High regioselectivity in electrochemical α-methoxylation of N-protected cyclic amines

Article abstract of DOI:10.1016/j.tet.2008.02.060

N-Protecting groups of α-substituted cyclic amines strongly affected the regioselectivity in electrochemical methoxylation of these compounds. Namely, N-acyl derivatives were transformed into α′-methoxylated compounds, while N-cyano derivatives changed into α-methoxylated derivatives. Furthermore, Lewis acid catalyzed nucleophilic substitution of the α-methoxylated compounds protected with cyano group afforded α,α-disubstituted cyclic amines.

Full text of DOI:10.1016/j.tet.2008.02.060

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3935e3942
www.elsevier.com/locate/tet
High regioselectivity in electrochemical a-methoxylation of
N-protected cyclic amines
*
Samuel S. Libendi, Yosuke Demizu, Yoshihiro Matsumura, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 21 January 2008; received in revised form 16 February 2008; accepted 19 February 2008
Available online 23 February 2008
This paper is dedicated to the loving memories of Professor Yoshihiro Matsumura
Abstract
N-Protecting groups of a-substituted cyclic amines strongly affected the regioselectivity in electrochemical methoxylation of these com-
pounds. Namely, N-acyl derivatives were transformed into a0-methoxylated compounds, while N-cyano derivatives changed into a-methoxylated
derivatives. Furthermore, Lewis acid catalyzed nucleophilic substitution of the a-methoxylated compounds protected with cyano group afforded
a,a-disubstituted cyclic amines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclic amines; Methoxylation; Electrochemical oxidation; Regioselective
1. Introduction
although a mechanism for high regioselectivity has not been
investigated.
Selective methods for preparation of cyclic amine deriva-
tives having quaternary carbon center at the a position are im-
portant in organic synthesis.1 Xiao and co-workers reported
that 2-phenyl substituted pyrrolidine and piperidine are lithi-
ated at the C-2 or C-5 in the case of pyrrolidine and the C-2
or C-6 for piperidine depending on diamine ligand used.2
However, alkyl substituents are exclusively lithiated at the
C-5 for pyrrolidine and the C-6 for piperidine.3 A uniform
method to achieve regioselective activation of the C-2 of
both pyrrolidine and piperidine is highly desirable,2 so far,
no method is available to this end.
( )n
( )n
N
PG
2
PG=CO2R',
COR'
MeOH
R
R
MeO
R
N
PG
Path a
-2e
( )n
R
N
PG
1
( )n
( )n
OMe
R
Path b
?
MeOH
N
PG
N
PG
3
Scheme 1. Electrochemical methoxylation of N-protected cyclic amines 1.
On the other hand, electrochemically selective activation of
the more substituted site has not been achieved to date (Path
b in Scheme 1).7 Finding a method to achieve it is both syn-
thetically and mechanistically worthwhile.
Electrochemical methoxylation of N-protected cyclic
amines 1 selectively functionalizes readily available amines
as starting materials for building biologically active molecules
that contain nitrogen atoms.4 Alkoxycarbonylated or acylated
amines which direct methoxylation to less substituted site
(Path a in Scheme 1) have been extensively studied,5,6
2. Result and discussion
We envisioned that since the product formed is determined
by the most stable iminium ion, and that the stability of this
iminium ion must depend on the protecting group on the
* Corresponding author: Tel.: þ81 95 819 2429; fax: þ81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.060

3936
S.S. Libendi et al. / Tetrahedron 64 (2008) 3935e3942
Table 1
Screening of N-protecting group of 2-methylpiperidines 1aeg and 2-methyl-
pyrrolidines 1h, i
Table 3
Electrochemical methoxylation of various 2-substituted N-cyanocyclic amines
1g,jera
Entry Substrate
n
PG
Ratio of product
Yield of
2aeiþ3aei (%)
Entry Substrate
R
n
Ratio of product
Yield of
2g, jerþ
3g, jer (%)
2aei (%) 3aei (%)
2g,jer (%) 3g,jer (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2
2
2
2
2
2
2
1
1
CO2Me 2a (100)
3a (0)
3b (0)
3c (0)
3d (0)
3e (0)
78
91
98
92
82
95
85
85
78
1
2
3
4
5
6
7
8
1j
Et
1
1
1
2
2
2
2
2
2j (13)
2k (18)
2l (17)
2g (13)
2m (7)
2n (3)
3j (87)
3k (82)
3l (83)
99
96
73
93
96
97
50
98
Ts
CHO
2b (100)
2c (100)
1k
1l
n-Pr
Allyl
Me
CONH2 2d (100)
1g
1m
1n
1o
1p
3g (87)
3m (93)
3n (97)
3o (70)
3p (100)
Cbz
Boc
CN
CN
2e (100)
Et
2f (100)a 3f (0)
n-Pr
Allyl
Ph
1g
1h
1i
2g (18)
2h (48)
3g (82)
3h (52)
3i (0)
2o (30)
2p (0)
CO2Me 2i (100)
a
Since 2f was somewhat unstable, it was transformed into the corresponding
1,2,3,4-tetrahydropyridine on silica gel.
OMe
Me
9b
1q
1r
2
2
2q (9)
2r (0)
3q (91)
96
75
Br
nitrogen. Therefore, the protecting group must play a role on
the regioselectivity of the final product. We began thus by sur-
veying different N-protecting groups (PG) as a chemical de-
vice (Eq. 1). Into an undivided electrochemical cell
containing Et4NBF4 (0.5 mmol), MeOH (5 mL), and N-pro-
tected 2-methyl cyclic amines 1aei (1 mmol) were placed Pt
electrodes and 3 F/mol of electricity was passed through at
a constant current of 0.1 A (terminal voltage; ca. 10 V) at
room temperature. The results are summarized in Table 1.
10
3r (100)
a
Graphite electrodes were used. 2.5 F/mol of electricity was passed at
ꢀ50 ꢁC.
b
Reaction was carried out at room temperature.
6), further lowering of reaction temperature led to supporting
electrolyte precipitate out of the solution.8
The optimized reaction condition was then applied to vari-
ous substrates 1g, jer (Eq. 2). The results are summarized in
Table 3.
( )n
( )n
( )n
Pt electrodes
OMe
Me
-2e, 3 F/mol
+
MeO
Me
Me
Graphite electrodes
N
PG
3a-i
( )n
N
PG
2a-i
N
PG
1a-i
( )n
( )n
ð1Þ
OMe
R
Et4NBF4
MeOH, at rt
-2e, 2.5 F/mol
+
MeO
R
R
N
CN
2g,j-r
N
N
CN
1g,j-r
ð2Þ
Et4NBF4
CN
3g,j-r
MeOH, at -50 °C
All protecting groups screened directed methoxyl group to
the least substituted site (Table 1, entries 1e6 and 9) except
cyano group, which gave an almost 2:8 mixture of regio-iso-
mers 2g and 3g from 1g (entry 7) and an almost 1:1 mixture
of regio-isomers 2h and 3h from 1h (entry 8). Impressed by
the findings we sort a way to improve this regioselectivity.
We tried different anode materials with platinum giving the
lowest selectivity to oxidize 1h (Table 2, entry 1), while glassy
carbon had the lowest yield due to lower current efficiency
(entry 3). Graphite gave the best result both in yield and selec-
tivity because the reaction takes place on its surface thus re-
giocontrol is possible (entry 4). To improve these results
further, we examined temperature effect on regioselectivity.
When the reaction was carried out at ꢀ20 ꢁC, there was
a marked improvement on the regioselectivity of 3h (entry
5). At ꢀ50 ꢁC the best regioselectivity was achieved (entry
Increase in size of the R substituent at the C-2 for pyrroli-
dine had little effect on regioselectivity (entries 1 and 2), while
in the case of piperidine ring it led to better selectivity (entries
4e6). To our delight, phenyl substituents, which are found in
many biologically interesting compounds gave excellent re-
gioselectivity (entries 8 and 10).9 Introduction of methoxyl
and bromo groups on the phenyl substituent was well tolerated
and gave 9:91 regioselectivity at room temperature (entry 9),
however, on lowering the temperature the reaction did not pro-
ceed. Allyl substituent on the pyrrolidine ring gave good selec-
tivity 17:83 (entry 3), while that on piperidine gave moderate
selectivity (entry 7).
To understand the mechanism behind the regiocontrol in
N-protected cyclic amines we considered the intermediary
iminium ions A and B for cyanopiperidine while C and D
for methoxycarbonyl protecting group representing the least
substituted position directing groups (Fig. 1).
Since stabilities of iminium ions might determine the regio-
selectivities, we calculated the LUMO for iminium ions AeD
using DFT/6-31G* method of Gaussian 03 software. Iminium
ion A is much more stable than iminium ion B thus leading to
methoxylation on the more substituted side (Table 4, entries 1
and 2). In contrast, for methoxycarbonyl protected iminium
ions, iminium ion D is somewhat stable compared with imi-
nium ion C, thereby leading to methoxylation on the less
substituted side (entries 3 and 4).
Table 2
Effect of electrodes and temperature on the electrochemical oxidation of 1h
Entry Electrodes
Temp (ꢁC) F/mol Ratio
2h (%) 3h (%)
Yield of
2hþ3h (%)
1
2
3
4
5
6
Pt
Carbon fiber
rt
rt
3.0
2.5
5.0
2.5
2.5
2.5
48
28
26
22
16
13
52
72
74
78
84
87
85
95
40
96
96
98
Glassy carbon rt
Graphite
Graphite
Graphite
rt
ꢀ20
ꢀ50

S.S. Libendi et al. / Tetrahedron 64 (2008) 3935e3942
4. Experimental section
4.1. General
3937
N
C
N
C
N
B
N
A
Electrochemical reactions were carried out using DC Power
1
Supply (GP 050-2) of Takasago Seisakusho, Inc. H NMR
spectra were measured on a Varian Gemini 300 and 400 spec-
trometer with TMS as an internal standard. 13C NMR spectra
were measured on a Varian Gemini 400 spectrometer with
TMS as an internal standard. IR spectra were obtained on
a Shimadzu FTIR-8100A. Elemental analyses were carried
in Center for Instrumental Analysis, Nagasaki University.
Mass spectra were obtained on a JEOL JMS-DX 303
instrument.
N
N
CO2Me
C
CO2Me
D
Figure 1. Plausible intermediary iminium ions for the oxidation of N-cyano-2-
ethylpiperidine and N-methoxycarbonyl-2-ethylpiperidine.
Table 4
LUMO values for A, B, C, and Da
All solvents were used as supplied without further
purification.
Entry
Iminium ions
LUMOb
1
2
3
4
a
A
B
C
D
0.09412
0.00824
4.2. Starting N-protected (except for N-cyano) cyclic amines
ꢀ0.07393
ꢀ0.08117
N-Protected cyclic amines 1a,4a 1b,12 1c,5d 1d,13 1e,14 1f,3b
and 1i15 are known compounds with their spectroscopic data
available in literature.
Calculated with DFT/6-31G* method of Gaussian 03 software.
Relatively stable species have bigger absolute value than that of relatively
unstable species.
b
4.2.1. N-Cyanation of cyclic amines
We could apply our product 3g to Lewis acid catalyzed
cyanation and allylation for preparation of 2,2-disubstituted
piperidines 4 and 5, respectively (Eqs. 3 and 4).
A 50 mL flask containing 5 mmol of cyclic amine, K2CO3
(829 mg, 6 mmol), and BrCN (530 mg, 5 mmol) in MeCN
(10 mL) was stirred for 6 h at room temperature monitored
by TLC. After completion of reaction, the reaction mixture
was filtered and then the filtrate was concentrated in vacuo.
The residue was run through a silica gel column to obtain
a quantitative yield of protected amines 1j and 1m.
N-Cyanoamines 1g13 and 1h16 are known compounds.
TMSCN
OMe
Me
CN
Me
CH2Cl2
N
CN
3g
N
CN
ð3Þ
ð4Þ
TiCl4
0 °C
4, 65%
AllylTMS
CH2Cl2
4.2.2. 2-Ethylpyrrolidine-1-carbonitrile (1j)
1H NMR (400 MHz, CDCl3) d 3.52e3.37 (m, 3H), 2.08e
1.97 (m, 1H), 1.96e1.76 (m, 3H), 1.59e1.43 (m, 2H), 0.97
(t, J¼7.8 Hz, 3H); IR n cmꢀ1 (neat): 2961, 2210, 1460,
1356; High Resolution Mass Spectrum [FAB(þ)]: m/z calcd
for C7H13N2 [MþH]þ 125.1079, found 125.1072.
3g
N
CN
Me
TiCl4
0 °C
5, 68%
Similarly the allylation of 3l afforded 2,2-diallylated pyrro-
lidine 6, which might easily be transformed to pharmaceuti-
cally important spiro compounds, which are challenging to
synthesize (Eq. 5).7,10
4.2.3. 2-Ethylpiperidine-1-carbonitrile (1m)
1H NMR (300 MHz, CDCl3) d 3.50e3.38 (m, 1H), 3.06e
2.95 (m, 1H), 2.77 (t, J¼6.3 Hz, 1H), 1.82e1.52 (m, 6H),
1.49e1.21 (m, 2H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR
(100 Hz, CDCl3) d 117.32 (1C), 60.58 (1C), 51.16 (1C),
29.90 (1C), 26.49 (1C), 24.68 (1C), 23.51 (1C), 10.39 (1C);
IR n cmꢀ1 (neat): 2966, 2214, 1446, 1383, 1223; High Reso-
lution Mass Spectrum [EI(þ)]: m/z calcd for C8H14N2 [M]þ
138.1157, found 138.1162.
AllylTMS
CH2Cl2
3l
N
N
BF3-OEt2
ð5Þ
CN
CN
-78 °C to 0°C
6, 52%
3. Conclusion
4.2.4. 2-Propylpyrrolidine-1-carbonitrile (1k)
2-Methoxypyrrolidine-1-carboxylic acid benzyl ester
(1176 mg, 5 mmol) prepared according to literature17 was
transferred into a 50 mL flask containing allyltrimethylsilane
(1714 mg, 15 mmol) and CH2Cl2 (20 mL). The mixture was
stirred at 0 ꢁC as BF3$OEt2 (1.28 mL, 10 mmol) was added
dropwise and left to stir for 8 h. After confirmation of
We have for the first time demonstrated a method for high
regioselectivity in electrochemical oxidation of N-protected
cyclic amines and also proposed a mechanism for least and
most substituted methoxylation. We have also shown the ap-
plication for the methoxylated intermediates.11

3938
S.S. Libendi et al. / Tetrahedron 64 (2008) 3935e3942
completion of reaction by TLC, 10 mL of H2O was added and
the organic layer separated. The aqueous layer was extracted
by AcOEt (3ꢂ10 mL) and the combined organic layer dried
by MgSO4 and filtered. The solvent was removed under re-
duced pressure. The crude product was then transferred to
a 20 mL flask containing 5% Pd on activated carbon and
MeOH (5 mL). The mixture was then stirred under 1 atm of
H2 for 8 h. Upon completion of reaction the mixture was
then filtered through Celite and solvent removed in vacuo to
obtain 2-propylpyrrolidine, which was protected according to
the procedure above without further purification to afford 1k
as an oil (415 mg, 3 mmol) (60%).
1H NMR (400 MHz, CDCl3) d 3.58e3.50 (m, 1H), 3.48e
3.36 (m, 2H), 2.05e1.74 (m, 4H), 1.57e1.48 (m, 1H),
1.46e1.35 (m, 3H), 0.96 (t, J¼7.3 Hz, 3H); IR n cmꢀ1
(neat): 2961, 2210, 1460, 1356; High Resolution Mass Spec-
trum [FAB(þ)]: m/z calcd for C8H15N2 [MþH]þ 139.1236,
found 139.1244.
4.2.7. 2-Allylpiperidine-1-carbonitrile (1o) [from 8]
A 50 mL flask containing 2-methoxypiperidine-1-carboni-
trile (8) (701 mg, 5 mmol) and allyltrimethylsilane (857 mg,
7.5 mmol) in CH2Cl2 (10 mL) under nitrogen was stirred at
0 ꢁC as TiCl4 (0.35 mL, 2.5 mmol) was added dropwise. The
mixture was then stirred at 0 ꢁC as reaction was monitored
by TLC. On completion of the reaction, H2O (6 mL) was
slowly added and then the mixture extracted by AcOEt
(3ꢂ10 mL). The combined organic layer was dried using
MgSO4 and solvent removed in vacuo.
Crude product was purified using silica gel column (n-hex-
ane/AcOEt¼10:1) to afford a pure product 1o (526 mg, 70%).
1H NMR (400 MHz, CDCl3) d 5.83e5.73 (m, 1H), 5.18 (d,
J¼19.0 Hz, 1H), 5.13 (d, J¼10.5 Hz, 1H), 3.45 (d, J¼4.2 Hz,
1H), 3.06e2.93 (m, 2H), 2.58e2.51 (m, 1H), 2.35e2.27 (m,
1H), 1.85e1.58 (m, 4H), 1.47e1.34 (m, 2H); 13C NMR
(100 Hz, CDCl3) d 133.17 (1C), 118.34 (1C), 116.86 (1C),
58.30 (1C), 50.88 (1C), 37.57 (1C), 29.54 (1C), 24.21 (1C),
23.01 (1C); IR n cmꢀ1 (neat): 2942, 2859, 2209, 1644,
1445; High Resolution Mass Spectrum [EI(þ)]: m/z calcd
for C9H14N2 [M]þ 150.1157, found 150.1127.
4.2.5. 2-Allylpyrrolidine-1-carbonitrile (1l) [from 7]
A 50 mL flask containing 2-methoxypyrrolidine-1-carboni-
trile (7) (631 mg, 5 mmol) and allyltrimethylsilane (857 mg,
7.5 mmol) in CH2Cl2 (10 mL) under nitrogen was stirred at
0 ꢁC as BF3$OEt2 (1.28 mL, 10 mmol) was added dropwise.
The mixture was then stirred at 0 ꢁC as reaction was monitored
by TLC. On completion of the reaction, H2O (6 mL) was
slowly added and then the mixture extracted by AcOEt
(3ꢂ10 mL). The combined organic layer was dried using
MgSO4 and solvent removed in vacuo. Crude product was
purified using silica gel column (n-hexane/AcOEt 10:1) to
afford a pure product (136 mg, 20%) (1l).
1H NMR (400 MHz, CDCl3) d 5.82e5.70 (m, 1H), 5.21e
5.10 (m, 2H), 3.68e3.61 (m, 1H), 3.48e3.38 (m, 2H),
2.57e2.46 (m, 1H), 2.31e2.20 (m, 1H), 2.05e1.83 (m, 3H),
1.67e1.58 (m, 1H); IR n cmꢀ1 (neat): 2978, 2210, 1641,
1458, 1439; High Resolution Mass Spectrum [FAB(þ)]: m/z
calcd for C8H13N2 [MþH]þ 137.1078, found 137.1099.
4.2.8. 2-Phenylpiperidine-1-carbonitrile (1p) [from 8]
A 50 mL flask containing 8 (701 mg, 5 mmol) in benzene
(15 mL) was stirred at room temperature as AlCl3 (1333 mg,
10 mmol), was added slowly. The mixture was left to stir at
the same condition for 8 h monitored by TLC. The reaction
was then quenched by adding H2O (6 mL) slowly, then ex-
tracted with AcOEt (3ꢂ10 mL). The combined organic layer
was then dried with MgSO4, solvent removed in vacuo and
the crude product purified on silica gel (n-hexane/
AcOEt¼10:1) to give 1p (466 mg, 50%).
1H NMR (400 MHz, CDCl3) d 7.36 (s, 5H), 3.97 (dd,
J¼10.7 and 2.9 Hz, 1H), 3.56 (dt, J¼12.2 and 3.2 Hz, 1H),
3.21 (td, J¼11.7 and 3.9 Hz, 1H), 1.94e1.52 (m, 5H), 1.54e
1.48 (m, 1H); 13C NMR (100 Hz, CDCl3) d 138.78 (1C),
128.74 (2C), 128.66 (1C), 127.57 (2C), 117.41 (1C), 63.80
(1C), 51.44 (1C), 32.48 (1C), 24.35 (1C), 23.48 (1C); IR n
cmꢀ1 (neat): 2943, 2858, 2210, 1495, 1454, 1377, 1267;
High Resolution Mass Spectrum [EI(þ)]: m/z calcd for
C12H14N2 [M]þ 186.1157, found 186.1132.
4.2.6. 2-Propylpiperidine-1-carbonitrile (1n)
2-Methoxypiperidine-1-carboxylic acid benzyl ester
(1247 mg, 5 mmol) prepared according to literature18 was
transferred into a 50 mL flask containing allyltrimethylsilane
(1714 mg, 15 mmol) and CH2Cl2 (20 mL). The mixture was
stirred at 0 ꢁC as BF3$OEt2 (1.28 mL, 10 mmol) was added
dropwise and left to stir for 8 h. After confirmation of comple-
tion of reaction by TLC, 10 mL of H2O was added and the or-
ganic layer separated. The aqueous layer was extracted by
AcOEt (3ꢂ10 mL) and the combined organic layer dried by
MgSO4 and filtered. The solvent was removed under reduced
pressure. The crude product was then transferred to a 20 mL
flask containing 5% Pd on activated carbon and MeOH
(5 mL). The mixture was then stirred under 1 atm of H2 for
8 h. Upon completion of reaction the mixture was then filtered
through Celite and solvent removed in vacuo to obtain 2-pro-
pylpiperidine, which was protected according to the procedure
above without further purification to afford 1n19 as an oil
(639 mg, 4.2 mmol) (60%).
4.2.9. 2-(3-Bromo-4-methoxyphenyl)piperidine-
1-carbonitrile (1q) [from 8]
A 50 mL flask containing 8 (701 mg, 5 mmol) in CH2Cl2
(10 mL) and 2-bromoanisole (1870 mg, 10 mmol) was stirred
at room temperature as AlCl3 (1333 mg, 10 mmol) was added
slowly. The reaction was left to stir for 12 h and then H2O
(5 mL) was slowly added. The mixture was extracted by
AcOEt (3ꢂ10 mL), then the combined organic layer was dried
by MgSO4, solvent removed in vacuo, and the crude product
purified on silica gel column (n-hexane/AcOEt¼10:1) to
afford 1q as white solid (1328 mg, 90%).
1
Solid, mp¼104 ꢁC; H NMR (400 MHz, CDCl3) d 7.55 (s,
1H), 7.30 (d, J¼6.8 Hz, 1H), 6.90 (d, J¼8.8 Hz, 1H), 3.89 (s,
4H), 3.56 (dd, J¼12.2 and 3.4 Hz, 1H), 3.19 (td, J¼12.0
and 3.7 Hz, 1H), 1.94e1.84 (m, 2H), 1.79e1.47 (m, 4H);

S.S. Libendi et al. / Tetrahedron 64 (2008) 3935e3942
3939
13C NMR (100 Hz, CDCl3) d 156.11, 132.60, 132.35, 127.92,
4.3.3. 1,2,3,4-Tetrahydro-2-methylpyridine-1-carboxylic
117.24, 111.95, 62.75, 56.22, 51.51, 32.41, 24.27, 23.54; IR n
cmꢀ1 (neat): 2926, 2855, 2361, 2209, 1605, 1501, 1458; High
Resolution Mass Spectrum [FAB(þ)]: m/z calcd for
C13H16BrN2O [MþH]þ 295.0446, found 295.0431.
acid tert-butyl ester (2f) [from 1f]
Electrochemical methoxylation of 1f gave 6-methoxylated
compound 2f, which was somewhat unstable to be changed
to 1,2,3,4-tetrahydropyridine on silica gel.
1H NMR (300 MHz, CDCl3) d 6.82e6.60 (m, 1H), 4.90e
4.72 (m, 1H), 4.42e4.22 (m, 1H), 2.14e1.55 (m, 4H), 1.49
(s, 9H), 1.10 (d, J¼6.6 Hz, 3H); IR n cmꢀ1 (neat): 2978,
1713, 1697, 1651, 1410, 1180, 1105; High Resolution Mass
Spectrum [FAB(þ)]: m/z calcd for C11H20NO2 [MþH]þ
198.1494, found 198.1494.
4.2.10. 2-(4-Methylphenyl)piperidine-1-carbonitrile (1r)
[from 8]
A 50 mL flask containing 8 (701 mg, 5 mmol) in toluene
(15 mL) was stirred at room temperature as AlCl3 (1333 mg,
10 mmol), was added slowly. The mixture was left to stir at
the same condition for 8 h monitored by TLC. The reaction
was then quenched by adding H2O (6 mL) slowly, then ex-
tracted with AcOEt (3ꢂ10 mL). The combined organic layer
was then dried with MgSO4, solvent removed in vacuo, and
the crude product purified on silica gel (n-hexane/
AcOEt¼10:1) to give 1r (400 mg, 40%).
4.3.4. 5-Methoxy-2-methylpyrrolidine-1-carboxylic acid
methyl ester (2i) [from 1i]
1H NMR (300 MHz, CDCl3) d 5.29e5.12 (m, 1H), 4.00e
3.81 (m, 1H), 3.73 (s, 3H), 3.34 (br s, 3H), 2.18e1.68 (m,
4H), 1.36e1.30 (m, 3H); IR n cmꢀ1 (neat): 2988, 2876,
1724, 1697, 1456, 1388, 1368, 1319; High Resolution Mass
Spectrum [FAB(þ)]: m/z calcd for C8H16NO3 [MþH]þ
174.1130, found 174.1120.
1H NMR (300 MHz, CDCl3) d 7.30e7.14 (m, 4H), 3.94
(dd, J¼10.2, 3.6 Hz, 1H), 3.60e3.47 (m, 1H), 3.19 (t, J¼
11.7 Hz, 1H), 2.34 (s, 3H), 2.04e1.41 (m, 6H); IR n cmꢀ1
(neat): 2943, 2858, 2210, 1516, 1444, 1375, 1267, 1228;
High Resolution Mass Spectrum [FAB(þ)]: m/z calcd for
C13H17N2 [MþH]þ 201.1392, found 201.1412.
4.3.5. 2-Methoxypyrrolidine-1-carbonitrile (7) [from
pyrrolidine-1-carbonitrile]
1H NMR (300 MHz, CDCl3) d 4.91 (d,, J¼3.9 Hz, 1H),
3.63e3.57 (m, 1H), 3.44 (s, 3H), 3.39e3.48 (m, 1H), 2.03e
1.90 (m, 4H); IR n cmꢀ1 (neat): 2986, 2218, 1458, 1356, 1252,
1205; High Resolution Mass Spectrum [EI(þ)]: m/z calcd for
C6H10N2O [M]þ 126.0793, found 126.0799.
4.3. General procedure for electrochemical methoxylation
of N-protected amines
The substrate (1 mmol) was measured into an electrochem-
ical cell containing Et4NBF4 (109 mg, 0.5 mmol), graphite an-
ode and cathode electrodes and a stirring bar. MeOH (6 mL)
was added and the mixture stirred for 1 min to dissolve the re-
actants. The cell was then placed at ꢀ60 ꢁC and allowed to at-
tain this temperature, 2.5 F/mol of electricity was then passed
through, then the reaction mixture was transferred to a 50 mL
flask and the solvent removed in vacuo. The crude mixture was
re-dissolved in AcOEt (1 mL) and filtered. The filtrate was
concentrated and then flash chromatography was done on
the residue to afford methoxylated product as oil.
4.3.6. 2-Methoxypiperidine-1-carbonitrile (8) [from
piperidine-1-carbonitrile]
Piperidine-1-carbonitrile (2.20 g, 20 mmol) was measured
into a 100 mL beaker containing Et4NBF4 (1.10 g, 5 mmol),
a stirring bar and fitted with platinum electrodes and then
60 mL of MeOH was added and the beaker placed at 0 ꢁC,
then 3 F/mol of current was passed through it.
The mixture was then transferred to a 200 mL flask and the
solvent removed in vacuo. The crude mixture was re-dissolved
in AcOEt (10 mL) and filtered. The filtrate was concentrated
and then flash chromatography was done on the residue to af-
ford 8 as oil (2.75 g, 98% yield).
1H NMR (300 MHz, CDCl3) d 4.50 (s, 1H), 3.47 (s, 3H),
3.40e3.26 (m, 1H), 3.18 (d, J¼12.6 Hz, 1H), 1.81e1.64 (m,
6H); IR n cmꢀ1 (neat): 2972, 2218; High Resolution Mass
Spectrum [EI(þ)]: m/z calcd for C7H12N2O [M]þ 140.0949,
found: 140.0939.
Compounds 2a,4a 2b,12 and 2c5d are known compounds
with their spectroscopic data available in literature.
4.3.1. 1-Carbamoyl-2-methoxy-6-methylpiperidine (2d)
[from 1d]
1H NMR (300 MHz, CDCl3) d 5.46 (br s, 1H), 4.80 (br s,
2H), 3.95 (br s, 1H), 3.29 (s, 3H), 1.97e1.49 (m, 6H), 1.34
(d, J¼7.2 Hz, 3H); IR n cmꢀ1 (neat): 3360, 2944, 1655,
1591, 1426; High Resolution Mass Spectrum [EI(þ)]: m/z
calcd for C8H16N2O2 [M]þ 172.1211, found 172.1202.
4.3.7. 2-Ethyl-2-methoxypyrrolidine-1-carbonitrile (3j)
[from 1j]
4.3.2. 2-Methoxy-6-methylpiperidine-1-carboxylic acid
benzyl ester (2e) [from 1e]
1H NMR (300 MHz, CDCl3) d 3.62 (m, 2H), 3.26 (s, 3H),
2.19e1.66 (m, 6H), 0.99 (t, J¼7.5 Hz, 3H); IR n cmꢀ1 (neat):
2883, 2220, 1466, 1354; High Resolution Mass Spectrum
[FAB(þ)]: m/z calcd for C8H15N2O [MþH]þ 155.1185, found
155.1188.
1H NMR (300 MHz, CDCl3) d 7.36 (s, 5H), 5.52e5.32 (m,
1H), 5.20e5.10 (m, 2H), 4.52e4.30 (m, 1H), 3.22 (br s, 3H),
2.00e1.27 (m, 6H), 1.29 and 1.25 (2d, J¼7.2 Hz, 3H); IR n
cmꢀ1 (neat): 2957, 2930, 1709, 1655, 1415, 1392; High Res-
olution Mass Spectrum [FAB(þ)]: m/z calcd for C15H22NO3
[MþH]þ 264.1600, found 264.1578.
The ratio of 2j/3j was determined by gas chromatography
[(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ25 m,

3940
S.S. Libendi et al. / Tetrahedron 64 (2008) 3935e3942
160 ꢁC): 2j/3j¼13:87 (retention time: 11.58 and 11.73 min,
4.3.12. 2-Ethyl-2-methoxypiperidine-1-carbonitrile (3m)
[from 1m]
respectively)].
1H NMR (400 MHz, CDCl3) d 3.40ꢀ3.15 (m, 2H), 3.23 (s,
3H), 2.20e2.03 (m, 1H), 1.88e1.30 (m, 7H), 0.95 (t, J¼
7.5 Hz, 3H); 13C NMR (100 Hz, CDCl3) d 116.47 (1C),
88.02 (1C), 48.52 (1C), 46.69 (1C), 32.82 (1C), 27.13 (1C),
24.22 (1C), 18.70 (1C), 7.13 (1C); IR n cmꢀ1 (neat): 2946,
2211, 1676, 1447, 1375; High Resolution Mass Spectrum
[EI(þ)]: m/z calcd for C9H16N2O [M]þ 168.1262, found
168.1249.
The ratio of 2m/3m was determined by gas chromatogra-
phy [(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ
25 m, 190 ꢁC): 2m/3m¼7:93 (retention time: 11.92 and
11.34 min, respectively)].
4.3.8. 2-Methoxy-2-propylpyrrolidine-1-carbonitrile (3k)
[from 1k]
1H NMR (300 MHz, CDCl3) d 3.63e3.47 (m, 2H), 3.26 (s,
3H), 2.18e1.50 (m, 6H), 1.45e1.32 (m, 2H), 0.99 (t,
J¼7.2 Hz, 3H); IR n cmꢀ1 (neat): 2964, 2218, 1713, 1460,
1367; High Resolution Mass Spectrum [FAB(þ)]: m/z calcd
for C9H17N2O [MþH]þ 169.1341, found 169.1347.
The ratio of 2k/3k was determined by gas chromatography
[(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ25 m,
80 ꢁC): 2k/3k¼18:82 (retention time: 12.71 and 13.25 min,
respectively)].
4.3.9. 2-Allyl-2-methoxypyrrolidine-1-carbonitrile (3l)
[from 1l]
4.3.13. 2-Methoxy-2-propylpiperidine-1-carbonitrile (3n)
[from 1n]
1H NMR (400 MHz, CDCl3) d 5.85e5.72 (m, 1H), 5.25e
5.12 (m, 2H), 3.72e3.51 (m, 2H), 3.30 (s, 3H), 2.84 (dd,
J¼14.4 and 7.1 Hz, 1H), 2.51 (dd, J¼14.4 and 7.1 Hz, 1H),
2.13e1.81 (m, 4H); IR n cmꢀ1 (neat): 2982, 2216, 1643,
1462, 1441; High Resolution Mass Spectrum [FAB(þ)]: m/z
calcd for C9H15N2O [MþH]þ 167.1184, found 167.1199.
The ratio of 2l/3l was determined by gas chromatography
[(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ25 m,
80 ꢁC): 2l/3l¼17:83 (retention time: 12.45 and 12.91 min,
respectively)].
1H NMR (400 MHz, CDCl3) d 3.41e3.25 (m, 2H), 3.23 (s,
3H), 2.05e1.70 (m, 6H), 1.63e1.30 (m, 4H), 0.98 (t,
J¼6.8 Hz, 3H); IR n cmꢀ1 (neat): 2969, 2876, 2222, 1221;
High Resolution Mass Spectrum [EI(þ)]: m/z calcd for
C10H18N2O [M]þ 182.1419, found 182.1409.
The ratio of 2n/3n was determined by gas chromatography
[(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ25 m,
200 ꢁC): 2n/3n¼3:97 (retention time: 13.20 and 12.69 min,
respectively)].
4.3.14. A mixture of 2-allyl-2-methoxypiperidine-
1-carbonitrile (3o) and 2-allyl-6-methoxypiperidine-
1-carbonitrile (2o) [from 1o]
4.3.10. 2-Methoxy-2-methylpyrrolidine-1-carbonitrile (3h)
[from 1h]
1H NMR (400 MHz, CDCl3) d 3.54e3.46 (m, 2H), 3.29 (s,
1H NMR (400 MHz, CDCl3) d 5.88e5.69 (m, 1H), 5.23e
5.11 (m, 2H), 4.59 (s, 0.3H), 3.44 (s, 0.9H) and 3.30 (s,
2.1H), 3.29e2.28 (m, 3.7H), 1.86e1.60 (m, 4H), 1.58e1.24
(m, 2H); IR n cmꢀ1 (neat): 2946, 2215, 1738, 1644, 1445,
1377; High Resolution Mass Spectrum [FAB(þ)]: m/z calcd
for C10H17N2O [MþH]þ 181.1341, found 181.1334.
The ratio of 2o/3o was determined by gas chromatography
[(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ25 m,
200 ꢁC): 2o/3o¼30:70 (retention time: 12.89 and 12.47 min,
respectively)].
3H), 2.27e1.91 (m, 3H), 1.78e1.74 (m, 1H), 1.62 (s, 3H); 13
C
NMR (100 Hz, CDCl3) d 115.13 (1C), 94.66 (1C), 50.49 (1C),
50.05 (1C), 37.58 (1C), 22.80 (1C), 21.44 (1C); IR n cmꢀ1
(neat): 2986, 2890, 2220, 1713, 1487, 1383; High Resolution
Mass Spectrum [EI(þ)]: m/z calcd for C7H12N2O [M]þ
140.0949, found: 140.0967.
The ratio of 2h/3h was determined by gas chromatography
[(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ25 m,
80 ꢁC): 2h/3h¼13:87 (retention time: 18.05 and 16.86 min,
respectively)].
4.3.11. 2-Methoxy-2-methylpiperidine-1-carbonitrile (3g)
[from 1g]
4.3.15. 2-Methoxy-2-phenylpiperidine-1-carbonitrile (3p)
[from 1p]
1H NMR (300 MHz, CDCl3) d 3.28 (s, 3H), 3.28e3.20 (m,
2H), 1.90e1.56 (m, 6H), 1.54 (s, 3H); 13C NMR (100 Hz,
CDCl3) d 118.15 (1C), 86.03 (1C), 50.91 (1C), 46.34 (1C),
36.54 (1C), 23.96 (1C), 22.44 (1C), 18.92 (1C); IR n cmꢀ1
(neat): 2948, 2215, 1715, 1449, 1385; High Resolution Mass
Spectrum [EI(þ)]: m/z calcd for C8H14N2O [M]þ 154.1107,
found: 154.1084.
1H NMR (400 MHz, CDCl3) d 7.52e7.36 (m, 5H), 3.52e
3.46 (m, 2H), 3.39 (s, 3H), 1.90e1.59 (m, 6H); 13C NMR
(100 Hz, CDCl3) d 138.98 (1C), 128.75 (2C), 128.69 (1C),
126.49 (2C), 116.93 (1C), 91.28 (1C), 51.07 (1C), 47.72
(1C), 40.09 (1C), 24.04 (1C), 19.54 (1C); IR n cmꢀ1 (neat):
3061, 2948, 2211, 1448, 1244, 1132; High Resolution Mass
Spectrum [EI(þ)]: m/z calcd for C13H16N2O [M]þ 216.1263,
found 216.1237.
The ratio of 2g/3g was determined by gas chromatography
[(Shinwa Chemical Industries, Ltd. HR-1, 0.25 mmfꢂ25 m,
80 ꢁC): 2g/3g¼13:87 (retention time: 21.59 and 19.82 min,
respectively)].
Obtained 3p was deduced to be the single regio-isomer by
use of GC (Shinwa Chemical Industries, Ltd. HR-1,
0.25 mmfꢂ25 m) and NMR.

S.S. Libendi et al. / Tetrahedron 64 (2008) 3935e3942
3941
4.3.16. 2-(3-Bromo-4-methoxyphenyl)-2-methoxypiperidine-
4.6. 2,2-Diallylpiperidine-1-carbonitrile (6) [from 3l]
1-carbonitrile (3q) [from 1q]
1H NMR (400 MHz, CDCl3) d 7.65 (s, 1H), 7.42 (d,
J¼6.8 Hz, 1H), 6.94 (d, J¼8.8 Hz, 1H), 3.91 (s, 3H), 3.57e
3.49 (m, 2H), 3.37 (s, 3H), 1.90e1.61 (m, 6H); 13C NMR
(100 Hz, CDCl3) d 156.10, 132.55, 131.53, 127.09, 116.65,
111.94, 90.50, 56.27, 51.05, 47.75, 39.79, 23.92, 19.52; IR n
cmꢀ1 (neat): 2944, 2215, 1734, 1601, 1499, 1458; High
Resolution Mass Spectrum [FAB(þ)]: m/z calcd for
C14H18BrN2O2 [MþH]þ 325.0552, found 325.0557.
A 50 mL flask containing 3l (176 mg, 1 mmol) and allyltri-
methylsilane (228 mg, 2 mmol) in CH2Cl2 (3 mL) was stirred
at ꢀ78 ꢁC and BF3$Et2O (0.13 mL, 1 mmol) was added drop-
wise. The mixture was then left to stir as temperature in-
creased to 0 ꢁC while being monitored by TLC. Upon
completion of the reaction, it was quenched by addition of
10 mL of H2O and then extracted with CH2Cl2 (3ꢂ10 mL).
The combined organic layer was then dried by anhydrous
MgSO4 and solvent removed in vacuo. The crude product
was then subjected to silica gel column (n-hexane/
1
4.3.17. 2-(4-Methylphenyl)-2-methoxypiperidine-
1-carbonitrile (3r) [from 1r]
AcOEt¼10:1) to obtain 6 as an oil (91 mg, 52%). H NMR
(400 MHz, CDCl3) d 5.82e5.65 (m, 2H), 5.22e5.10 (m,
4H), 3.76e3.60 (m, 2H), 2.59e2.45 (m, 2H), 2.40e2.20 (m,
2H), 2.19e1.85 (m, 2H), 1.80e1.50 (m, 2H).; IR n cmꢀ1
(neat): 2978, 2928, 2204, 1641, 1591, 1525, 1483, 1475;
High Resolution Mass Spectrum [FAB(þ)]: m/z calcd for
C11H17N2 [MþH]þ 177.1392, found 177.1415.
1H NMR (400 MHz, CDCl3) d 7.38 (d, J¼8.3 Hz, 2H), 7.25
(d, J¼7.8 Hz, 2H), 3.60e3.41 (m, 2H), 3.38 (s, 3H), 2.36 (s,
3H), 1.90e1.55 (m, 6H); IR n cmꢀ1 (neat): 2941, 2872,
2214, 1653, 1512, 1448, 1375, 1352, 1319; High Resolution
Mass Spectrum [FAB(þ)]: m/z calcd for C14H19N2O
[MþH]þ 231.1497, found 231.1506.
Acknowledgements
4.4. 2-Methylpiperidine-1,2-dicarbonitrile (4) [from 3g]
This work was supported in part by a Taisho Award in Syn-
thetic Organic Chemistry, Japan and by the President’s discre-
tion fund of Nagasaki University, Japan.
A 50 mL flask containing 3g (154 mg, 1 mmol) and trime-
thylsilyl cyanide (198 mg, 2 mmol) in CH2Cl2 (3 mL) was
stirred at 0 ꢁC and TiCl4 (0.07 mL, 0.5 mmol) was added drop-
wise. The mixture was then left to stir at this temperature
while being monitored by TLC. Upon completion of the reac-
tion, it was quenched by addition of 10 mL of H2O and then
extracted with CH2Cl2 (3ꢂ10 mL). The combined organic
layer was then dried by anhydrous MgSO4 and solvent re-
moved in vacuo. The crude product was then subjected to sil-
ica gel column (n-hexane/AcOEt¼10:1) to obtain 4 as an oil
References and notes
1. (a) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843e9873; (b)
´
Caltiviela, C.; Dıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11,
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1
(97 mg, 65%). H NMR (300 MHz, CDCl3) d 3.58e3.44 (m,
1H), 3.38 (t, J¼12.3 Hz, 1H), 2.08e1.79 (m, 3H), 1.78 (s,
3H), 1.72e1.55 (m, 3H); IR n cmꢀ1 (neat): 2992, 2224;
High Resolution Mass Spectrum [EI(þ)]: m/z calcd for
C8H11N3 [M]þ 149.0953, found 149.0944.
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4.5. 2-Allyl-2-methylpiperidine-1-carbonitrile (5) [from 3g]
A 50 mL flask containing 3g (154 mg, 1 mmol) and allyltri-
methylsilane (228 mg, 2 mmol) in CH2Cl2 (3 mL) was stirred
at 0 ꢁC and TiCl4 (95 mg, 0.5 mmol) was added dropwise. The
mixture was then left to stir at this temperature while being
monitored by TLC. Upon completion of the reaction, it was
quenched by addition of 10 mL of H2O and then extracted
with CH2Cl2 (3ꢂ10 mL). The combined organic layer was
then dried by anhydrous MgSO4 and solvent removed in va-
cuo. The crude product was then subjected to silica gel column
(n-hexane/AcOEt¼10:1) to obtain 5 as an oil (112 mg, 68%).
1H NMR (300 MHz, CDCl3) d 5.84e5.72 (m, 1H), 5.19e5.11
(m, 2H), 3.42e3.20 (m, 2H), 2.61e2.36 (m, 2H), 1.78e1.40
(m, 6H), 1.30 (s, 3H); IR n cmꢀ1 (neat): 2970, 2945, 2868,
2212, 1641, 1456, 1383, 1311. Anal. Calcd for C10H16N2: C,
73.13; H, 9.82; N, 17.06. Found: C, 72.82; H, 9.94; N, 17.24.
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3942
S.S. Libendi et al. / Tetrahedron 64 (2008) 3935e3942
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ˇ
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