Indirect electrochemical oxidation of piperidin-4-ones mediated by sodium halide-base system

Article abstract of DOI:10.1016/j.tet.2006.06.031

Indirect electrochemical oxidation of 1-N-subsituted piperidin-4-ones in methanol in an undivided cell in the presence of sodium iodide/sodium methoxide system leads to the corresponding α-hydroxyketals in 50-80% substance yield (50-65% current yield). 2,2,6,6-Tetramethylpiperidin-4-one under the same conditions forms a mixture of methyl 2,2,5,5-tetramethyl-3-pyrrolidinecarboxylate and methyl 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylate in 70% substance yield (60-70% current yield) via electrochemically induced Favorskii rearrangement.

Full text of DOI:10.1016/j.tet.2006.06.031

Tetrahedron 62 (2006) 8021–8028
Indirect electrochemical oxidation of piperidin-4-ones mediated
by sodium halide-base system
*
Michail N. Elinson, Alexander S. Dorofeev, Sergey K. Feducovich, Ruslan F. Nasybullin,
Evgeny F. Litvin, Mikhail V. Kopyshev and Gennady I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia
Received 23 March 2006; revised 29 May 2006; accepted 8 June 2006
Available online 30 June 2006
Abstract—Indirect electrochemical oxidation of 1-N-subsituted piperidin-4-ones in methanol in an undivided cell in the presence of sodium
iodide/sodium methoxide system leads to the corresponding a-hydroxyketals in 50–80% substance yield (50–65% current yield). 2,2,6,6-
Tetramethylpiperidin-4-one under the same conditions forms a mixture of methyl 2,2,5,5-tetramethyl-3-pyrrolidinecarboxylate and methyl
2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylate in 70% substance yield (60–70% current yield) via electrochemically induced
Favorskii rearrangement.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
transformation of the initially produced cation radical
ꢀ
R1R2C]O+ .12,13
The oxidation of ketones is a known method for preparing
carboxylic acids and their derivatives, bifunctional com-
pounds such as a-hydroxyketones, diketones and other use-
ful intermediates in organic synthesis.1 The formation of
adipic acid from cyclohexanone is an important industrial
process. a-Hydroxyketones are significant ‘building blocks’
in the construction of natural products and fine chemicals.2,3
In the case of aryl alkyl ketones, the corresponding
a-hydroxyketones and a-hydroxyketals are convenient
compounds for synthesis of the pharmacologically active
2-arylalkanoic acids.4,5
In some oxidative transformations of ketones, such as in the
haloform reaction, the a-halogenation of ketones is an im-
portant step.14 So for certain cases, the selective indirect
electrooxidation of ketones with the electrochemically gen-
erated halides is also possible. Thus, the electrocatalytic
variant of the haloform reaction–the procedure to prepare
carboxylic acid esters by the electrooxidation of methyl
alkyl and methyl aryl ketones in methanol in the presence
of alkali metal bromides is well known.15
The NaI/NaOH mediatory system is also known for the ef-
fective indirect electrochemical oxidation of carbonyl com-
pounds. Using this mediatory system aryl alkyl ketones are
oxidized into the corresponding a-hydroxyketals.16 Elec-
trolysis of alkyl benzyl ketones in methanol in an undivided
cell in the presence of the NaI/NaOH system induces a pro-
cess similar to the Favorskii rearrangement of a-haloalkyl
benzyl ketones to produce methyl arylalkanecarboxylates.17
Electrolysis of dialkyl ketones under the same conditions in-
volves a process analogous to the Favorskii rearrangement of
a,a-dihalodialkyl ketones giving rise to methyl esters of
a,b-unsaturated carboxylic acids.18,19
Due to the considerable progress in the electrochemistry of
organic compounds in the last decades, the electrosynthesis
became a highly competitive method in modern organic
chemistry.6,7 However, in the case of the electrochemical
oxidation of ketones, only some examples of the procedures,
which could ensure product-selectivity are known.
The direct electrochemical oxidation of ketones led to the
formation of a mixture of acids, saturated and unsaturated
hydrocarbons, carbon monoxide and dioxide.8–11 Remote
non selective oxidative functionalization of aliphatic ketones
was observed when electrooxidation was carried out in ace-
tonitrile or trifluoroacetic acid as a result of the subsequent
It has been found that the result of the indirect electrochemi-
cal oxidation of cyclic ketones in methanol in an undivided
cell in the presence of sodium halide or sodium halide-base
system depends on the ring size of ketone. Cyclopentanone
affords 2,2-dimethoxycyclopentanone, while cyclohexa-
none gives rise to 2,2-dimethoxycyclohexanol. Cyclic
Keywords: Electrochemical reactions; Mediators; 4-Piperidinones;
a-Hydroxyketals; Favorskii rearrangement.
* Corresponding author. Tel.: +7 495 137 38 42; fax: +7 495 135 53 28;
e-mail: elinson@ioc.ac.ru
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.031

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M. N. Elinson et al. / Tetrahedron 62 (2006) 8021–8028
Table 2. Electrooxidation of 2,2,6,6-tetramethylpiperidin-4-one 2 in meth-
ketones with higher ring size after a,a-dihalogenation
undergo the electrochemically induced Favorskii rearrange-
ment with the formation of methyl cycloalkenecarboxylates
containing in the ring one carbon less than starting ketone.
So the simple electrocatalytic system can distinguish the
ring size of cyclic ketones.20,21
anola
No. Ketone Mediator Base
equivalent
Product,
yield %b
Current
yield %c
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
2
2
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaI
NaI
NaI
NaI
NaI
— 6a, 18; 7a, 28
0.1 MeONa 6a, 29; 7a, 42
0.3 MeONa 6a, 42; 7a, 34 (59) 55
0.5 MeONa 6a, 36; 7a, 29 (57) 50
0.8 NaONa 6a, 32; 7a, 21
1.0 MeONa 6a, 28; 7a, 15
37
57
Recently we have found that electrolysis of 4-substituted cy-
clohexanones in methanol in the presence of sodium halides
in an undivided cell results in the stereoselective formation
of cis-5-substituted-2,2-dimethoxycyclohexanols.22
37
29
17
30
40
—
6a, 23; 7a, 5
0.1 MeONa 6a, 43; 7a, 8
0.3 MeONa 6a, 52; 7a, 14
0.5 MeONa 6a, 59; 7a, 26 (71) 56
0.8 MeONa 6a, 53; 7a, 29 (68) 56
1.0 MeONa 6a, 38; 7a, 45 (69) 64
3.0 MeONa 6a, 29; 7a, 58 (73) 73
9
10
11
12
13
Continuing our studies on the electrocatalytic and indirect
electrooxidation of ketones15–22 we have accomplished
indirect electrochemical oxidation of substituted piperidin-
4-ones 1a–d and 2 in the presence of sodium halides as
mediators and in the presence of mediatory systems sodium
halide-base (Scheme 1).
NaI
NaI
a
Ketone (10 mmol), 10 mmol of mediator, 20 ml of MeOH, Fe-cathode,
C-anode, current density 200 mA/cm2, 4 F/mol electricity passed,
30 ꢁC, conversion of 2 (95–100%).
Determined by gas chromatography and NMR spectra, in parenthesis–
isolated yields for the mixture of 6a and 7a.
For the mixture of 6a and 7a.
b
c
Me Me
HN
O
Table 3. Electrooxidation of 2,2,6,6-tetramethylpiperidin-4-one
2
in
R
N
O
ethanola
Me Me
1a-d
No. Ketone Mediator Base
Product,
Current,
yield %c
equivalent yield %b
2
a R = CH2Ph, b R = Me,
c R = CO2Et, d R = CO2Bu-t
1
2
3
4
2
2
2
2
NaI
NaI
NaI
NaI
— 6b, 36
0.1 EtONa 6b, 53 (40)
0.3 EtONa 6b, 65 (51); 7b, 2 35
0.5 EtONa 6b, 44; 7b, 11 33
18
27
Scheme 1.
a
Ketone (10 mmol), 10 mmol of NaI, 20 ml of EtOH, Fe-cathode,
C-anode, current density 200 mA/cm2, 4 F/mol electricity passed,
30 ꢁC, conversion of 2 (95–100%).
Determined by gas chromatography and NMR spectra, in parenthesis–
isolated yields for 6b.
For 6b or the mixture of 6b and 7b.
2. Results and discussion
b
c
In the present study we report our results on the indirect
electrochemical oxidation of substituted piperidin-4-ones
1a–d and 2 (Tables 1–4). It has been found that electrooxida-
tion of N-substituted 4-piperidinones 1a–d in methanol in
the presence of sodium halides as mediators led to the forma-
tion of 1-substituted 4,4-dimethoxypiperidine-3-ols 3a–d
(Scheme 2) (Table 1).
Table 4. Electrooxidation of 3,3,5,5-tetramethylcyclohexanone 8 in metha-
nola
No. Ketone Base
equivalent
Product,
yield %b
Current
yield %c
1
2
3
8
8
8
—
9 7; 10 53 (38); 11 15
72
0.5 MeONa 9 12; 10 34 (18); 11 29 (17) 69
1 MeONa 9 17 (11); 10 13; 11 46 (31) 68
Thus the general result of the indirect electrochemical oxida-
tion of N-substituted piperidin-4-ones 1a–d is similar to the
result of indirect electrochemical oxidation of cyclohexa-
none 420,21 and 4-substituted cyclohexanones22 (Scheme 3).
a
Ketone (10 mmol), 10 mmol of NaI, 20 ml of MeOH, Fe-cathode,
C-anode, current density 200 mA/cm2, electricity passed 4 F/mol,
30 ꢁC, conversion of 8 (95–100%).
Determined by gas chromatography and NMR spectra, in parenthesis–
isolated yields.
For the mixture of 9, 10 and 11.
b
c
But there is a difference in the conditions of the electrooxi-
dation. In the indirect electrooxidation of cyclohexanone21
Table 1. Electrooxidation of N-substituted piperidin-4-ones 1a–da
No.
Ketone
R
Mediator
Base equivalent
Electricity passed, F/mol
Product, yield %b
Current yield %
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Me
NaBr
NaI
NaI
NaI
NaI
NaI
NaBr
NaI
NaI
NaI
—
—
6
4.5
4
4
4
3
3
3
3
3a, 45
3a, 56
3a, 67
3a, 74 (59)
3a, 61
3a, 86 (71)
3a, 66
3b, 94 (81)
3c, 69 (55)
3d, 67 (52)
15
25
34
37
31
57
44
65
46
45
0.3 NaOH
0.5 NaOH
1.0 NaOH
0.5 MeONa
0.5 MeONa
0.5 MeONa
0.5 MeONa
0.5 MeONa
CO2Et
CO2Bu-t
3
Ketone (10 mmol), 10 mmol of mediator, 20 ml of MeOH, Fe-cathode, C-anode, current density 200 mA/cm2, 30 ꢁC, conversion of 1a–d (98–100%).
Determined by gas chromatography and NMR spectra, in parenthesis–isolated yields.
a
b

M. N. Elinson et al. / Tetrahedron 62 (2006) 8021–8028
8023
OMe
OMe
The reactions at the electrodes, which take place during the
process, are shown below (Scheme 5):
-e
R
N
R
N
O
NaHal, MeOH
OH
1a-d
Hal = Br, I
3a-d
-
anode: 2 Hal
2e
Hal2
Hal = Br, I
-
a R = CH2Ph, b R = Me,
c R = CO2Et, d R = CO2Bu-t
-
+
2 MeO
H2
cathode:
2 MeOH
+
2e
Scheme 5.
Scheme 2.
The formation of iodine or bromine at the anode is a well-
known process and the corresponding colour was observed
when the electrolysis was conducted without stirring the
reaction mixture, as well as evolution of hydrogen at the
cathode.
OMe
OMe
OH
-e
O
NaHal, MeOH
Hal = Br, I
4
5
Scheme 3.
Further bromination of enolate anion of 1 takes place in
solution with following addition of methoxide anion to the
carbonyl group and intramolecular substitution of halogen
with the formation of intermediate epoxide (A). Then the
attack of another methoxide anion leads to epoxide ring
opening, and finally to formation of 3 (Scheme 6).
or 4-substituted cyclohexanones22 into a-hydroxyketals of
type 5, there is no significant difference between the use of
NaI or NaBr as a mediator and it is not necessary to use
base additive to ensure good current efficiency.
As it follows from the data of Table 1, NaI is more efficient
as mediator when compared with NaBr for the indirect elec-
trooxidation of 1a–d into a-hydroxyketals 3a–d. In the case
of NaOH as additive the best results were obtained with
0.5 equiv of NaOH. The next improvement of the conditions
for the indirect electrochemical oxidation of 1a was
achieved using 0.5 equiv of MeONa. Under these optimal
conditions 3a was obtained in 86% substance and 57% cur-
rent yields. Earlier only NaOH was used as additive for the
electrooxidation of carbonyl compounds into corresponding
a-hydroxyketals. Aryl alkyl ketones were successfully elec-
trooxidized in the presence of NaI as mediator and 0.1 equiv
of NaOH;16 analogous transformation of aliphatic aldehydes
was performed in the presence of NaI and 0.4 equiv of
NaOH23(Scheme 4):
Hal
-
Hal2
MeO
-
R
R
N
N
O
R
R
N
N
O
R
N
O
-
-Hal
MeOH
1
-
MeO
Hal
OH
-
O
-
-Hal
-
OMe
OMe
MeO
O
OMe
R
N
MeOH
OMe
3
A
Scheme 6.
Sodium iodide gives better results for the indirect electro-
chemical oxidation of ketone 1 into a-hydroxyketal 3 com-
pared to sodium bromide as bromine generated at anode is
more effective for competitive oxidation of methoxide
anions.
OH
-e
R
Nal-NaOH, MeOH
R
H
MeO OMe
Taking into consideration that the indirect electrochemical
oxidation of N-substituted piperidin-4-ones 1a–d is similar
to the result of indirect electrochemical oxidation of cyclo-
hexanone 4 and leads to N-substituted 4,4-dimethoxypiperi-
dine-3-ols 3a–d, it was strange for us to find in recent
preliminary communication that 2,2,6,6-tetramethylpiperi-
din-4-one 2 under conditions of the indirect electrochemical
oxidation in methanol in the presence of sodium halides and
2.5 equiv of MeONa undergoes the electrochemically
induced Favorskii rearrangement with the formation of
mixtures of methyl 2,2,5,5-tetramethylpyrrolidine-3-car-
boxylate 6a and methyl 2,2,5,5-tetramethyl-2,5-dihydro-
1H-pyrrole-3-carboxylate 7a26 (Scheme 7).
O
75-85%
R1
R1
OH
H
-e
R2
R2
Kl-KOH, MeOH
MeO OMe
33-85%
O
Scheme 4.
Earlier oxidation of 1a by iodine/KOH (0 ꢁC, 2.5 h)24 re-
sulted in 3a formation in 50% yield and 3b was obtained
by oxidation of 1b with iodobenzenediacetate25 in MeOH/
KOH (36 h) in 32% yield.
Indirect electrochemical oxidation of 2 in the presence of
NaCl under our conditions without base or in the presence
of 0.5 equiv of MeONa resulted in the formation of a
complex mixture of compounds. The combined yields of
esters 6 and 7 were less than 10% by GC and NMR
data. The results of the electrochemical oxidation of 2 in
the presence of NaI and NaBr in methanol are given in
the Table 2.
Taking into consideration the above results and the data on the
mechanism of the electrocatalytic oxidation of cyclohexa-
none and 4-substituted cyclohexanones with sodium halide
as mediator the following mechanism of the electrochemical
oxidation of N-substituted piperidin-4-ones 1a–d into a-hy-
droxyketals 3a–d in the presence of sodium halide/NaOMe
system is suggested.

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M. N. Elinson et al. / Tetrahedron 62 (2006) 8021–8028
O
O
O
OMe
Me
OMe
Me
Me
-e
Me
Me
Me
Me
Me
Me
Me
Me
+
NaHal-MeONa, MeOH
Me
N
H
N
H
N
H
2
6a
7a
Hal = Cl, Br, I
Scheme 7.
O
O
O
OEt
Me
Me
OEt
Me
Me
Me
Me
-e
Me
Me
Me
Me
Me
Me
+
NaI-EtONa, EtOH
N
H
N
H
N
H
2
6b
7b
Scheme 8.
-
As it follows from the data of Table 2, NaI is more efficient
mediator when compared with NaBr for the indirect elec-
trooxidation of cyclic ketone 2 into the mixture of the cy-
clic esters 6a and 7a. Nevertheless, NaBr as mediator with
0.3 or 0.5 equiv of MeONa also led to good results. The
best yields for the mixture of cyclic esters 6a and 7a
were obtained using NaI–0.5 and more equivalents of
MeONa mediatory system. Under these conditions cyclic
esters 6a and 7a were isolated in 70% yield. The ratio
of 6a and 7a changes from 2:1 to 1:2 with the increase
of MeONa quantity from 0.5 to 3.0 equiv. Hydrogenation
of the mixture of 6a and 7a in autoclave on Pd/C catalyst
(5% Pd) in methanol resulted in formation of 6a in quanti-
tative yield.
anode: 2 Hal
2e
+
Hal2
Hal = Br, I
-
-
+
cathode:
2e
2 RO
H2
R= Me, Et
2 ROH
Scheme 9.
Further bromination and dibromination of enolate anion of
2 take place in solution, followed by proton abstraction
with methoxide anion and Favorskii rearrangement27 while
the attack of methoxide anion on the carbonyl group is
blocked by steric hindrance of the four methyl substituents
(Scheme 10).
To determine an influence of tetramethyl substitution on the
result of the electrocatalytic oxidation of the 6-membered
cyclic ketones, the electrocatalytic oxidation of 3,3,5,5-
tetramethylcyclohexanone has been studied (Table 4).
What are the main differences of the electrooxidation 2 in
MeOH under our conditions from those published earlier?26
(1) The electrooxidation of 2 in the presence of NaCl in our
case has no selectivity. (2) In the electrooxidation of 2 in the
presence of NaBr under our conditions, the optimal quantity
of MeONa is 0.3–0.5 equiv (ratio 6a/7a, 4:3); earlier
2.6 equiv of MeONa (ratio 6a/7a, 2:3). (3) In the electro-
oxidation of 2 in the presence of NaI under our conditions,
the optimal quantity of MeONa is 0.5–3.0 equiv (whereas
ratio 6a/7a changes from 2:1 to 1:2), earlier 2.6 equiv of
MeONa (ratio 6a/7a, 1:1). (4) And the last but not least, cur-
rent yields for the mixture of 6a and 7a in our case comprise
50–70%, the twice improvement on the earlier reported 30%
yields.26
It was found that the result of electrocatalytic oxidation of 6-
membered tetramethyl ketone 8 (Scheme 11) is very similar
to the oxidation of 6-membered azatetramethyl ketone 2 and
quite different from the electrocatalytic oxidation of cyclo-
hexanone where only corresponding a-hydroxyketal was
obtained.21 The steric hindrance for the elimination of the
iodine substituent in the ester 10 is even more stronger
than in the corresponding ester formed from ketone 2
(according to the mechanism shown in Scheme 10), since
only a part of iodoester 10 was converted into unsaturated
ester 11 under conditions studied. Thus the steric influence
of four methyl substituents is the main reason for the change
in route of the indirect electrochemical oxidation of tetra-
methylpiperidinone 2 compare to N-substituted piperidin-
4-ones 1a–d.
Indirect electrochemical oxidation of 2 in the presence of
NaI in ethanol was found to be more selective process, in
this case 6b was isolated from the reaction mixture directly
after electrolysis (Scheme 8) (Table 3).
Taking into consideration the results of the electrocatalytic
oxidation of 2 and the data on the mechanism of the electro-
catalytic oxidation of cyclic ketones with sodium halide as
mediator,12 the following mechanism of the indirect electro-
chemical oxidation of 2 in the presence of sodium halide/
NaOR system is suggested.
3. Conclusion
To summarize, we have found that electrolysis with NaI/
MeONa mediatory system in an undivided cell affords
under mild conditions in methanol electrochemical oxida-
tion of 1-N-substituted piperidin-4-ones into corresponding
a-hydroxyketals in 50–80% yields. Under the similar condi-
tions 2,2,6,6-tetramethylpiperidin-4-one in methanol was
The reactions at the electrodes, which take place during the
process, are shown below (Scheme 9):

M. N. Elinson et al. / Tetrahedron 62 (2006) 8021–8028
8025
O-
O
-
RO
ROH
Hal2
Me
Me
Me
Me
Me
Me
Me
Me
-
-Hal
N
H
N
H
2
O
O-
O
Hal
Hal
Me
Me
Hal
Hal
-
Hal2
RO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
-
-Hal
ROH
N
H
N
H
N
H
-ROH
-Hal
ROH
-ROH
-Hal
ROH
-
-
-
RO
-
RO
O
Hal
O
OR
Me
Me
Me
OR
Me
N
H
Me
Me
Me
Me
N
H
-ROH
-
-
RO
-Hal
6
O
OR
Me
Me
Me
Me
N
H
7
Scheme 10.
O
O
O
I
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
-e
Nal-MeONa, MeOH
+
+
8
9
10
O
OMe
Me
Me
Me
Me
11
Scheme 11.
transformed into the mixture of methyl 2,2,5,5-
tetramethylpyrrolidine-3-carboxylate and methyl 2,2,5,5-
tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylate in 70%
overall yield or in ethanol directly into ethyl 2,2,5,5-tetra-
methyl-3-pyrrolidinecarboxylate in 40–50% yields as the
result of the electrochemically induced Favorskii rearrange-
ment. The simple two-step procedure, i.e., electrolysis and
further hydrogenation affords methyl 2,2,5,5-tetramethyl-
3-pyrrolidinecarboxylate in 70% yield. These methods
require the use of common and commercially available re-
agents, inexpensive apparatus and an undivided cell. The
techniques for electrolysis and isolation of the reaction prod-
ucts are simple and convenient to use both under laboratory
conditions and in large-scale apparatus.
4. Experimental
4.1. General
All melting points were measured on a Gallenkamp melting
point apparatus and are uncorrected. GC analysis was carried
out on LKhM-80 chromatograph with a flame-ionization
detector. Columns: (1) fused-silica capillary column HP-1
(5 mꢂ0.53 mmꢂ2.65 mm) and (2) glass column 3 mꢂ
3 mm with 10% FFAP on Chromaton N-Super (0.13–
0.16 mm). 1H NMR spectra were run for solutions in CDCl3
and recorded with Bruker AM-300 and Bruker DRX-500
spectrometers. Chemical shifts are presented in d scale with
tetramethylsilane (TMS) used as an internal standard.

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M. N. Elinson et al. / Tetrahedron 62 (2006) 8021–8028
4.2. General electrolysis procedure
2.94–3.18 (m, 2H), 3.20 (s, 3H, OCH3), 3.22 (s, 3H,
OCH3), 3.72–3.90 (m, 3H), 4.18 (q, 2H, J¼7.1 Hz). 13C
NMR (CDCl3): d 14.3 (CH3), 27.0 (CH2), 40.2 (CH2), 46.3
(CH2), 47.4 (OCH3), 47.6 (OCH3), 61.1 (OCH2), 66.33
(OCH), 98.84 [C(OCH3)2], 156.10 (C]O). MS (70 eV)
m/z (relative intensity %): 233 (M+, 20), 218 (8), 204 (16),
202 (11), 173 (15), 160 (18), 156 (21), 144 (43), 101 (57),
88 (100), 56 (67), 42 (98). IR (KBr): nmax 3460, 2944,
2832, 1685, 1436, 1272, 1228, 1120, 1076, 940.
A solution of ketone (10 mmol), sodium halide (10 mmol)
and base (type of the base and amount used are specified
in the corresponding Tables 1–4) in methanol or ethanol
(20 ml) was electrolyzed in an undivided cell equipped
with C-anode and Fe-cathode at 30 ꢁC under constant cur-
rent density 200 mA/cm2 until the quantity of the electricity
indicated in tables was passed. The reaction mixture was
neutralized by dilute HCl, the solvent was then removed,
and the reaction mixture was extracted with ether, washed
with solution of Na2S2O3 in water, then with water, and dried
over Na2SO4. Solvent was removed and then products were
isolated by sublimation (3a and 3b), vacuum distillation
(mixture of 6a and 7a, 6b) or column chromatography on
silica gel (eluent: hexane/ethyl acetate 1:1–10:1) (3c, 3d,
9, 10 and 11). Mixtures of 6a and 7a were converted into
6a by hydrogenation.
4.3.4. tert-Butyl 3-hydroxy-4,4-dimethoxypiperidine-1-
carboxylate (3d).23 Compound 3d was isolated by column
chromatography (eluent: hexane/ethyl acetate 1:1), yield
1
1.35 g (52%), colourless oil, H NMR (CDCl3): d 1.40 (s,
9H), 1.71–1.86 (m, 2H), 2.65 (s, 1H, OH), 2.95 (m, 1H),
3.15 (s, 3H, OCH3), 3.18 (s, 3H, OCH3), 3.29 (m, 1H),
3.61–3.73 (m, 3H). 13C NMR (CDCl3): d 28.1 (CH3), 28.4
(CH2), 42.2 (CH2), 47.5 (OCH3), 47.6 (OCH3), 48.47
(CH2), 65.86 (OCH), 79.12 (C–O), 99.92 [C(OCH3)2],
154.56 (C]O). MS (70 eV) m/z (relative intensity %): 261
(M+, 2), 204 (5), 188 (2), 160 (4), 146 (14), 101 (15), 89
(24), 57 (100), 43 (66). IR (KBr): nmax 3400, 2944, 2832,
1692, 1428, 1368, 1172, 1120, 1076, 940.
4.3. General hydrogenation procedure
Mixtures of 6a and 7a (0.5 g–2.0 g) in 20 ml of MeOH in the
presence of 0.12 g, 5% Pd/C catalyst was hydrogenated in
steel autoclave equipped with magnetic stirrer (500 rounds
per minute) under 20 bar of hydrogen pressure during 5 h.
Conversion of 7a into 6a was controlled by GC analysis
on 11 mꢂ0.25 mm Supelco SPÔ 2380 capillary column
(column temperature 120 ꢁC). After 5 h compound 7a was
fully converted into 6a with quantitative yield. The catalyst
was filtered off, and after solvent removing 6a was isolated.
4.3.5. Methyl 2,2,5,5-tetramethyl-3-pyrrolidinecarboxyl-
ate (6a).31,32 Yield 1.26 g (70%) [two-step procedure: elec-
trolysis (exp.10, Table 2) and hydrogenation], colourless oil,
bp 96–99 ꢁC (14 Torr), [lit.33 bp 86 ꢁC (10.5 Torr)], 1H NMR
(CDCl3): d 1.10 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.31 (s, 3H,
CH3), 1.40 (s, 3H, CH3), 1.91 (dd, 1H, J1¼7.3 Hz,
J2¼13.1 Hz), 2.19 (dd, 1H, J1¼11.5 Hz, J2¼13.1 Hz), 2.88
4.3.1. 1-Benzyl-4,4-dimethoxypiperidine-3-ol (3a).23,28
Yield 1.78 g (71%) [exp. 6, Table 1], white solid, mp 89–
(dd, 1H, J1¼7.3 Hz, J2¼11.5 Hz), 3.65 (s, 3H, OCH3). 13
C
NMR (CDCl3): d 25.9 (CH3), 30.8 (CH3), 31.0 (CH3), 31.3
(CH3), 42.4 (CH2), 51.2 (OCH3), 54.7 (CH), 57.5 (C), 62.0
(C), 173.2 (C]O). MS (70 eV) m/z (relative intensity %):
185 (M+, 4), 170 (100), 154 (11), 138 (14), 124 (10), 110
(45), 99 (33), 84 (24), 58 (98). IR (KBr): nmax 2964, 2930,
2872, 1736, 1464, 1436, 1368, 1288, 1188, 1148.
1
90 ꢁC, H NMR (CDCl3): d 1.75–2.0 (m, 2H), 2.12–2.25
(m, 1H), 2.50–2.56 (m, 1H), 2.65–2.75 (m, 1H), 2.74 (s,
1H, OH), 2.83–2.90 (m, 1H), 3.22 (s, 3H, OCH3), 3.28 (s,
3H, OCH3), 3.57 (s, 2H, CH2Ph), 3.70–3.74 (m, 1H, CH–
O), 7.25–7.38 (m, 5H, Ph). 13C NMR (CDCl3): d 27.8
(CH2), 47.5 (OCH3), 47.6 (OCH3), 49.2 (CH2), 56.1
(CH2), 61.9 (CH2), 66.8 (OCH), 98.9 [C(OCH3)2], 127.0,
128.2, 128.8, 137.8 (Ph). MS (70 eV) m/z (relative intensity
%): 251 (M+, 12), 236 (14), 220 (23), 202 (15), 188 (10), 142
(6), 120 (21), 91 (100), 65 (15), 42 (17). IR (KBr): nmax 3450,
2912, 2832, 1584, 1452, 1340, 1212, 1132, 1076, 948.
4.3.6. Methyl 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyr-
role-3-carboxylate (7a).26,32 Compound 7a was obtained
by method as described in Ref. 34. 70% Yield, colourless
oil, bp 110–112 ꢁC (15 Torr) [lit.34 bp 56–58 ꢁC
1
(1.3 Torr)], H NMR (CDCl3): d 1.29 (s, 6H), 1.40 (s, 6H),
3.71 (s, 3H, OCH3), 6.60 (s, 1H). 13C NMR (CDCl3):
d 29.7 (CH3), 29.8 (CH3), 51.0 (OCH3), 63.2 (C), 65.7 (C),
139.0 (C]), 148.9 (CH]), 164.3 (C]O). MS (70 eV)
m/z (relative intensity %): 183 (M+, 25), 168 (100), 152
(18), 136 (43), 122 (30), 108 (82), 94 (49), 67 (45). IR
(KBr): nmax 2964, 2928, 2872, 1730, 1632, 1436, 1368,
1328, 1148, 1064.
4.3.2. 1-Methyl-4,4-dimethoxypiperidine-3-ol (3b). Yield
1.41 g (81%), white solid, mp 108–109 ꢁC [lits.29,30 109–
1
110 ꢁC], H NMR (CDCl3): d 1.80–1.94 (m, 2H), 2.05–
2.13 (m, 1H), 2.25 (s, 3H, CH3), 2.38–2.43 (m, 1H),
2.58–2.65 (m, 1H), 2.76–2.81 (m, 1H), 2.85 (s, 1H, OH),
3.19 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.71–3.75 (m,
1H, CH–O). 13C NMR (CDCl3): d 27.5 (CH2), 45.5 (CH3),
47.5 (OCH3), 47.6 (OCH3), 51.6 (CH2), 58.2 (CH2), 66.9
(OCH), 98.5 [C(OCH3)2]. MS (70 eV) m/z (relative intensity
%): 175 (M+, 24), 160 (23), 144 (29), 126 (31), 112 (20), 100
(7), 87 (45), 70 (11), 58 (49), 44 (100). IR (KBr): nmax 3136,
2944, 2772, 1468, 1360, 1292, 1152, 1116, 1068, 948.
4.3.7. Ethyl 2,2,5,5-tetramethyl-3-pyrrolidinecarboxyl-
ate (6b).35 Compound 6b was isolated by reaction mixture
distillation (exp. 3, Table 3), 1.01 g (51%) colourless oil,
1
bp 114–116 ꢁC (15 Torr) [lit.35 bp 217 ꢁC (748 Torr)], H
NMR (CDCl3): d 1.07 (s, CH3), 1.20 (s, CH3), 1.25 (t, 3H,
J¼7.1 Hz), 1.29 (s, CH3), 1.39 (s, CH3), 1.89 (dd, 1H,
J1¼7.3 Hz, J2¼13.0 Hz), 2.15 (dd, 1H, J1¼11.6 Hz,
J2¼13.0 Hz), 2.85 (dd, 1H, J1¼7.3 Hz, J2¼11.6 Hz), 4.05–
4.20 (m, 2H). 13C NMR (CDCl3): d 14.1 (CH3), 25.9
(CH3), 30.9 (CH3), 31.1 (CH3), 31.4 (CH3), 42.4 (CH2),
54.9 (CH), 57.5 (C), 60.0 (OCH2), 62.0 (C), 172.73
4.3.3. Ethyl 3-hydroxy-4,4-dimethoxypiperidine-1-car-
boxylate (3c).28 Compound 3c was isolated by column
chromatography (eluent: hexane/ethyl acetate 1:1), yield
1
1.28 g (55%), colourless oil, H NMR (CDCl3): d 1.22 (t,
3H, J¼7.1 Hz), 1.65–1.88 (m, 2H), 2.65 (s, 1H, OH),

M. N. Elinson et al. / Tetrahedron 62 (2006) 8021–8028
8027
(C]O). MS (70 eV) m/z (relative intensity %): 199 (M+, 3),
Acknowledgements
184 (100), 154 (14), 138 (12), 124 (6), 110 (39), 99 (24), 84
(18), 58 (50). IR (KBr): nmax 2968, 2932, 1736, 1464, 1368,
1284, 1256, 1184, 1148, 1064.
The authors gratefully acknowledge the financial support of
the Russian Foundation for Basic Research (Project N 06-
03-32181a).
4.3.8. Ethyl 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-
3-carboxylate (7b).36 Compound 7b was obtained by
method as described in Ref. 34. 55% Yield, colourless oil,
References and notes
1
bp 120–122 ꢁC (12 Torr) [lit.36 bp 212 ꢁC (740 Torr)], H
NMR (CDCl3): d 1.26 (s, 6H), 1.30 (t, 3H, J¼7.2 Hz),
1.41 (s, 6H), 4.22 (q, 2H, J¼7.2 Hz), 6.65 (s, 1H). 13C
NMR (CDCl3): d 14.2 (CH3), 29.9 (2CH3), 30.1 (2CH3),
59.9 (OCH2), 63.2 (C), 65.9 (C), 139.4 (C]), 148.6
(CH]), 163.9 (C]O). MS (70 eV) m/z (relative intensity
%): 197 (M+, 2), 182 (100), 152 (21), 136 (15), 122 (10),
109 (66), 94 (18), 58 (11). IR (KBr): nmax 2928, 2868,
1720, 1632, 1468, 1360, 1328, 1160, 1060.
1. Chakrabartty, S. K. Oxidation in Organic Chemistry, Part C;
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4.3.9. Methyl 2,2,4,4-tetramethylcyclopentanecarboxyl-
ate (9). Compound 9 was isolated by column chromato-
graphy (exp. 3, Table 4) (eluent: hexane/ethyl acetate 8:1)
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1
0.20 g (11%), colourless oil, H NMR (CDCl3): d 0.85 (s,
3H), 0.95 (s, 3H), 1.04 (s, 3H), 1.13 (s, 3H), 1.41 (s, 2H),
1.65 (dd, 1H, J1¼7.3 Hz, J2¼13.0 Hz), 1.95 (dd, 1H,
J1¼11.7 Hz, J2¼13.0 Hz), 2.63 (dd, 1H, J1¼7.3 Hz, J2¼
11.7 Hz), 3.59 (s, 3H, OCH3). 13C NMR (CDCl3): d 25.8
(q), 30.6 (q), 31.0 (q), 31.2 (q), 36.3 (s), 42.5 (s), 42.9 (t),
50.9 (q), 54.0 (t), 56.6 (d), 174.2 (s). MS (70 eV) m/z (rela-
tive intensity %): 184 (M+, 7), 169 (24), 153 (8), 137 (11),
123 (61), 109 (100), 95 (92), 83 (97), 56 (30). IR (KBr):
nmax 2956, 2930, 2868, 1736, 1464, 1436, 1256, 1192,
1172, 1064. Anal. Calcd for C11H20O2: C, 71.70; H, 10.94.
Found: C, 71.56; H, 11.05.
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9999–10003.
17. Elinson, M. N.; Feducovich, S. K.; Dorofeev, A. S.;
Vereshchagin, A. N.; Nikishin, G. I. Izv. Akad. Nauk Ser.
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4.3.10. Methyl 5-iodo-2,2,4,4-tetramethylcyclopentane-
carboxylate (10). Compound 10 was isolated by column
chromatography (exp. 1, Table 4) (eluent: hexane/ethyl
1
acetate 10:1) 1.17 g (38%), pink oil, H NMR (CDCl3):
0.91 (s, 3H), 1.05 (s, 3H), 1.13 (s, 3H), 1.27 (s, 3H), 1.52
(d, 1H, J¼13.2 Hz), 1.71 (d, 1H, J¼13.3 Hz), 3.11 (d, 1H,
J¼12.4 Hz), 3.72 (s, 3H, OCH3), 4.29 (d, 1H, J¼12.4 Hz).
13C NMR (CDCl3): d 27.7 (CH3), 28.1 (CH3), 29.2 (CH3),
31.6 (CH3), 41.4 (C), 41.9 (CH), 48.1 (C), 51.3 (CH2),
51.6 (OCH3), 63.8 (CH), 172.1 (C]O). MS (70 eV) m/z
(relative intensity %): 310 (M+, 6), 279 (7), 251 (3), 237
(11), 183 (M+ꢃI, 43), 167 (6), 151 (26), 123 (100), 109
(16), 97 (40). IR (KBr): nmax 2960, 2932, 2868, 1740,
1460, 1436, 1372, 1256, 1192, 1168. Anal. Calcd for
C11H19IO2: C, 42.60; H, 6.17; I, 40.91. Found: C, 42.46;
H, 6.03; I, 40.77.
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matography (exp. 3, Table 4) (eluent: hexane/ethyl acetate
1
8:1) 0.56 g (31%), colourless oil, H NMR (CDCl3): 1.08
(s, 6H), 1.21 (s, 6H), 1.67 (s, 2H), 3.65 (s, 3H, OCH3),
6.40 (s, 1H). 13C NMR (CDCl3): d 29.2 (q), 29.4 (q), 35.1
(s), 45.6 (s), 50.8 (q), 55.4 (t), 139.8 (s), 152.1 (d), 165.4
(s). MS (70 eV) m/z (relative intensity %): 182 (M+, 18),
167 (33), 151 (7), 135 (15), 120 (20), 107 (100), 93 (22),
65 (25). IR (KBr): nmax 2960, 2930, 2869, 1720, 1628,
1436, 1340, 1304, 1192, 1060. Anal. Calcd for C11H18O2:
C, 72.49; H, 9.95. Found: C, 72.35; H, 9.81.
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