1721; (b) M. Feroci, M. A. Casadei, M. Orsini, L. Palombi and
A. Inesi, J. Org. Chem., 2003, 68, 1548–1561; (c) L. Palombi, M. Feroci,
M. Orsini, L. Rossi and A. Inesi, Tetrahedron Lett., 2002, 43,
2881–2884.
4 (a) V. A. Petrosyan, Russ. Chem. Bull., 1995, 44, 1–12; (b) J. H. P. Utley
and N. M. Folmer, in Organic Electrochemistry; H. Lund, O. Hammer-
ich, Eds; Marcel Dekker: New York, 2001; pp. 1227–1257 and references
therein.
6b
7b
1d
1d
2d
2e
7
87
67
18
8b,c
1d
2f
0.5
93
a The yields refer to isolated, chromatographically pure products 3 and are
calculated on the starting material 2. b Electrolysis was performed under
argon atmosphere, using a two-compartment cell, Pt anode and cathode with
a G-5-glass separator septum. Catholyte: pure 1d (5 ml); anolyte: 0.1 M
TEAP/DMF solution. c The reaction was performed at 230 °C.
5 L. Palombi, M. Feroci, M. Orsini and A. Inesi, Tetrahedron: Asymmetry,
2002, 13, 2311–2316.
6 A. V. Samet, M. E. Niyazymbetov, V. V. Semenov, A. L. Laikhter and D.
H. Evans, J. Org. Chem., 1996, 61, 8786–8791.
7 C. Suba, M. E. Niyazymbetov, M. E. Niyazymbetov and D. H. Evans,
Electrochim. Acta, 1997, 42, 2247.
8 Z. I. Niazimbetova, D. H. Evans, L. M. Liable-Sands and A. L.
Rheingold, J. Electrochem. Soc., 2000, 147, 256–259.
Scheme 2
C h e m . C o m m u n . , 2 0 0 4 , 1 8 4 6 – 1 8 4 7
1847