Anodic cyanation of 1-arylpyrrolidines

Article abstract of DOI:10.1246/bcsj.79.577

The electrochemical cyanation of 1-arylpyrrolidines was carried out in methanol containing sodium cyanide at a platinum anode in a divided cell. The reaction gave the corresponding α-aminonitriles 2, together with the unexpected 1-arylpyrrolidine-2-carboximidic acid methyl esters 3 as byproducts.

Full text of DOI:10.1246/bcsj.79.577

Short Articles
Bull. Chem. Soc. Jpn. Vol. 79, No. 4, 577–579 (2006)
577
with the requisite primary amines according to the procedure
in Ref. 4. The oxidation potentials of 1-arylpyrrolidines were
measured by cyclic voltammetry. Peak potentials, expressed
in V vs SCE and ohmic drop has not been corrected, were col-
lected in Table 1. These title compounds exhibited irrevers-
ible oxidation waves. 1-(2-Methylphenyl)pyrrolidine (1b) was
here selected as the model compound. Three successive irre-
versible peaks were observed (Fig. 1) at EpA ¼ þ0:85, EpB ¼
þ1:23, and EpC ¼ þ1:60 V vs SCE. It could be explained that
the species (iminium cation) electrogenerated at peak A was
trapped by cyanide anions leading to the ꢀ-aminonitrile 2b,
which could be further oxidized at EpB. Indeed, a similar peak
B0 was recorded on a cyclic voltammogram of a methanolic
solution of the ꢀ-aminonitrile 2b in the presence of eight equiv
of sodium cyanide relative to the substrate. In the absence of
substrate, no peak was observed in its CV (Fig. 1). Therefore,
the remaining peak C is probably attributed to the oxidation of
the product formed at peak B, not to the oxidation of the cya-
nide anion. As shown in Table 1, the 1-arylpyrrolidines 1a–1f
were oxidized at less positive potentials than those of 1g–1j.
The potential shift could be explained by the electron-with-
drawing effect of the trifluoromethyl or nitro group. Taken
together, these results indicated that selective transformations
might be performed at the first oxidation peak of amines 1a–
1j during macroscale electrolyses.
Anodic Cyanation of
1-Arylpyrrolidines
ꢀ
Wei Liu, Yuan Ma, Yingwu Yin, and Yufen Zhao
The Key Laboratory for Bioorganic Phosphorus
Chemistry and Chemical Biology, Ministry of Education,
Department of Chemistry, Tsinghua University,
Beijing 100084, P. R. China
Beijing TH-UNIS Insight Co., Ltd.,
Beijing 100084, P. R. China
Received September 15, 2005; E-mail: liu-wei03@mails.
tsinghua.edu.cn
The electrochemical cyanation of 1-arylpyrrolidines
was carried out in methanol containing sodium cyanide at
a platinum anode in a divided cell. The reaction gave the cor-
responding ꢀ-aminonitriles 2, together with the unexpected
1-arylpyrrolidine-2-carboximidic acid methyl esters 3 as
byproducts.
Controlled potential electrolysis was performed under the
conditions described in Table 1. Results of the anodic cyana-
tion are also given in Table 1. In each case, cyanation occurred
exclusively at the carbon atom ꢀ to the nitrogen atom and the
corresponding ꢀ-aminonitriles 2 were produced in moderate to
good yields. A possible electrocyanation mechanism is shown
in Scheme 2.3
ꢀ-Aminonitriles derived from pyrrolidine derivatives have
proven to be extremely versatile synthons in a number of syn-
thetic applications.1 These applications have stimulated further
efforts for the development of the regiocontrolled synthesis of
this class of compounds.
It is interesting that the 1-arylpyrrolidine-2-carboximidic
acid methyl esters 3 were also observed as byproducts in this
electrolysis (GC-MS analysis). This surprising result could
be explained by concomitant solvolysis of the aminonitriles 2
in a methanolic sodium cyanide solution at room temperature.
In order to clarify the proposed mechanism, alkaline hydroly-
sis of the aminonitrile 2j in a methanolic sodium cyanide solu-
Anodic cyanation of organic compounds is expected to pro-
vide a promising method for the synthesis of nitriles by reason
of its positional reactivity, clean reaction products, and mild
reaction conditions.2 However, few investigations on the anod-
ic cyanation of pyrrolidine derivatives have been studied. Pre-
viously, Chiba et al.3 reported anodic cyanation of tertiary
heterocyclic amines involving several 1-alkylpyrrolidines in
aqueous methanol containing sodium cyanide. They found
steric hindrance around the nitrogen atom of amines affected
product yields and regioselectivity. We herein investigate the
anodic cyanation of 1-arylpyrrolidines and the effect of the
aryl-substituents on both peak potentials and product yields.
The structures of the title compounds are shown in Scheme 1.
The starting tertiary cyclic amines 1a–1j were easily pre-
pared by direct treatment of 2,5-dimethoxytetrahydrofuran
Table 1. Anodic Cyanation of 1-Arylpyrrolidines: Voltam-
metric Data and Products
Product yield/%
2cÞ
Substrate
R
Epa)/V
Eb)/V
3dÞ
H
0.818, 1.152, 1.595
0.846, 1.228, 1.602
0.755, 1.081, 1.469
0.666, 0.990, 1.388
0.810, 1.148, 1.565
0.785, 1.115, 1.511
1.048, 1.492
0.7
0.7
0.6
0.6
0.7
0.6
0.9
1.0
1.0
1.1
41
70
79
81
71
75
83
30
39
41
5
—
3
o-CH3
m-CH3
p-CH3
p-Cl
3
11
10
2
37
46
42
p-F
N
o-CF3
o-NO2
m-NO2
p-NO2
1.158, 1.498
1.033, 1.385
1.089, 1.403
R
1b R = o-CH ; 1c R = m-CH ; 1d R = p-CH
a) Peak potential from cyclic voltammetry. Pt anode, CH3OH,
0.16 M NaCN. SCE reference. Scan rate is 0.1 V sꢁ1. Values
are obtained on first scan from 0.00 to 2.00 V. Substrate con-
centration is 0.02 M. b) Potential for preparative electrolysis.
c) Isolated yield. d) Determined yield by GC-MS.
1a R = H;
1e R = p-Cl;
3
3
3
2
1f R = p-F;
1g R = o-CF ; 1h R = o-NO
3
1i R = m-NO ; 1j R = p-NO
2
2
Scheme 1.
Published on the web April 7, 2006; DOI: 10.1246/bcsj.79.577

578 Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
Ó 2006 The Chemical Society of Japan
0.0007
0.0006
0.0005
eter. HRMS spectra were taken with the Bruker APEX II FT-ICR
MS. The cyclic voltammetric experiments were performed by a
CHI 660B analyzer.
2b
1b
Cyclic voltammetry was performed in a three-compartment
cell. The working electrode was a platinum disk electrode,
2 mm in diameter, and the counter electrode was a platinum sheet.
All potentials were referred to a saturated calomel electrode (SCE)
and ohmic drop was not corrected. Prior to each measurement, the
solution was saturated with pure nitrogen for five minutes in order
to remove oxygen. The electrode was activated by anodic and
cathodic potential cycles between 1.4 and ꢁ0:25 V at a rate of
0.05 V sꢁ1 in 0.5 M H2SO4 until the cyclic voltammogram was
the same as the standard curve. The Ep values are shown in
Table 1.
B
0.0004
C
B'
A
0.0003
0.0002
0.0001
0.0000
0.0
0.5
1.0
1.5
2.0
Potential (V vs SCE)
General Procedure for Constant Potential Electrolysis of
the 1-Arylpyrrolidines 1.
Fig. 1. Voltammetric investigations in the amine 1b, ami-
nonitrile 2b, and MeOH + NaCN, respectively. Scan
The preparative-scale electrolysis
was performed in an H-type cell with a glass frit separating two
compartments fitted with Pt sheet electrodes having an area of
3 cm2. The anolyte was made up of the pyrrolidines 1 (0.02 M)
in methanolic sodium cyanide solution (0.16 M) and was stirred
magnetically. The catholyte was a methanolic solution of sodium
cyanide. The reaction was carried out at controlled anode poten-
tials as indicated in Table 1 at 25 ꢂC. The electrolysis was stopped
when 2 F molꢁ1 of electricity was passed. The final anolyte was
concentrated under reduced pressure; a saturated aqueous sodium
chloride solution was then added and the mixture was extracted
with ether. The organic layer was dried over sodium sulfate and
concentrated. The products were purified by column chromatogra-
phy on silica gel using ethyl acetate/petroleum ether (1:5) as the
eluent. Elemental analyses of the ꢀ-aminonitriles 2 are uncertain
because they easily eliminate HCN under combustion conditions.3
The byproducts 3 were unstable for chromatographic purification
and resulted in partial decomposition. 3a–3d and 3g were not
isolated due to trace amounts.
rate = 100 mV sꢁ1
.
-
+
CN
CN
-H ,-e
-e
N
N
N
N
R
R
R
R
Scheme 2.
C NH
OCH
CN
N
N
NaCN/CH OH
3
3
room temperature
24 h
NO
NO
2
2
1-Phenyl-2-pyrrolidinecarbonitrile (2a): Oil; IR (KBr) ꢁ
2922, 2851, 2230 (CN), 1600, 1505, 1360, 750, 691 cmꢁ1
;
2j
3j
1H NMR (CDCl3, 300 MHz) ꢂ 2.08–2.47 (m, 4H), 3.42 (m, 2H),
4.44 (d, J ¼ 6:9 Hz, 1H), 6.70 (d, J ¼ 8:3 Hz, 2H), 6.82 (t, J ¼
7:2 Hz, 1H), 7.30 (m, 2H); 13C NMR (CDCl3, 75 MHz) ꢂ 24.1,
31.7, 47.6, 49.2, 112.8, 118.3, 119.4, 129.6, 145.3; HRMS (ESI)
calcd for C11H13N2 [M þ H]þ 173.1078, found 173.1079.
1-(2-Methylphenyl)-2-pyrrolidinecarbonitrile (2b): Oil; IR
(KBr) ꢁ 2955, 2879, 2225 (CN), 1600, 1493, 1301, 1143, 1106,
962, 762, 721 cmꢁ1; 1H NMR (CDCl3, 300 MHz) ꢂ 1.95–2.20 (m,
2H), 2.24–2.51 (m, 2H), 2.31 (s, 3H), 3.17 (m, 1H), 3.48 (m, 1H),
4.40 (dd, J ¼ 7:9, 3.8 Hz, 1H), 7.01–7.27 (m, 4H); 13C NMR
(CDCl3, 75 MHz) ꢂ 18.9, 22.8, 30.8, 50.1, 52.1, 119.2, 119.8,
124.2, 126.9, 131.5, 132.2, 144.9; HRMS (ESI) calcd for C12H15-
N2 [M þ H]þ 187.1235, found 187.1238.
Scheme 3.
tion was investigated at room temperature. The same ester
product 3j was obtained in reasonable yield (Scheme 3).
This side reaction is favored for the structure of the sub-
strate, the 1-arylpyrrolidines 1 bearing an electron-withdraw-
ing group on the aromatic ring. Moderate yields of the imidates
3 were observed when a strongly electron-withdrawing group,
such as a nitro group, was employed, while the use of an elec-
tron-donating group, such as a methyl group, resulted in a sig-
nificant decrease in the yield (Table 1). It is worth noting that
when a trifluoromethyl substituent was located at the ortho
position as an electron-withdrawing group, the desired amino-
nitrile 2g was obtained in 83% yield with only a trace amount
of the byproduct 3g. In addition, when ortho-substituted 1-
arylpyrrolidines (1b and 1h) were used, the byproduct yields
were lower than those of para- or meta-substituted substrates
[(1c and 1d) and (1i and 1j)]. These results suggested that
the steric hindrance of the ortho-substituents on the aromatic
ring could probably suppress the side reaction.
1-(3-Methylphenyl)-2-pyrrolidinecarbonitrile (2c): Oil; IR
(KBr) ꢁ 2951, 2873, 2229 (CN), 1605, 1496, 1360, 1179, 1023,
768, 691 cmꢁ1 1H NMR (CDCl3, 300 MHz) ꢂ 2.15–2.47 (m,
;
4H), 2.37 (s, 3H), 3.31 (m, 2H), 4.43 (d, J ¼ 6:9 Hz, 1H), 6.52
(s, 2H), 6.66 (d, J ¼ 7:6 Hz, 1H), 7.19 (m, 1H); 13C NMR (CDCl3,
75 MHz) ꢂ 21.9, 24.0, 31.7, 47.6, 49.2, 110.0, 113.5, 119.3, 119.5,
129.4, 139.4, 145.4; HRMS (ESI) calcd for C12H15N2 [M þ H]þ
187.1235, found 187.1234.
1-(4-Methylphenyl)-2-pyrrolidinecarbonitrile (2d): Light
yellow solid; mp 50–51 ꢂC; IR (KBr) ꢁ 2922, 2852, 2229 (CN),
Experimental
General. Methanol and reagent-grade sodium cyanide were
used without further purification.
NMR spectra were recorded on a JEOL JNM-A300 spectrom-
1623, 1522, 1360, 1161, 809, 516 cmꢁ1 1H NMR (CDCl3, 300
;
MHz) ꢂ 2.19–2.43 (m, 4H), 2.30 (s, 3H), 3.40 (m, 2H), 4.42 (d,
J ¼ 7:2 Hz, 1H), 6.62 (d, J ¼ 8:6 Hz, 2H), 7.11 (d, J ¼ 8:5 Hz,

W. Liu et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
579
2H); 13C NMR (CDCl3, 75 MHz) ꢂ 20.4, 24.0, 31.6, 47.7, 49.4,
112.9, 119.5, 127.6, 130.1, 143.2; ESI-MS (+): m=z ¼ 186:8
[M þ H]þ.
1-(4-Fluorophenyl)-2-pyrrolidinecarboximidic Acid Methyl
Ester (3f): 1H NMR (CDCl3, 300 MHz) ꢂ 1.84–2.21 (m, 4H),
3.17 (m, 1H), 3.57 (t, J ¼ 7:2 Hz, 1H), 3.83 (s, 3H), 3.90 (d, J ¼
8:9 Hz, 1H), 6.49 (m, 2H), 8.13 (t, J ¼ 9:0 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) ꢂ 23.9, 31.2, 49.6, 53.8, 62.3, 113.2, 113.3,
115.6, 115.9, 143.8, 154.3, 157.4, 173.8; HRMS (ESI) calcd for
C12H16FN2O [M þ H]þ 223.1247, found 223.1250.
1-(4-Chlorophenyl)-2-pyrrolidinecarbonitrile (2e):
Light
yellow solid; mp 83–84 ꢂC; IR (KBr) ꢁ 2904, 2862, 2229 (CN),
1601, 1497, 1360, 1094, 808, 713 cmꢁ1 1H NMR (CDCl3, 300
;
MHz) ꢂ 2.18–2.46 (m, 4H), 3.38 (m, 2H), 4.39 (dd, J ¼ 7:2,
2.4 Hz, 1H), 6.60 (d, J ¼ 9:3 Hz, 2H), 7.23 (d, J ¼ 8:9 Hz, 2H);
13C NMR (CDCl3, 75 MHz) ꢂ 24.0, 31.7, 47.8, 49.3, 113.9, 119.0,
123.4, 129.4, 143.9; HRMS (ESI) calcd for C11H12ClN2 [M þ
H]þ 207.0689, found 207.0686.
1-(2-Nitrophenyl)-2-pyrrolidinecarboximidic Acid Methyl
Ester (3h): 1H NMR (CDCl3, 300 MHz) ꢂ 1.81–2.08 (m, 3H),
2.50 (m, 1H), 2.83 (t, J ¼ 7:5 Hz, 1H), 3.66 (m, 1H), 3.81 (s, 3H),
4.30 (t, J ¼ 7:8 Hz, 1H), 6.75–6.87 (m, 2H), 7.35 (t, J ¼ 8:6 Hz,
1H), 7.54 (d, J ¼ 8:1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) ꢂ 25.6,
32.0, 52.8, 53.9, 61.8, 116.5, 118.2, 126.6, 133.2, 139.2, 141.8,
172.7; HRMS (ESI) calcd for C12H16N3O3 [M þ H]þ 250.1192,
found 250.1185.
1-(4-Fluorophenyl)-2-pyrrolidinecarbonitrile (2f):
Light
yellow solid; mp 54–55 ꢂC; IR (KBr) ꢁ 2923, 2853, 2224 (CN),
1
1512, 1233, 1151, 961, 822 cmꢁ1; H NMR (CDCl3, 300 MHz) ꢂ
2.11–2.43 (m, 4H), 3.40 (m, 2H), 4.36 (d, J ¼ 7:2 Hz, 1H), 6.62
(m, 2H), 7.00 (t, J ¼ 9:0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) ꢂ
24.0, 31.6, 48.0, 49.7, 113.6, 113.7, 115.9, 116.2, 119.3, 142.0,
154.7, 157.8; HRMS (ESI) calcd for C11H12FN2 [M þ H]þ
191.0984, found 191.0982.
1-(3-Nitrophenyl)-2-pyrrolidinecarboximidic Acid Methyl
Ester (3i): 1H NMR (CDCl3, 300 MHz) ꢂ 1.95–2.30 (m, 4H),
3.33 (m, 1H), 3.70 (t, J ¼ 6:9 Hz, 1H), 3.86 (s, 3H), 4.10 (d, J ¼
7:5 Hz, 1H), 6.76 (d, J ¼ 8:3 Hz, 1H), 7.35 (m, 2H), 7.58 (d, J ¼
8:2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) ꢂ 23.7, 31.2, 49.4, 54.3,
61.9, 106.9, 112.2, 118.5, 129.9, 147.6, 149.4, 173.0; HRMS (ESI)
calcd for C12H16N3O3 [M þ H]þ 250.1192, found 250.1190.
Synthesis of 1-(4-Nitrophenyl)-2-pyrrolidinecarboximidic
Acid Methyl Ester (3j). The aminonitrile 2j (0.2 mmol) was dis-
solved in methanolic sodium cyanide solution (0.16 M, 10 mL).
The mixture was stirred for 24 h at room temperature. The solvent
was removed. Then, saturated aqueous sodium chloride solution
was added and the mixture was extracted with ether. The organic
layer was concentrated. The product was purified by column chro-
matography on silica gel using dichloromethane/methanol as the
eluent (20:1). 3j as a yellow solid; yield 77%; mp 119–121 ꢂC;
IR (KBr) ꢁ 3309, 2950, 2872, 1667, 1606, 1517, 1488, 1358,
1-[2-(Trifluoromethyl)phenyl]-2-pyrrolidinecarbonitrile (2g):
Oil; IR (KBr) ꢁ 2962, 2844, 2226 (CN), 1604, 1496, 1318, 1139,
962, 767 cmꢁ1; 1H NMR (CDCl3, 300 MHz) ꢂ 2.01–2.22 (m, 2H),
2.23–2.47 (m, 2H), 3.21 (m, 1H), 3.47 (m, 1H), 4.34 (dd, J ¼ 7:6,
3.0 Hz, 1H), 7.30 (t, J ¼ 6:5 Hz, 1H), 7.60 (m, 2H), 7.76 (d, J ¼
7:5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) ꢂ 23.0, 31.2, 51.6, 54.5,
119.1, 122.2, 125.2, 125.7, 127.5, 133.1, 145.1; HRMS (ESI)
calcd for C12H12F3N2 [M þ H]þ 241.0952, found 241.0963.
1-(2-Nitrophenyl)-2-pyrrolidinecarbonitrile (2h): Light yel-
low solid; mp 64–65 ꢂC; IR (KBr) ꢁ 2977, 2886, 2244 (CN), 1605,
1515, 1361, 1178, 741 cmꢁ1; 1H NMR (CDCl3, 300 MHz) ꢂ 1.99–
2.55 (m, 4H), 3.25 (m, 1H), 3.42 (m, 1H), 4.57 (t, J ¼ 7:2 Hz, 1H),
7.01 (t, J ¼ 8:1 Hz, 1H), 7.13 (d, J ¼ 8:7 Hz, 1H), 7.51 (t, J ¼ 8:1
Hz, 1H), 7.79 (d, J ¼ 8:2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) ꢂ
24.1, 31.4, 50.2, 50.4, 118.2, 118.5, 120.3, 126.6, 133.6, 139.7,
140.4; HRMS (ESI) calcd for C11H12N3O2 [M þ H]þ 218.0929,
found 218.0927.
1071, 817, 750 cmꢁ1 1H NMR (CDCl3, 300 MHz) ꢂ 1.99–2.26
;
(m, 4H), 3.39 (m, 1H), 3.70 (t, J ¼ 8:0 Hz, 1H), 3.84 (s, 3H), 4.19
(d, J ¼ 7:7 Hz, 1H), 6.49 (d, J ¼ 9:0 Hz, 2H), 8.13 (d, J ¼ 9:0 Hz,
2H); 13C NMR (CDCl3, 75 MHz) ꢂ 23.4, 30.9, 49.0, 53.8, 61.7,
111.5, 126.0, 138.2, 151.2, 171.6; ESI-MS (+): m=z ¼ 271:8
[M þ Na]þ; Found: C, 57.83; H, 6.09; N, 17.11%. Calcd for
C12H15N3O3: C, 57.82; H, 6.07; N, 16.86%.
1-(3-Nitrophenyl)-2-pyrrolidinecarbonitrile (2i):
solid; mp 105–107 ꢂC; IR (KBr) ꢁ 2920, 2866, 2233 (CN),
1618, 1518, 1340, 856, 730, 667 cmꢁ1 1H NMR (CDCl3, 300
Yellow
;
MHz) ꢂ 2.21–2.54 (m, 4H), 3.41–3.59 (m, 2H), 4.51 (d, J ¼ 7:2
Hz, 1H), 6.98 (dd, J ¼ 8:3, 2.8 Hz, 1H), 7.44 (m, 2H), 7.66 (d, J ¼
8:3 Hz, 1H); 13C NMR (CDCl3, 75 MHz) ꢂ 24.0, 31.7, 48.0, 49.2,
107.2, 112.9, 118.4, 118.4, 130.3, 145.9, 149.4; HRMS (ESI)
calcd for C11H12N3O2 [M þ H]þ 218.0929, found, 218.0935.
The authors thank the financial support of Beijing TH-
UNIS-Insight Co., Ltd. and the Chinese National Science
Foundation (No. 20132020), the Ministry of Science and
Technology, the Chinese Ministry of Education and Tsinghua
University.
1-(4-Nitrophenyl)-2-pyrrolidinecarbonitrile (2j):
Yellow
solid; mp 114–115 ꢂC; IR (KBr) ꢁ 2924, 2878, 2229 (CN), 1601,
1486, 1307, 1108, 965, 826, 751 cmꢁ1 1H NMR (CDCl3, 300
;
References
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1H), 6.67 (d, J ¼ 9:1 Hz, 2H), 8.20 (d, J ¼ 9:1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) ꢂ 24.1, 31.6, 48.0, 48.9, 111.8, 117.9, 126.2,
139.2, 149.7; HRMS (ESI) calcd for C11H12N3O2 [M þ H]þ
218.0929, found 218.0937.
1
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122.5, 129.1, 145.7, 173.5; HRMS (ESI) calcd for C12H16ClN2O
[M þ H]þ 239.0951, found 239.0947.
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