Organocatalyzed α-oxyamination of aldehydes using anodic oxidation

Article abstract of DOI:10.1002/ejoc.200900871

Electrochemical oxidation was performed during the organocatalyzed α-oxyanimation of aldehydes by using a one-compartment electrolytic cell under galvanostatic conditions. In the presence of substoichiometric amounts of sec-amines, the desired coupling pr

Full text of DOI:10.1002/ejoc.200900871

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900871
Organocatalyzed α-Oxyamination of Aldehydes Using Anodic Oxidation
Nhat-Nguyen Bui,[a] Xuan-Huong Ho,[a] Sun-il Mho,[a] and Hye-Young Jang*[a]
Keywords: Oxidation / Organocatalysis / Enamines / Oxyamination / Cyclic voltammetry
Electrochemical oxidation was performed during the organo-
examined by using chiral sec-amines. Control experiments
catalyzed α-oxyamination of aldehydes by using a one-com- and cyclic voltammetry confirmed the key intermediate of
partment electrolytic cell under galvanostatic conditions. In
the presence of substoichiometric amounts of sec-amines, the
desired coupling products were formed in good yield. The
asymmetric variant of the α-oxyamination of aldehydes was
this reaction to be the cationic radical of the enamine derived
from the sec-amine catalysts and aldehydes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Results and Discussion
Prior to conducting the α-oxyamination of aldehydes by
anodic oxidation, the electrochemical properties of hydro-
cinnamaldehyde (1a), pyrrolidine (organocatalyst), and en-
amine 1b were evaluated by cyclic voltammetry (CV) on
a platinum electrode over the potential range 0.0 to 2.0 V
(Figure 1). The structures of aldehyde 1a, pyrrolidine, and
enamine 1b are illustrated in Scheme 1. No particular redox
wave for aldehyde 1a (0.01 ) was observed in a dichloro-
methane solution containing 0.1  tetrabutylammonium
perchlorate (TBAP) as the electrolyte. During the anodic
scan, an oxidation wave for pyrrolidine peaking was ob-
served at 1.41 V vs. a silver wire pseudoreference electrode
at a scan rate of 0.1 Vs–1, but no reduction wave was ob-
served during the reverse scan. The absence of a reverse
reduction peak of the oxidized pyrrolidine during the oxi-
dation scan was attributed to the subsequent chemical reac-
tion of the oxidized species.[10] Enamine 1b exhibits an elec-
trochemically irreversible redox pattern at the platinum
electrode. In the range 0.0 to 2.0 V, two oxidation waves
appeared at Ep,a = 0.71 and 0.95 V, which are assumed to
be the cationic radical and the allylic cation, respectively[11]
(Scheme 2).
Cyclic voltammetry of a mixture containing compound
1a (0.01 ) and pyrrolidine (0.005 ) was performed to ob-
tain more information on the electrochemical properties of
the intermediates formed during the catalytic reaction con-
ditions. To consume pyrrolidine completely, 2 equivalents of
the aldehyde was used with respect to pyrrolidine (1 equiv.).
An oxidation wave appeared with a peak potential at
0.72 V, whereas the oxidation current peak at 1.41 V corre-
sponding to the oxidation of pyrrolidine disappeared. The
anodic wave at 0.72 V was attributed to the first oxidation
of enamine 1b derived from pyrrolidine and compound 1a,
which was verified by the CV of enamine 1b prepared inde-
pendently. The second oxidation current peak of enamine
Electrochemical oxidation and reduction have been used
as powerful and clean methods for the synthesis of compli-
cated organic molecules.[1] In particular, cationic radicals
and cations generated by electrochemical oxidation are in-
volved in further chemical reactions, which can avoid the
use of toxic chemical oxidants, leading to green chemical
processes.[1,2] As part of an ongoing investigation aimed at
developing green catalytic reactions, this study examined
the anodic oxidation of enamines, forming the cationic radi-
cal intermediate to perform radical-mediated reactions.[3,4]
In the context of oxidized enamine radical-mediated reac-
tions, enantioselective α-substitution reactions of aldehydes
catalyzed by chiral secondary amines have been re-
ported.[5,6] During the reaction, the enamine generated in
situ from the chiral amine and aldehyde undergoes oxi-
dation by transition-metal oxidants (Fe3+ or Ce4+) to pro-
duce cationic radicals. Subsequently, the cationic radicals
react with the coupling partner to give α-substituted alde-
hydes. This paper reports the sec-amine-catalyzed coupling
of an aldehyde to TEMPO by using electrochemical oxi-
dation, where the cationic radicals are formed by the anodic
oxidation of the enamine intermediates, rendering a reac-
tion with the TEMPO radical. Although a wide range of
electrooxidation reactions have been reported, there are no
papers on the organocatalyzed α-substitution of an alde-
hyde by anodic oxidation.[2,7–9]
[a] Division of Energy Systems Research, Ajou University,
Suwon 443-749, Korea
Fax: +82-31-219-1615
E-mail: hyjang2@ajou.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900871.
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N.-N. Bui, X.-H. Ho, S.-i. Mho, H.-Y. Jang
SHORT COMMUNICATION
commercially available oxopiperidinium salt (TEMPO+)
was carried out but no product was obtained. As a result,
the electrophilic addition of TEMPO+ to the enol or en-
amine to form compound 1c was excluded under these reac-
tion conditions.
Figure 1. Cyclic voltammograms of 1a (0.01 ), pyrrolidine
(0.01 ), 1b (0.01 ), and the mixture of 1a (0.01 ) and pyrrolidine
(0.005 ) in 0.1  TBAP dichloromethane solution at a scan rate
of 100 mVs–1.
Scheme 3. Plausible mechanisms for the formation of compound
1c.
With the cyclic voltammetry and control experimental
results indicating that the enamine-radical-mediated reac-
tion is possible by an anodic oxidation, the electrolytically
organocatalyzed α-oxyamination of aldehydes was con-
ducted in a simple undivided cell under a constant anodic
current. As shown in Scheme 4, the desired radical coupling
products were obtained in good yield with a pyrrolidine cat-
alyst. Hydrocinnamaldehyde (1a) and octanal (2a) partici-
pated in the reaction, providing coupling products 1c and
2c in 54 and 58% yield, respectively. The reaction of isova-
leraldehyde (3a) and TEMPO showed higher yield com-
pared to those of compounds 1a and 2a.
Scheme 1. The reaction of aldehyde 1a with pyrrolidine.
Scheme 2. Electrooxidation of enamine 1b.
1b at 0.95 V was not observed in the CV of the solution
containing compound 1a (2 equiv.) and pyrrolidine
(1 equiv.). Presumably, the cationic radical species generated
from the first oxidation readily underwent a chemical reac-
tion with the excess amount of the aldehyde.
In accordance with the electrochemical analysis of each
component and their mixtures in Figure 1, a mechanism in-
volving cationic radical 1b·+ generated from the electrooxid-
ation of 1b and its reaction with TEMPO was considered
to provide product 1c (Scheme 3, Equation 1). Because the
electrophilic addition of TEMPO+ to enols has been re-
ported,[7,12] oxidized TEMPO+, and not cationic radical
1b·+, might react with the enolized aldehyde to form com-
pound 1c under anodic electrolysis conditions (Scheme 3,
Equation 2). To clarify the mechanism, the electrochemical
oxidation of a solution containing 1a and H+ (p-toluenesul-
fonic acid) for enol formation was carried out in the pres-
ence of TEMPO, but no product was obtained. In addition,
the possible route involving the electrophilic addition of
TEMPO+ to enamines (Scheme 3, Equation 3) was ex-
Scheme 4. Pyrrolidine-catalyzed α-oxyamination using anodic oxi-
dation.
Various chiral sec-amines for the α-oxyamination of alde-
cluded on the basis of the following experiment. A chemical hydes were examined under the anodic electrolysis condi-
reaction of compound 1b prepared independently with a tions to perform asymmetric conversion. Among the sec-
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Organocatalyzed α-Oxyamination of Aldehydes Using Anodic Oxidation
amine compounds listed, -proline methyl ester hydrochlo-
Conclusions
ride, (S)-pyrrolidine methanol, and (S)-α,α-diphenyl-2-pyr-
rolidine methanol trimethylsilyl ether promoted this trans-
formation (Scheme 5). In terms of the enantioselectivity,
(S)-α,α-diphenyl-2-pyrrolidine methanol trimethylsilyl ether
catalyzed the reaction to provide a product with higher
enantioselectivity (64%ee) than the other catalysts, and it
was chosen for study of the substrate scope. The absolute
stereochemistry of compound 1c was assigned as S by com-
paring the HPLC data reported in the literature.[5]
The organocatalyzed α-oxyamination of aldehydes by
anodic oxidation was conducted in the presence of an achi-
ral sec-amine (pyrrolidine) and chiral sec-amines, showing
good yield and enantioselectivity. Despite the enormous ef-
fort to employ the electrolysis in a wide range of organic
reactions including asymmetric reactions, this study is the
first to show that anodic oxidation can be used to promote
enamine-mediated organocatalytic reactions, where the cat-
ionic radical enamine intermediates are formed for singly
occupied molecular orbital (SOMO) catalysis. Cyclic vol-
tammetry and control experiments were carried out to con-
firm the mechanism.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures and spectroscopic data for
compound 2 and 3.
Acknowledgments
This study was supported by the Korea Science and Engineering
Foundation (R01-2007-000-20223-0 and 2009-0072421) and Korea
Research Foundation (KRF-2008-331-C00166).
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Scheme 5. Chiral amine-catalyzed α-oxyamination using anodic
oxidation.
As shown in Table 1, enantioselective organocatalyzed α-
oxyaminations of octanal (2a) and isovaleraldehyde (3a)
were tested under the electrolysis conditions. Using 2a, the
desired coupling product was obtained in 23% yield and
70%ee. In the case of 3a, 49% yield and 60%ee were ob-
served under the electrolysis conditions.
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Entry
R
Time [h] Yield [%]
ee [%][a]
1
2
3
Ph (1a)
(CH2)5CH3 (2a)
CH(CH3)2 (3a)
9
57
23
49
64
70
60
10
9
[a] The enantioselectivity was measured by HPLC after modifying
the product, as stated in the Supporting Information.
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Received: July 31, 2009
Published Online: September 21, 2009
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