The first electro-induced asymmetric Stevens rearrangement of (S)- and (R)-N-benzyl proline-derived ammonium salts

Article abstract of DOI:10.1016/j.catcom.2010.10.027

The Stevens rearrangement of N-benzyl proline derivatives ammonium ylides can be readily accomplished by galvanostatic electrolysis of the corresponding ammonium salts in the cathode compartment of a divided-cell. With respect to the well-established chem

Full text of DOI:10.1016/j.catcom.2010.10.027

Catalysis Communications 12 (2011) 485–488
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Catalysis Communications
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Short Communication
The first electro-induced asymmetric Stevens rearrangement of (S)- and (R)-N-benzyl
☆
proline-derived ammonium salts
⁎
Laura Palombi
Dipartimento di Chimica, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano (Sa), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The Stevens rearrangement of N-benzyl proline derivatives ammonium ylides can be readily accomplished by
galvanostatic electrolysis of the corresponding ammonium salts in the cathode compartment of a divided-cell.
With respect to the well-established chemical methods, the electro-induced process showed a significant
amplification of the nitrogen to carbon chirality transmission.
Received 24 September 2010
Received in revised form 26 October 2010
Accepted 27 October 2010
Available online 3 November 2010
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Electrocatalysis
Stevens rearrangement
Chiral ammonium salts
1. Introduction
On the other hand, because of their sensitivity to undergo cathodic
reduction yielding ylides, -onium salts are long-standing subject
The rearrangements of -onium structures via ylide intermediates,
are powerful synthetic tools to convert readily available C-heteroatom
bond into a new C–C bond [1].
In particular, in these last years, [1,2] and [2,3]-shift of temporary
quaternary ammonium ylides stereogenic at nitrogen have been
exploited for moderate to very effective chirality transfer (CT) to the
adjacent C-position [2,3]. In such a way, a class of compounds of
synthetic significance, i.e. variously substituted α-quaternary amino
acid derivatives and tertiary amines, can be easily obtained from the
corresponding ammonium salts [2].
As showed by West [3] by means of the substrates 1a and 1b, the
efficiency of the chirality transmission is strictly dependent on the
mechanism of the reaction, so that, whereas [2,3]-sigmatropic
rearrangement involves total chirality transmission, the [1,2]-shift,
which proceed via diradical intermediates, showed modest stereo-
selectivity [4]. Furthermore, under West's reaction conditions, the use
of viscous solvents to accomplish the [1,2]-shift (aiming at amplifying
the e.e. by reducing diffusion from solvent cage), implied disappoint-
ing chemical yields (Scheme 1).
matter for electroorganic chemistry [6] [7]. Indeed, some recent
electrochemical investigations have been focused on phosphonium,
sulfonium and selenonium salts [8], whereas, regarding ammonium
salts, no further reports have appeared in the literature after the
pioneering studies of Iversen [9] and Shono [10]. Moreover, no
attention at all has been paid to the electrochemical behaviour of the
respective chiral compounds.
In connection with our previous researches on the galvanostatic
activation of methylene active compounds [11], we envisaged the
chance to design an electrochemical method to induce the Stevens
rearrangement of the above mentioned chiral ammonium salts.
We here report our preliminary results on the reactivity of the
electroreductively generated (S)- and (R)-N-benzyl proline-derived
ammonium ylides, on the efficiency and the stereochemical outcome
of the electro-induced [1,2]-shift.
2. Experimental
2.1. General
As proved recently by Tayama [5], the ionization conditions
(careful selection of the solvent and base systems) may partially affect
the enantioselectivity of the [1,2]-shift process, though a significant
enantiomeric enrichment could be obtained only by insertion of a t-
butyl group on the ester functionality (Scheme 2).
Ammonium iodides (1S, 2S)- and (1R, 2R)-1b showed in Scheme 3
were synthesized according to the literature procedure [2] [12],
starting respectively from L- and D-proline and both obtained as
optically pure compounds by three subsequent recrystallizations.
(1S, 2S)-1b and (1R, 2R)-1b gave spectroscopic and analytical data
as reported in ref. 2. The [α]D for (1R, 2R)-1b was +43.3 °(c=0.25,
CH2Cl2).
☆
In memory of Professor Arduino Oratore.
Tel.: +39 089 969575; fax: +39 089 969603.
E-mail address: lpalombi@unisa.it.
Constant current electrolyses were performed under an argon
atmosphere, using an Amel Model 552 potentiostat. Unless otherwise
⁎
1566-7367/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.10.027

486
L. Palombi / Catalysis Communications 12 (2011) 485–488
Scheme 1. Base-induced [2,3]-sigmatropic rearrangement and [1,2]-shift on proline derivatives.
mentioned, Platinum spirals (apparent areas 0.5 cm2) were used as
cathode and anode.
reported in ref. 2. The [α]D for (S)-2b (85% e.e.) was −4.3° (c=0.55,
CH2Cl2).
2.2. Electrolysis methods and general procedures
3. Result and discussion
Method A
The preliminary constant current electrolyses of (1S, 2S)-1b on a
preparative scale were carried out in an undivided glass cell equipped
with a Platinum anode and cathode, using THF or acetonitrile (AN) as
a solvent. Quite disappointingly, the analytical data on the crude
electrolyzed solution showed a rather complex mixture of products
containing the expected product 2b in negligible yield (Table 1,
entries 1–3). Furthermore, the complete conversion of the starting
material 1b was achieved only by supplying electricity in large excess
(more than 3 Faraday/mol) (Table 1, entry 3).
Such poor results can be reasonably attributed to the generation of
I2 through the anodic semi-reaction (2I- → I2 +2e) resulting in
undesired side-reactions and competing with the ammonium moiety
for the cathodic reduction. The supposed I2 generation has been
experimentally evidenced by the appearance of two typical absorp-
tion bands (λ1max =290 nm and λ2 max =360 nm) in the UV–vis
spectrum of the electrolyzed solution [13].
The constant current electrolysis of 1b solutions was performed in
a single compartment glass cell equipped with two Pt spirals as anode
and cathode. The potential difference was applied until the current
quantity reported in Table 1 was passed.
Method B
The constant current electrolysis was carried out in a U-divided
glass cell connected through a porous G-4 glass plug. Catholyte: 0.04 M
solution of 1b in AN; Anolyte: 0.02 M solution of (CH3CH2)4N+ClO4− in
AN. The reactions were performed on a 0.1 mmol scale. Workup and
purification: at the end of the electrolysis, the cathodic solution was
evaporated and the crude mixture directly purified on silica gel
(eluent: hexane: ethylacetate 5:1), yielding 2-benzyl-1-methyl-
pyrrolidine-2-carboxylic acid methyl ester (2) as a mixture of
enatiomers.
With this established precedent, the following electrolysis was
performed using a U-two compartment cell fitted with a separator
septum; this strategy proved to be successful since the asymmetric
Stevens rearrangement took place affording 2b in very good yield and
promising enantiomeric excess. Notably, in agreement with a mono-
electron reduction process, an almost complete extinction of the
starting material 1b might be accomplished using a slight excess of
electricity (Table 1, entry 4).
Enantiomeric excesses of 2 were gauged by GC analyses with 6850
Agilent Tecn. instrument (chiral column: Supelco BETA DEX 120;
oven: 100 °C for 5 min., then 1 °C/min to 170 °C). tR of (R)-2 (major
isomer obtained with starting material (1S,2S)-1b) 68.40 min., tR of
(S)-2 (major isomer obtained with starting material (1R,2R)-1b)
68.75 min. The absolute configurations were determined by compar-
ison of the GC retention times of 2 with the authentic sample prepared
according to ref. 2. 2b gave spectroscopic and analytical data as
The above statement was further supported by the cyclic voltam-
metry experiments performed on the ammonium salt (1S, 2S)-1b in
Scheme 3. Enantiomers of 2-benzyl-1-methyl-pyrrolidine-2-carboxylic acid methyl
Scheme 2. Chirality transfer under biphasic conditions.
ester used as starting materials.

L. Palombi / Catalysis Communications 12 (2011) 485–488
487
Table 1
The electrochemical responses reasonably demonstrate the occur-
rence of a direct cathodic deprotonation of 1b in AN (−Ep≅2.0 V) and PN
(−Ep≅2.5 V); contrariwise, this appears quite suppressed in DMSO.
As the above was ascertained, the next step was the setup of the
optimal experimental conditions. As summarized in Table 2, oper-
ational parameters such as the nature of the solvent, temperature,
starting material concentration, current density and cathode mate-
rial were investigated in order to improve both chemical and optical
yield of 2b. In particular, we noted an appreciable enhancement of
the e.e. by increasing the viscosity of the electrolysis medium (i.e. by
using PN, DMSO or the ionic liquid ethyl methyl imidazolium ethyl
sulphate (EMImSO4), instead of AN). On the contrary, a fall in the
temperature (Table 2, entry 7–9) or a change in the concentration
(Table 2, entry 5, 6), was detrimental both to the yield and e.e.
Since the voltammetric experiments excluded the direct electro-
reduction of the ammonium salt in DMSO, we speculate that, under the
galvanostatic conditions used for the electrosynthetic experiments, the
formation of the ammonium ylide occurred through the abstraction of a
proton from 1b by the electrogenerated dimsyl ion (Scheme 4):
It has to be noted that the use of a more viscous solvent (i.e.
EMImSO4) as an electrolysis medium implied a satisfactory e.e. but
also a significant drop in yield of 2, because of the possible, concurrent
reduction of the imidazolium moiety of the ionic liquid [14]. Finally,
while the stereoselectivity was not influenced by the working
electrode material (Table 2, entry 11, 12), a slight lowering of the
yield was noted when Au or Ag was used instead of Pt as cathode.
According to the above observations, we deduced that the process
proved to be very sensitive to certain electrolysis conditions, both in
terms of yield and enantiomeric excess, so that the best result was
achieved under the condition reported in Table 2, entry 10. In particular,
parameters such as current density, temperature and concentration
appeared as the most important factors to maximize the selectivity
(both chemo- and stereoselectivity) of this electro-induced process.
Although further experiments are necessary to exactly rationalize the
role of these factors, it seems reasonable to suppose that high
concentration values, as well as high current density, might strain a
competitive intermolecular benzyl transfer with a consequent lowering
in stereoselectivity. On the other hand a lowering in the temperature
might lead to lower chemoselectivity as a consequence of a competitive
Sommelet–Hauser rearrangement process [15].
Electrochemically-promoted Stevens rearrangement of 1b.
electrolysis
(method A or B)
Bn
CO2Me
N
CO2Me
N
THF or AN, r.t.
I
Bn
(1S,2S)-1b
(R)-2b
Entry Solvent Conc. (M) Current quantity (F/mol) 2 Yield (%)b 2 e.e. (%)c
1a
2a
3a
4d
THF
AN
AN
AN
0.02
0.02
0.04
0.04
1
1
3
traces
traces
10
n.d.
n.d.
n.d.
47 (R)
1.2
82
a
Electrolysis: method A (see experimental).
Isolated yields.
The e.e. was determined by GC analysis of 2 (see experimental).
b
c
d
Electrolysis: method B (see experimental).
I , mA
-0,008
-0,006
-0,004
-0,002
0
1b in PN
1b in AN
1b in DMSO
E, mV
-3,00
0,00
-0,50
-1,00
-1,50
-2,00
-2,50
Fig. 1. Cyclic voltammetric curves of (1R, 2R)-1b in DMSO (black line), AN (blue line),
and PN (red line) (the curves have been obtained with 3 mM solutions, GCE working
electrode; sweep rate: 0.015 V/s; pulse amplitude 0.050 V; Ag/AgCl as external
reference electrode; T=25 °C).
4. Conclusion
various solvents, as reported in Fig. 1. Cyclic voltammograms display the
presence of a single irreversible reduction peak in the range of the
respective electrochemical windows, both in AN and propionitrile (PN),
while no reduction peak is observed (in the range of 0–3 V) in
dimethylsulfoxide (DMSO).
In conclusion, we have developed the first electro-induced
asymmetric Stevens rearrangement of N-benzyl proline-derived
ammonium salts. Although the chirality transfer was not completely
satisfying, the proposed electrochemical method allowed to achieve
Table 2
Electrochemically-promoted Stevens rearrangement of 1 under different conditions.
Entrya
1
Solvent
Conc. (M)
Current quantity
(F/mol)
Current density
(mA/cm2)
Temp. (°C)
Working electrode
material
2 Yieldb (%)
2 e.e.c (%)
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1b
1b
1b
1b′
1b′
1b′
1b′
1b′
1b
AN
AN
DMSO
PN
PN
PN
PN
PN
PN
PN
PN
PN
EMImSO4
0.04
0.04
0.12
0.12
0.04
0.24
0.12
0.12
0.12
0.12
0.12
0.12
0.12
1.2
1.2
1.1
1.1
1.5
1.1
1
1.1
1.1
1.1
1.1
1.1
1.1
10
30
10
10
10
10
8
10
5
5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
−20
−25
45
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Au
Ag
Pt
82
65
70
80
86
62
77
44
20
92
86
82
29
47 (R)
46 (R)
72 (R)
70 (R)
54 (R)
66 (R)
65 (R)
67 (S)
54 (S)
84 (S)
84 (S)
84 (S)
85 (S)
9
10
11
12
13
5
5
5
45
45
r.t.
a
All the electrolyses were performed by using method B (see experimental).
Isolated yields.
See Table 1, note c.
b
c

488
L. Palombi / Catalysis Communications 12 (2011) 485–488
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ment of proline derivatives in DMSO.
compound 2b with the highest enantiopurity level reported so far.
Furthermore, thanks to the ionic character of the substrate and the
features of the electrochemical protocol the use of environmental
armful supporting electrolytes, metals and base reagents was avoided.
We are currently investigating the scope of such electrochemical
methodology for the rearrangement of other chiral synthetically
interesting -onium salts.
Acknowledgments
M. Feroci, M. Orsini, L. Palombi, A. Inesi, Green Chem. 9 (2007) 323–325;
L. Palombi, C. Bocchino, T. Caruso, R. Villano, A. Scettri, Catal. Commun. 10 (2008)
321–324.
The authors thank Dr. Tonino Caruso for his most valuable
contribution to the voltammetry experiments and discussions. The
authors also thank the referees of this work for useful discussions. This
work was supported by research grants from MIUR.
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References
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