Enantioselective electrocatalytic oxidation of racemic amines using a chiral 1-azaspiro[5.5]undecane N-oxyl radical

Article abstract of DOI:10.1039/a905894j

A preparative electrocatalytic oxidation of racemic amines, which contain a chiral centre α to the amino group, on (6S, 7R, 10R)-4-acetylamino-2,2,7-trimethyl-10-isopropyl-1-aza-spiro[5.5]undecane N-oxyl yielded mixtures of carbonyl compounds (54.3-66.1%) and amines (33.9-45.7%) after 5 h of electrolysis, in which the current efficiency, turnover number, enantiopurity of the remaining (R)-isomers and S values were 90.7-94.8%, 21.7-26.5, 62-78% and 4.7-5.8, respectively.

Full text of DOI:10.1039/a905894j

Enantioselective electrocatalytic oxidation of racemic amines using a chiral
1-azaspiro[5.5]undecane N-oxyl radical
Yoshitomo Kashiwagi,*a Futoshi Kurashima,a Chikara Kikuchi,a Jun-ichi Anzai,a Tetsuo Osaa and James M.
Bobbittb
a
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
E-mail: kashi@mail.pharm.tohoku.ac.jp
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, USA
b
Received (in Cambridge, UK) 21st July 1999, Accepted 23rd August 1999
A preparative electrocatalytic oxidation of racemic amines,
which contain a chiral centre a to the amino group, on (6S,
7R, 10R)-4-acetylamino-2,2,7-trimethyl-10-isopropyl-1-aza-
spiro[5.5]undecane N-oxyl yielded mixtures of carbonyl
compounds (54.3–66.1%) and amines (33.9–45.7%) after 5 h
of electrolysis, in which the current efficiency, turnover
number, enantiopurity of the remaining (R)-isomers and S
values were 90.7–94.8%, 21.7–26.5, 62–78% and 4.7–5.8,
respectively.
deprotonating agent are shown in Fig. 1. The anodic peak
current for (S)-PEA was significantly enhanced in comparison
with the blank voltammogram (1 itself) and a small cathodic
peak was observed on the reverse scan, showing that (S)-PEA
was efficiently oxidized electrocatalytically. In contrast to the
CV for (S)-PEA, the anodic peak current for (R)-PEA increased
only slightly. These results clearly show that the electrocatalytic
oxidation of (S)-PEA on 1 occurred in preference to that of (R)-
PEA.
Preparative potential-controlled electrolysis was performed
on a graphite felt electrode (Nippon Kynol Inc., 5 3 5 3 5 mm)
in MeCN–H2O (4+1) solution, using an ‘H type divided cell
separated by a cationic exchange membrane (Nafion 117). The
anolyte contained 0.05 mmol of 1, 1 mmol of substrate, 0.5
mmol of tetralin as a chromatographic standard, 4 mmol of
2,6-lutidine and 0.5 mmol of NaClO4 in a total volume of 5 ml.
The catholyte was 5 ml of MeCN–H2O (4+1) solution
containing 0.5 mmol of NaClO4. The electrolysis was carried
out at +0.8 V vs. Ag/AgCl under an argon atmosphere. During
electrolysis, aliquots of anolyte were analyzed occasionally by
HPLC.‡ The consumption of racemic 1-phenylethylamine and
formation of acetophenone are plotted against electrolysis time
in Fig. 2. 1-Phenylethylamine was probably oxidized to the
corresponding imine, the expected oxidation intermediate,
which can be easily hydrolyzed to acetophenone; imine was not
actually detected. After 5 h of electrolysis, the (R)- and (S)-
forms of 1-phenylethylamine were oxidized to acetophenone in
45.9 and 92.4% yield, respectively. The current efficiency and
turnover number (given by ratio of mole of product 32/mol of
1) were 91.5% and 26.2, respectively, at 5 h of electrolysis. The
remaining (R)-PEA and (S)-PEA equalled 56.1 and 7.6%,
respectively. Thus, the ee of the unreacted amine was 78%. The
efficiency of the resolution is characterized by the selectivity
factor, S ( = ks/kR).9 The S value of this reaction was 5.3.
Optically active amines are some of the most important chiral
intermediates in organic synthesis. They have been prepared by
many methods, including optical resolution of their racemates,
usually by preferential crystallization.1 Several enantioselective
chemical oxidations for optical resolution of the racemates
using chiral aminoxyl radicals have been reported, but these
works were mainly carried out with secondary alcohols as the
racemate.2–4 On the other hand, 2,2,6,6-tetramethylpiperidin-
1-yloxyl is known to be an effective redox mediator for the
electrooxidation of amines to nitriles and carbonyl com-
pounds.5–7 Here we report the first efficient, enantioselective
electrocatalytic oxidation of a number of racemic amines using
(6S, 7R, 10R)-4-acetylamino-2,2,7-trimethyl-10-isopropyl-
1-azaspiro[5.5]undecane N-oxyl 13 as a chiral 1-azaspiro-
[5.5]undecane N-oxyl radical.
The cyclic voltammetry† of 1 was carried out in a MeCN
solution containing 0.1 M NaClO4 as supporting electrolyte.
Fig. 1 shows the cyclic voltammogram (CV) of 1, in which a
reversible redox couple was observed. This redox couple
corresponds to one-electron oxidation of the oxoammonium
ion. Similar electrochemical behavior has been reported by
Bobbitt et al.3 The redox potential and peak split between the
anodic and cathodic peak potentials were +0.62 V (vs. Ag/
AgCl) and 70 mV, respectively. These values are comparable to
those for TEMPO derivatives.8 In addition, the diffusion
coefficient of 1 was estimated to be 1.3 3 1025 cm2 s21 based
on a plot of the peak current vs. the square root of scan rate in
the cyclic voltammetry.9 These observations suggest a possible
use of 1 as catalyst in the electrocatalytic oxidation of
amines.
The enantioselective oxidation of a chiral amine on 1 was
investigated using (R)-(+)- and (S)-(2)-1-phenylethylamine
[(R)-PEA and (S)-PEA] as substrates. The CVs of 0.1 M (R)-
PEA and (S)-PEA in the presence of 0.8 M 2,6-lutidine as
Fig. 1 Cyclic voltammograms of 0.01 M 1 in 0.1 M NaClO4/MeCN at the
scan rate of 50 mV s21: (a) in the presence of 0.1 M (S)-PEA and 0.2 M
2,6-lutidine, (b) in the presence of 0.1 M (R)-PEA and 0.2 M 2,6-lutidine,
and (c) blank.
Chem. Commun., 1999, 1983–1984
This journal is © The Royal Society of Chemistry 1999
1983

Table 1 Electrocatalytic oxidation of racemic secondary amines by 1
Efficiencya Ee
Conversion
(%)
R1
R2
Amine
Charge/C
(%)
(%)
S
TONb
Ph
p-Tol
1-Naphthyl
2-Naphthyl
PhMeCHCH2
Me
Me
Me
Me
H
R
R
R
R
—
137.9
134.6
115.5
124.8
192.4
91.5
94.8
90.7
92.3
96.1
78
75
62
66
0
65.4
66.1
54.3
59.7
95.8
5.3
4.7
5.8
4.9
0
26.2
26.5
21.7
23.9
38.3
a Current efficiency. b Turnover number.
This work was supported in part by Grants-in-Aid for
Scientific Research on Priority Areas (No. 11119208: ‘In-
novative Synthetic Reactions’) and for Encouragement Re-
search (No. 10771266) from the Ministry of Education,
Science, Sports and Culture of Japan.
Notes and references
† A glassy carbon disk electrode (3 mm diameter) and a platinum wire were
employed as working electrode and counter electrode, respectively. The
anode potentials were referred to Ag/AgCl (saturated AgCl and Me2EtNCl
in MeCN). Cyclic potential sweeps were generated by a Hokuto Denko
Model HABF-501 potentiostat/galvanostat. Cyclic voltammograms were
recorded on a Graphtec Model WX1200 X-Y recorder. All electrochemical
measurements were carried out at room temperature (ca. 20 °C).
‡ The HPLC analysis was carried out using Daisel CHIRALCELL-OD
column (46 mm f 3 250 mm). The column temperature was kept constant
at 40 °C. The analytes were eluted by PriOH–n-hexane (2+33) at 0.7 ml
min21 flow rate, and detected by UV absorption at 254 nm.
Fig. 2 Macroelectrolysis of racemic PEA by 1 in the presence of
2,6-lutidine: (5) (R)-PEA, (2) (S)-PEA and (8) acetophenone.
The results from the enantioselective oxidation reactions of a
variety of racemic amines are shown in Table 1. In the
electrocatalytic oxidation of the racemic amines such as
1-(1-naphthyl)ethylamine, 1-(2-naphthyl)ethylamine and 1-(p-
tolyl)ethylamine, which contain a chiral centre a to the amino
group, the (S)-isomers were oxidized in preference to the (R)-
isomers. After 5 h of electrolysis, the racemic amines were
oxidized to the corresponding ketones in 90.7–94.8% current
efficiency, 54.3–66.1% yield and 100% selectivity. The turn-
over numbers based on 1 are larger than 21. The enantiopurity
of the remaining (R)-isomers and S values were 62–78% and
4.7–5.8, respectively. On the contrary, the electrooxidation of
2-phenylpropylamine, which has a chiral centre b to the amino
group, was not enantioselective. After 5 h of electrolysis, it was
oxidized to the corresponding aldehyde in 96.1% current
efficiency, 95.8% yield and 100% selectivity. The turnover
numbers based on 1 is 38.3. These facts mean that an a-
hydrogen in a chiral centre adjacent to the amino group is
necessary to attain an enantioselective oxidation in the present
system. The enantioselective oxidation with 1 is applicable to
the optical resolution of racemic secondary amines.
1 H. Nohira, M. Kai, M. Nohira, J. Nishikawa, T. Hoshiko and K. Saigo,
Chem. Lett., 1981, 951.
2 C. Berti and M. J. Perkins, Angew. Chem., Int. Ed. Engl., 1979, 18,
864.
3 Z. Ma, G. Huang and J. M. Bobbitt, J. Org. Chem., 1993, 58, 4837.
4 S. D. Rychnovsky, T. L. McLernon and H. Rajapakse, J. Org. Chem.,
1996, 61, 1194.
5 M. F. Semmelhack and C. R. Schmid, J. Am. Chem. Soc.,1983, 105,
6732.
6 F. MacCorquodale, J. A. Crayston, J. C. Walton and D. J. Worsfold,
Tetrahedron Lett., 1990, 31, 771.
7 Y. Kashiwagi, F. Kurashima, C. Kikuchi, J. Anzai, T. Osa and J. M.
Bobbitt, J. Chin. Chem. Soc., 1998, 45, 135.
8 J. M. Bobbitt and M. C. L. Flores, Heterocycles, 1988, 27, 509.
9 A. J. Bard and L. R. Faulkner, Electrochemical Methods, Wiley, New
York, 1980, p. 215.
10 S = ln[(1 2 C)(1 2 ee)]/ln[(1 2 C)(1 + ee)], where ee is the fractional
enantiomeric excess and C is the conversion. For a discussion of kinetic
resolutions see: H. B. Kagan and J. C. Fiaund, Top. Stereochem., 1988,
18, 249.
Communication 9/05894J
1984
Chem. Commun., 1999, 1983–1984