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The first electro-induced asymmetric Stevens rearrangement of (S)- and (R)-N-benzyl proline-derived ammonium salts
Catalysis Communications 12 (2011) 485–488
Contents lists available at ScienceDirect
Catalysis Communications j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c a t c o m
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
Article history: Received 24 September 2010 Received in revised form 26 October 2010 Accepted 27 October 2010 Available online 3 November 2010
a b s t r a c t 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. © 2010 Elsevier B.V. All rights reserved.
Keywords: Electrocatalysis Stevens rearrangement Chiral ammonium salts
1. Introduction 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 stereoselectivity [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 disappointing chemical yields (Scheme 1). 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 tbutyl group on the ester functionality (Scheme 2).
☆ In memory of Professor Arduino Oratore. ⁎ Tel.: +39 089 969575; fax: +39 089 969603. E-mail address: [email protected]. 1566-7367/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.catcom.2010.10.027
On the other hand, because of their sensitivity to undergo cathodic reduction yielding ylides, -onium salts are long-standing subject 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 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). Constant current electrolyses were performed under an argon atmosphere, using an Amel Model 552 potentiostat. Unless otherwise
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 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.
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 absorption bands (λ1max = 290 nm and λ2 max = 360 nm) in the UV–vis spectrum of the electrolyzed solution [13]. 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 monoelectron reduction process, an almost complete extinction of the starting material 1b might be accomplished using a slight excess of electricity (Table 1, entry 4). The above statement was further supported by the cyclic voltammetry experiments performed on the ammonium salt (1S, 2S)-1b in
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+ClO− 4 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-methylpyrrolidine-2-carboxylic acid methyl ester (2) as a mixture of enatiomers. 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 comparison of the GC retention times of 2 with the authentic sample prepared according to ref. 2. 2b gave spectroscopic and analytical data as
Scheme 2. Chirality transfer under biphasic conditions.
Scheme 3. Enantiomers of 2-benzyl-1-methyl-pyrrolidine-2-carboxylic acid methyl ester used as starting materials.
L. Palombi / Catalysis Communications 12 (2011) 485–488 Table 1 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 1.2
traces traces 10 82
n.d. n.d. n.d. 47 (R)
a b c d
Electrolysis: method A (see experimental). Isolated yields. The e.e. was determined by GC analysis of 2 (see experimental). Electrolysis: method B (see experimental).
I , mA -0,008
1b in PN
-0,006 1b in AN
-0,004
-0,002 1b in DMSO
0
E, mV 0,00
-0,50
-1,00
-1,50
-2,00
-2,50
-3,00
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).
487
The electrochemical responses reasonably demonstrate the occurrence 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, operational parameters such as the nature of the solvent, temperature, starting material concentration, current density and cathode material 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 electroreduction 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]. 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 9 10 11 12 13
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 5 5 5
r.t. r.t. r.t. r.t. r.t. r.t. 0 −20 −25 45 45 45 r.t.
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)
a b c
All the electrolyses were performed by using method B (see experimental). Isolated yields. See Table 1, note c.
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L. Palombi / Catalysis Communications 12 (2011) 485–488
Scheme 4. Proposed mechanism for electrochemically-promoted Stevens rearrangement 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 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. References [1] For a recent review on sigmatropic rearrangements of onium ylides, see: J.B. Sweeney, Chem. Soc. Rev., 38 (2009) 1027–1038.
[2] (a) E.I. Marko, in: B.M. Trost, I. Fleming (Eds.), Comprehensive Organic Synthesis, vol. 3, Pergamon, Oxford, 1991, pp. 913–927; (b) J.B. Sweeney, A. Tavassoli, N.B. Carter, J.F. Hayes, Tetrahedron 58 (2002) 10113–101268 and references cited herein; (c) J.A. Workman, N.P. Garrido, J. Sançon, E. Roberts, H.P. Wessel, J.B. Sweeney, J. Am. Chem. Soc. 127 (2005) 1066–1067; (d) B. Drouillat, F. Couty, J. Marrot, Synlett. 5 (2009) 767–770. [3] K.W. Glaeske, F.G. West, Org. Lett. 1 (1999) 31–33. [4] A diradical mechanism does not prejudice a totally enantioselective [1,2]-shift if the translation occurs without the detachment of the group involved in the migration, see: (a) S. Hanessian, M. Mauduit, Angew. Chem. Int. Ed., 40 (2001), 3810–3813. (b) M.-H. Goncalves-Farbos, L. Vial, J. Lacour, Chem. Commun., (2008) 829–831. [5] (a) E. Tayama, S. Nanbara, T. Nakai, Chem. Lett. 35 (2006) 478–479; (b) E. Tayama, H. Kimura, Angew. Chem. Int. Ed. 46 (2007) 8869–8871; (c) E. Tayama, K. Orihara, H. Kimura, Org. Biomol. Chem. 6 (2008) 3673–3680. [6] (a) T. Shono, Electroorganic Chemistry as a New Tool in Organic Synthesis, Springer-Verlag, Berlin Heidelberg New York Tokyo, 19848, and references cited herein; (b) H. Lund, in: H. Lund, O. Hammerich (Eds.), Organic Electrochemistry, Marcel Dekker, New York, 2001; (c) W.A. Mowers, J.V. Crivello, Polym. Mater. Sci. Eng. 81 (1999) 479–480. [7] K.L. Vieira, M.S. Mubarak, D.G. Peters, J. Am. Chem. Soc. 106 (1984) 5372–5373; Hall E.A.H., Simonet J., Lund H., J. Electroanal. Chem. 100 (1979) 197–203; Benders J. , Kadys V. , Lavrinovics E. , Stradins J. , Electrochim. Acta 31 (1986) 1369–1379. [8] Y. Okazaki, F. Ando, J. Koketsu, Bull. Chem. Soc. Jpn 76 (2003) 2155–2165; Y. Okazaki, F. Ando, J. Koketsu, Bull. Chem. Soc. Jpn 77 (2004) 1687–1695; Y. Okazaki, A. Takeuchi, Y. Ninomiya, J. Koketsu, Electrochem. Tokyo Jpn 73 (2005) 798–806; Y. Okazaki, T. Asai, F. Ando, J. Koketsu, Chem. Lett. 35 (2006) 98–99. [9] P.E. Iversen, Tetrahedron Lett. 1 (1971) 55–56. [10] T. Shono, T. Akazawa, M. Mitani, Tetrahedron 29 (1973) 817–821. [11] L. Palombi, M. Feroci, M. Orsini, A. Inesi, Chem. Commun. (2004) 1846–1847; T. Caruso, M. Feroci, A. Inesi, M. Orsini, A. Scettri, L. Palombi, Adv. Synth. Catal. 348 (2006) 1942–1947; 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. [12] E.J. Corey, J.O. Link, J. Org. Chem. 56 (1991) 442–447. [13] UV–vis spectra have been also collected in situ by using spectroelectrochemical tecniques: these results will be published elsewhere. For literature data on the UV spectrum of the aqueous solution of iodine see: N. V. Guzenko, O. E. Voronina, N. N. Vlasova, E. F. Voronin, J. Appl. Spectros., 71 (2004) 151–155. [14] B. Gorodetsky, R. Ramnial, N.R. Branda, J.A.C. Clyburne, Chem. Commun. (2004) 1972. [15] G. Ghigo, S. Cagnina, A. Maranzana, G. Tonachini, J. Org. Chem. 75 (2004) 3608–3617.
Contents lists available at ScienceDirect
Catalysis Communications j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c a t c o m
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
Article history: Received 24 September 2010 Received in revised form 26 October 2010 Accepted 27 October 2010 Available online 3 November 2010
a b s t r a c t 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. © 2010 Elsevier B.V. All rights reserved.
Keywords: Electrocatalysis Stevens rearrangement Chiral ammonium salts
1. Introduction 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 stereoselectivity [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 disappointing chemical yields (Scheme 1). 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 tbutyl group on the ester functionality (Scheme 2).
☆ In memory of Professor Arduino Oratore. ⁎ Tel.: +39 089 969575; fax: +39 089 969603. E-mail address: [email protected]. 1566-7367/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.catcom.2010.10.027
On the other hand, because of their sensitivity to undergo cathodic reduction yielding ylides, -onium salts are long-standing subject 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 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). Constant current electrolyses were performed under an argon atmosphere, using an Amel Model 552 potentiostat. Unless otherwise
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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 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.
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 absorption bands (λ1max = 290 nm and λ2 max = 360 nm) in the UV–vis spectrum of the electrolyzed solution [13]. 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 monoelectron reduction process, an almost complete extinction of the starting material 1b might be accomplished using a slight excess of electricity (Table 1, entry 4). The above statement was further supported by the cyclic voltammetry experiments performed on the ammonium salt (1S, 2S)-1b in
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+ClO− 4 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-methylpyrrolidine-2-carboxylic acid methyl ester (2) as a mixture of enatiomers. 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 comparison of the GC retention times of 2 with the authentic sample prepared according to ref. 2. 2b gave spectroscopic and analytical data as
Scheme 2. Chirality transfer under biphasic conditions.
Scheme 3. Enantiomers of 2-benzyl-1-methyl-pyrrolidine-2-carboxylic acid methyl ester used as starting materials.
L. Palombi / Catalysis Communications 12 (2011) 485–488 Table 1 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 1.2
traces traces 10 82
n.d. n.d. n.d. 47 (R)
a b c d
Electrolysis: method A (see experimental). Isolated yields. The e.e. was determined by GC analysis of 2 (see experimental). Electrolysis: method B (see experimental).
I , mA -0,008
1b in PN
-0,006 1b in AN
-0,004
-0,002 1b in DMSO
0
E, mV 0,00
-0,50
-1,00
-1,50
-2,00
-2,50
-3,00
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).
487
The electrochemical responses reasonably demonstrate the occurrence 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, operational parameters such as the nature of the solvent, temperature, starting material concentration, current density and cathode material 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 electroreduction 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]. 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 9 10 11 12 13
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 5 5 5
r.t. r.t. r.t. r.t. r.t. r.t. 0 −20 −25 45 45 45 r.t.
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)
a b c
All the electrolyses were performed by using method B (see experimental). Isolated yields. See Table 1, note c.
488
L. Palombi / Catalysis Communications 12 (2011) 485–488
Scheme 4. Proposed mechanism for electrochemically-promoted Stevens rearrangement 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 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. References [1] For a recent review on sigmatropic rearrangements of onium ylides, see: J.B. Sweeney, Chem. Soc. Rev., 38 (2009) 1027–1038.
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