Oxidative Functionalization of Cyclic N -Arylamines with Nitromethane and TMSCN Using the T-HYDRO/ t -BuOK System

Article abstract of DOI:10.1055/s-0036-1590943

Tertiary cyclic N -arylamines react with nitromethane in the presence of the tert -butyl hydroperoxide (T-HYDRO)/ t -BuOK system to give β-nitroamines in up to 90% yield. When TMSCN is used in place of nitromethane, α-aminonitriles are obtained in up to 9

Full text of DOI:10.1055/s-0036-1590943

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
G. A. Rao, M. Periasamy
Paper
Synthesis
Oxidative Functionalization of Cyclic N-Arylamines with Nitro-
methane and TMSCN Using the T-HYDRO/t-BuOK System
Gunda Ananda Rao
n
n
n
t-BuOK, T-HYDRO
t-BuOK, T-HYDRO
NO2
R1
CN
R1
R1
Mariappan Periasamy*
N
MeCN, 80 °C
MeCN, 80 °C
N
N
TMSCN
24 h
MeNO2
48 h
School of Chemistry, University of Hyderabad, Central University
P.O, Hyderabad-500046, India
mpsc@uohyd.ac.in
R2
R2
R1 = H, Me, CH2OH
R2
18 examples
up to 96% yield
14 examples
up to 90% yield
R
n
2 = Me, F, Cl, Br, CF3
= 1, 2
metal-free
Received: 26.08.2017
Accepted after revision: 05.10.2017
Published online: 06.11.2017
port detailed studies on the nitroalkylation and cyanation
of tertiary cyclic arylamines using t-BuOK/T-HYDRO and ni-
tromethane or trimethylsilyl cyanide (TMSCN).
DOI: 10.1055/s-0036-1590943; Art ID: ss-2017-z0553-op
We first examined the reaction of N-phenylpyrrolidine
(1) and nitromethane with the T-HYDRO/t-BuOK system.
The results are summarized in Table 1.
Abstract Tertiary cyclic N-arylamines react with nitromethane in the
presence of the tert-butyl hydroperoxide (T-HYDRO)/t-BuOK system to
give β-nitroamines in up to 90% yield. When TMSCN is used in place of
nitromethane, α-aminonitriles are obtained in up to 96% yield. The
method is suitable for several unactivated cyclic arylamine substrates.
These transformations are rationalized considering the formation of the
corresponding iminium ion intermediates via an initial electron transfer
process.
Previous work:
CuBr (5 mol%)
t-BuOOH (1.0–1.2 equiv)
a)
(1)
(2)
N
N
rt
Ph
Ph
MeCN, MeNO2, 6 h
NO2
Key words N-arylamines, iminium ions, enamines, α-aminonitriles,
β-nitroamines
FeCl3⋅6H2O (10 mol%)
Sn(n-Bu)3
N
N
N
b)
c)
d)
t-BuOOH
The transformation of tertiary amines into the corre-
sponding α-functionalized compounds is a useful synthetic
method. Generally, such conversions involve oxidation of
the C–H bond adjacent to the nitrogen atom of tertiary
amines through iminium ion intermediates (Scheme 1).1–8
Recently, several methods were reported using Ru, Rh, Pt,
Au, Cu, Fe, Mo, Ti, Co and V complexes in the presence of
oxidants for the direct oxidative functionalization of tertia-
ry amines.9 Also, a few metal-free methods using oxidants
such as DDQ, I2, H2O2, TBHP, and PhI(OAc)2 were reported.10
Photoredox catalysts were also used for such transforma-
tions.11 We previously reported that the reactions of N-
arylpyrrolidines with a 70% aqueous solution of tert-butyl
hydroperoxide (T-HYDRO) produced the corresponding
iminium ions, which could be converted into tetracyclic
amines using sodium acetate in cyclohexane, or into the
corresponding cyclic amides or nitro-methylated products
under appropriate conditions (Scheme 2).12 Herein, we re-
MeCN, rt, 30 min
N
RuCl3, O2 (1 atm)
AcOH (6 mmol)
CN
(3)
(4)
MeOH, 60 °C, 2 h
NaCN
nucleophile
I
2 (10 mol%)
N
N
O2, rt, MeOH, 24 h
Ph
Ph
Nu: MeNO2, indole, TMSCN
Nu
Present work:
R1
n
n
t-BuOK, T-HYDRO
MeNO2 or TMSCN
R1
Nu
N
N
MeCN
80 °C, 24–48 h
R1 = H, Me, CH2OH
R2 = Me, F, Cl, Br, CF3
n = 1, 2
R2
R2
Scheme 1 C–H functionalization of tert-amines with nucleophiles
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
G. A. Rao, M. Periasamy
Paper
Synthesis
Table 1 Reactions of N-Phenylpyrrolidine (1) and Nitromethane Using
the T-HYDRO/t-BuOK Systema,b
N
NaOAc⋅3H2O
N
59–78%
cyclohexane
70 °C, 24 h
NO2
t-BuOK, T-HYDRO
R
N
N
MeNO2
R
MeCN
t-BuOK
O
T-HYDRO
80 °C, 48 h
N
N
MeOH
85–88%
74–79%
70 °C, 24 h
1
2a
Entry
Base
t-BuOK
Solvent
Oxidant
Yield (%)c2a
R
R
NO2
1d
2e
3f
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMSO
DMF
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
–
27
34
51
76
59
61
65
62
48
67
63
81
57
70
74
46
68
5
t-BuOK, MeNO2
N
t-BuOK
t-BuOK
t-BuOK
K3PO4
Cs2CO3
KOH
MeOH
70 °C, 48 h
R
4
Scheme 2 Synthesis of cyclic amides and tetracyclic amines
5
6
7
Initially, we examined the reaction using N-phenylpyr-
rolidine (1), nitromethane, T-HYDRO and t-BuOK in metha-
nol solvent at room temperature for 48 hours and observed
the formation of the corresponding β-nitroamine 2a in 27%
yield (Table 1, entry 1). Also, when the reaction was per-
formed for 12 hours and 24 hours at 80 °C, the products
were isolated in 34% and 51% yields, respectively (entries 2
and 3). When the reaction was performed at 80 °C for 48
hours, the product was obtained in 76% yield (entry 4).
Among various bases, t-BuOK was the most effective for
the nitroalkylation of N-phenylpyrrolidine (1) (Table 1, en-
tries 4–9). Solvents such as DMSO, DMF, MeCN, PEG-400,
toluene, and EtOH gave product 2a in good yields (Table 1,
entries 10–15). The product 2a was obtained in 81% yield
when t-BuOK (2 mmol) and T-HYDRO (4 mmol) were used
(Table 1, entry 12). Whereas the use of 1 equivalent each of
t-BuOK and T-HYDRO gave the product 2a in only 46% yield,
it was obtained in 68% yield when one equivalent of t-BuOK
and 2 equivalents of T-HYDRO were used (entries 16 and
17). Also, when the reaction was conducted without base,
the product 2a was obtained in only 5% yield (entry 18).
Further, when the reaction was carried out without T-HY-
DRO or in the presence of O2, product 2a was not obtained
(entries 19 and 20). We found that the optimum result was
obtained when 4 equivalents of T-HYDRO (as the oxidant)
and 2 equivalents of t-BuOK (as the base) were used in
MeCN as the solvent (entry 12).
8
NaOH
Et3N
9
10
11
12
13
14
15
16g
17h
18
19
20
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
–
MeCN
PEG-400
toluene
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
t-BuOK
t-BuOK
NR
NR
O2
a All the reactions were carried out with N-phenylpyrrolidine (1) (1 mmol),
base (2 mmol), T-HYDRO (4 mmol) and nitromethane (0.5 mL) for 48
hours at 80 °C, unless otherwise noted.
b The products were characterized from their spectral data (IR, 1H NMR,
13C NMR and HRMS).
c Yield of isolated 2a. NR = no reaction.
d Reaction was carried out at r.t.
e Reaction was carried out at 80 °C for 12 h.
f Reaction was carried out at 80 °C for 24 h.
g Reaction was carried out using t-BuOK (1 mmol) and T-HYDRO (1 mmol).
h Reaction was carried out using t-BuOK (1 mmol) and T-HYDRO (2 mmol).
ent positions on the phenyl ring of N-phenylpyrrolidine re-
acted with nitromethane to give the corresponding β-ni-
troamines (2b–e) in 77–92% yields.
The halogen substituted N-arylpyrrolidines furnished
the products 2f–h (Figure 1) in 73–79% yields. However,
when N-phenylpiperidine and 1-(4-bromophenyl)piperi-
dine were subjected to the functionalization using nitro-
methane, lower yields of the corresponding products 2i
(32%) and 2j (17%) were obtained. The reactions using 2-
methyl-1-phenylpyrrolidine and 2-methyl-1-(p-tolyl)pyr-
We next examined the substrate scope of the nitroal-
kylation of cyclic tertiary amines under the optimum con-
ditions. Reactions of various substituted pyrrolidine and
piperidine derivatives with nitromethane gave the corre-
sponding β-nitroamines 2a–n in 17–92% yields under the
optimized reaction conditions (Figure 1). Substrates with
methyl, dimethyl and trifluoromethyl substituents at differ-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
G. A. Rao, M. Periasamy
Paper
Synthesis
corresponding nitrile products in 68–96% yields. Methyl, di-
methyl, and halogen substituents at different positions on
the phenyl ring of N-phenylpyrrolidines and piperidines
gave the corresponding α-aminonitriles 3a–o in 68–96%
yields. The reactions using 2-methyl-1-phenylpyrrolidine
and 2-methyl-1-(p-tolyl)pyrrolidine gave the correspond-
ing α-aminonitriles 3p and 3q in 79% and 77% yields, re-
spectively, but there was no selectivity. Also, 2-phenyl-
1,2,3,4-tetrahydroisoquinoline gave the corresponding cou-
pled product 3r in 92% yield.
NO2
NO2
NO2
NO2
NO2
N
N
N
N
N
CF3
2a
81%
2b
86%
2c
85%
2d
92%
2e
77%
NO2
NO2
NO2
NO2
NO2
N
N
N
N
N
n
n
t-BuOK, T-HYDRO
R1
R1
CN
R1 = H, Me, CH2OH
2 = Me, F, Cl, Br, CF3
n = 1, 2
Cl
F
Br
Br
2j
17%
N
N
TMSCN
2f
79%
2g
73%
2h
78%
2i
32%
MeCN
R
80 °C, 24 h
HO
NO2
NO2
NO2
R2
R2
N
N
N
4
3
N
CN
CN
CN
N
CN
CN
N
F
O2N
N
N
N
2k
2l
2m
2n
82%, 1:1.1 dr
78%, 1:1.3 dr
73%, 1:1.1 dr
91%
Figure 1 Synthesis of β-nitroamine derivatives using the T-HYDRO/t-
BuOK system in MeCN. The reactions were carried out with N-arylamine
(1 mmol), t-BuOK (0.22 g, 2 mmol), T-HYDRO (4 mmol) and nitrometh-
ane (0.5 mL) for 48 h at 80 °C. Yields are those of isolated products,
which were characterized from their spectral data (IR, 1H NMR, 13C NMR
and HRMS)
3a
3b
3c
3d
3e
89%
93%
96%
95%
86%
CN
N
CN
N
N
CN
N
CN
N
CN
rolidine gave the corresponding β-nitroamines 2k and 2l in
82% and 78% yields with no selectivity. We also examined
the reaction of chiral (1-phenylpyrrolidine-2-yl)methanol,
which gave the desired product 2m in 73% yield with no se-
lectivity. The activated tertiary amine 2-phenyl-1,2,3,4-
tetrahydroisoquinoline reacted with nitromethane to fur-
nish the product 2n in 91% yield.
We also observed that the iminium ion intermediate
formed in situ readily reacts with TMSCN to afford the cor-
responding nitrile in an experiment using T-HYDRO and
t-BuOK at 80 °C for 24 hours in MeCN as the solvent
(Scheme 3).
Br
3g
90%
Cl
3f
3h
3i
3j
89%
75%
78%
73%
N
CN
N
CN
N
CN
N
CN
N
CN
CF3
Br
3o
69%
F
3m
71%
Cl
3n
77%
3k
87%
3l
68%
CN
CN
N
N
N
CN
T-HYDRO (3 equiv)
CN
N
N
t-BuOK (1.5 equiv)
3p
3q
77%, 1:1 dr
3r
92%
79%, 1:1.1 dr
TMSCN, MeCN
80 °C, 24 h
Scheme 4 Synthesis of α-aminonitriles using the T-HYDRO/t-BuOK
system. The reactions were carried out with N-arylamine 3 (1 mmol),
t-BuOK (0.17 g, 1.5 mmol), T-HYDRO (0.41 mL, 3 mmol) and TMSCN
(0.19 mL, 1.5 mmol) in MeCN (5 mL) for 24 hours at 80 °C. Yields are
those of isolated products, which were characterized from their spec-
tral data (IR, 1H NMR, 13C NMR and HRMS)
1
3a
89%
Scheme 3 Reaction of N-phenylpyrrolidine (1) and TMSCN using
T-HYDRO and t-BuOK
Furthermore, we have investigated the scope of this re-
action and the results are summarized in Scheme 4. A vari-
ety of substituted N-aryl derivatives containing electron-
donating and other substituents were converted into the
A tentative mechanism (Scheme 5) may be considered
for the formation of β-nitroamines and α-aminonitriles.
The reaction may go through the iminium ion intermediate
6, formed by activation of tert-butyl hydroperoxide using
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
G. A. Rao, M. Periasamy
Paper
Synthesis
the base via the formation of amine radical cation 5 and a
tert-butoxy radical.13 The iminium ion would then undergo
a Mannich-type reaction with nitromethane/t-BuOK or
TMSCN/t-BuOK to provide β-nitroamines 2a and the 2-
cyano-substituted cyclic tertiary amines 3a.
2-(Nitromethyl)-1-phenylpyrrolidine (2a)
Yellow oil; yield: 0.17 g (81%).
IR (neat): 2966, 2914, 2838, 1593, 1541, 1498, 1358, 1260, 1173, 990,
743 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m, 2 H), 6.83–6.79 (m, 1 H),
6.73 (d, J = 8.0 Hz, 2 H), 4.66–4.63 (m, 1 H), 4.46–4.42 (m, 1 H), 4.24–
4.18 (m, 1 H), 3.54–3.49 (m, 1 H), 3.27–3.20 (m, 1 H), 2.17–2.07 (m, 4
H).
NO2
MeNO2
N
13C NMR (100 MHz, CDCl3): δ = 145.8, 130.0, 117.4, 112.0, 111.7, 75.8,
t-BuOK
57.4, 48.1, 29.3, 22.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H15N2O2: 207.1134; found:
207.1134.
2a
H
t-BuOOH/base
t-BuO
N
N
N
t-BuOH
2-(Nitromethyl)-1-(p-tolyl)pyrrolidine (2b)
Yellow oil; yield: 0.19 g (86%).
t-BuO
CN
TMSCN
+
N
6
1
5
OH
t-BuOK
IR (neat): 2946, 2896, 2841, 1611, 1541, 1503, 1361, 1228, 1155, 807
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.07 (m, 2 H), 6.71–6.59 (m, 2 H),
4.72–4.58 (m, 1 H), 4.53–4.48 (m, 1 H), 4.29–4.13 (m, 1 H), 3.53–3.48
(m, 1 H), 3.25–3.19 (m, 1 H), 2.31 (s, 3 H), 2.19–2.07 (m, 4 H).
3a
Scheme 5 A tentative mechanism and the possible intermediates for
the reaction of N-phenylpyrrolidine with T-HYDRO
13C NMR (100 MHz, CDCl3): δ = 143.7, 130.2, 126.5, 112.0, 76.0, 57.6,
48.3, 29.3, 22.9, 20.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H17N2O2: 221.1291; found:
221.1294.
In summary, we have described the t-BuOK-promoted
metal-free C–H functionalization of cyclic tertiary amines
using T-HYDRO as the oxidizing agent and nitromethane or
TMSCN as nucleophiles. This method is a simple alternative
to the pool of methods available for the synthesis of ni-
tromethyl and nitrile derivatives, and hence has significant
potential for further synthetic exploitation.
2-(Nitromethyl)-1-(m-tolyl)pyrrolidine (2c)
Yellow oil; yield: 0.19 g (85%).
IR (neat): 3041, 2964, 2921, 2855, 1600, 1545, 1490, 1364, 1210, 767,
734 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.23–7.19 (m, 1 H), 6.65 (d, J = 8.0 Hz, 1
H), 6.57–6.54 (m, 2 H), 4.67–4.65 (m, 1 H), 4.47–4.42 (m, 1 H), 4.24–
4.19 (m, 1 H), 3.54–3.49 (m, 1 H), 3.24–3.22 (m, 1 H), 2.38 (s, 3 H),
2.17–2.05 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 145.9, 139.5, 129.6, 118.3, 112.7,
109.2, 75.9, 57.4, 48.2, 29.3, 22.8, 21.9.
All chemicals were obtained from Aldrich or local manufacturers and
were used without any further purification. For TLC, HyChem, India
glass micro slides coated with silica gel GF254 (mesh size 75 μ) were
used and spots were made visual using iodine or a UV chamber as ap-
propriate. Column chromatography was performed using E-Merck sil-
ica gel (100–200 mesh size). Melting points were determined using a
Super fit capillary point apparatus. Infrared spectra were recorded
neat or as KBr pellets on a JASCO FT/IR spectrophotometer, Model
5300, or a SHIMADZU FT-IR spectrophotometer, Model 8300, with
polystyrene as the reference. 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded in CDCl3 using 5 mm tubes on a Bruker-
Avance 400 MHz NMR spectrometer with shifts referenced to SiMe4
(δ = 0). All J values are in Hz. HRMS were recorded using a Bruker
Maxis/HRMS (ESI-TOF analyzer) spectrometer. X-ray data (see Sup-
porting Information) were collected at 298 K on a Bruker diffractome-
ter using Mo-Kα (λ = 0.71073 Å) radiation.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H17N2O2: 221.1291; found:
221.1292.
1-(3,5-Dimethylphenyl)-2-(nitromethyl)pyrrolidine (2d)
Yellow oil; yield: 0.22 g (92%).
IR (neat): 3047, 2948, 2915, 2844, 1600, 1540, 1485, 1425, 1370,
1227, 1118, 811, 685 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.49 (s, 1 H), 6.36 (s, 2 H), 4.69–4.65
(m, 1 H), 4.45–4.42 (m, 1 H), 4.23–4.18 (m, 1 H), 3.52–3.48 (m, 1 H),
3.26–3.19 (m, 1 H), 2.33 (s, 6 H), 2.17–2.06 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 146.0, 139.4, 119.4, 109.9, 75.9, 57.4,
48.2, 29.2, 22.8, 21.8.
β-Nitroamines 2; General Procedure
N-Arylpyrrolidine and piperidine derivatives were prepared by a re-
cently reported method from our laboratory.12 A mixture of the aryl-
amine (1 mmol), T-HYDRO (0.55 mL, 4 mmol), t-BuOK (0.22 g, 2
mmol), and nitromethane (0.5 mL) in MeCN (5 mL) was stirred for 48
h at 80 °C. After completion of the reaction, the solvent was evaporat-
ed. EtOAc (10 mL) and H2O (5 mL) were added and the organic layer
was washed with brine (10 mL), dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by column chro-
matography [silica gel, EtOAc–hexane (5:100)] to afford the β-ni-
troamines 2a–n.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H19N2O2: 235.1447; found:
235.1444.
2-(Nitromethyl)-1-[3-(trifluoromethyl)phenyl]pyrrolidine (2e)
Yellow oil; yield: 0.21 g (77%).
IR (neat): 2975, 2921, 2849, 1605, 1545, 1501, 1452, 1370, 1162,
1118, 992, 778, 696 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
G. A. Rao, M. Periasamy
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.42–7.38 (m, 1 H), 7.05–7.03 (d, J = 7.6
Hz, 1 H), 6.89–6.88 (m, 2 H), 4.62–4.59 (m, 1 H), 4.50–4.46 (m, 1 H),
4.29–4.23 (m, 1 H), 3.58–3.53 (m, 1 H), 3.29–3.26 (m, 1 H), 2.22–2.13
(m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 149.3, 129.5, 120.5, 116.9, 73.2, 54.9,
44.6, 26.4, 25.0, 19.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H17N2O2: 221.1291; found:
221.1291.
13C NMR (100 MHz, CDCl3): δ = 145.9, 132.1, 131.8 (d, JC–F = 31.8 Hz),
130.1, 125.6, 122.9 (d, JC–F = 271.0 Hz), 114.9, 113.79, 113.75, 113.71,
113.67 (q, JC–F = 4.0 Hz), 108.48, 108.44, 108.40, 108.36 (q, JC–F = 4.0
Hz), 75.5, 57.4, 48.2, 29.4, 22.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H14F3N2O2: 275.1008;
found: 275.1006.
1-(4-Bromophenyl)-2-(nitromethyl)piperidine (2j)
Yellow oil; yield: 0.051 g (17%).
IR (neat): 3386, 3058, 2959, 2921, 2877, 1595, 1545, 1501, 1353,
1036, 751, 690 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.37 (m, 2 H), 6.89–6.85 (m, 2 H),
4.61–4.55 (m, 2 H), 4.51–4.45 (m, 1 H), 3.43–3.39 (m, 1 H), 2.95–2.88
(m, 1 H), 1.98–1.90 (m, 1 H), 1.86–1.74 (m, 3 H), 1.72–1.59 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 132.3, 118.3, 112.5, 73.2, 54.8,
44.2, 26.3, 24.7, 18.9.
1-(4-Fluorophenyl)-2-(nitromethyl)pyrrolidine (2f)
Yellow oil; yield: 0.18 g (79%).
IR (neat): 3052, 2964, 2910, 2849, 1605, 1540, 1507, 1386, 1227, 816,
795 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H16BrN2O2: 299.0396;
found: 299.0395.
1H NMR (400 MHz, CDCl3): δ = 7.04–7.00 (m, 2 H), 6.66–6.62 (m, 2 H),
4.62–4.58 (m, 1 H), 4.40–4.36 (m, 1 H), 4.25–4.20 (m, 1 H), 3.51–3.47
(m, 1 H), 3.23–3.17 (m, 1 H), 2.18–2.06 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 156.9, 154.5 (d, JC–F = 235.9 Hz), 142.5,
116.2, 116.0 (d, JC–F = 22.2 Hz), 112.6, 112.5 (d, JC–F = 7.3 Hz), 76.0, 57.9,
48.6, 29.5, 23.0, 14.2.
2-Methyl-5-(nitromethyl)-1-phenylpyrrolidine (2k)
Yellow oil; yield: 0.18 g (82%); 1:1.1 mixture of diastereomers.
IR (neat): 3071, 2960, 2914, 2869, 2223, 1596, 1551, 1505, 1348,
1222, 1157, 1035, 747, 692 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H14FN2O2: 225.1040;
found: 225.1036.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.28 (m, 4 H), 6.84–6.79 (m, 2 H),
6.77–6.73 (m, 5 H), 4.77–4.73 (m, 1 H), 4.68–4.64 (m, 1 H), 4.56–4.51
(m, 1 H), 4.44–4.38 (m, 1 H), 4.31–4.26 (m, 1 H), 4.14–4.07 (m, 2 H),
3.92–3.85 (m, 1 H), 2.36–2.11 (m, 5 H), 2.09–2.04 (m, 2 H), 1.84–1.74
(m, 2 H), 1.31 (d, J = 6.0 Hz, 3 H), 1.16 (d, J = 6.0 Hz, 3 H).
1-(4-Chlorophenyl)-2-(nitromethyl)pyrrolidine (2g)
White solid; yield: 0.18 g (73%); mp 45–47 °C.
IR (KBr): 2959, 2921, 2882, 2844, 1595, 1551, 1501, 1364, 1189, 1101,
13C NMR (100 MHz, CDCl3): δ = 146.1, 143.5, 129.7, 129.6, 129.2,
117.6, 117.0, 116.5, 115.1, 113.5, 112.4, 111.8, 77.9, 74.8, 59.8, 56.6,
53.6, 53.0, 32.1, 29.8, 28.6, 21.7, 18.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H17N2O2: 221.1291; found:
221.1286.
811, 729 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 9.2 Hz, 2 H), 6.63 (d, J = 8.8
Hz, 2 H), 4.61–4.57 (m, 1 H), 4.41–4.38 (m, 1 H), 4.25–4.19 (m, 1 H),
3.51–3.47 (m, 1 H), 3.24–3.18 (m, 1 H), 2.20–2.06 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 144.4, 129.5, 122.2, 113.1, 75.7, 57.5,
48.3, 29.4, 22.9.
2-Methyl-5-(nitromethyl)-1-(p-tolyl)pyrrolidine (2l)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H14ClN2O2: 241.0745;
Yellow oil; yield: 0.18 g (78%); 1:1.3 mixture of diastereomers
found: 241.0742.
IR (neat): 3020, 2970, 2924, 2869, 2227, 1616, 1455, 1343, 1157,
1020, 808, 737 cm–1
.
1-(4-Bromophenyl)-2-(nitromethyl)pyrrolidine (2h)
Brown solid; yield: 0.22 g (78%); mp 61–63 °C.
1H NMR (400 MHz, CDCl3): δ = 7.12 (d, J = 8.0 Hz, 4 H), 6.69–6.64 (m, 4
H), 4.75–4.71 (m, 1 H), 4.66–4.63 (m, 1 H), 4.52–4.48 (m, 1 H), 4.39–
4.33 (m, 1 H), 4.30–4.25 (m, 1 H), 4.11–4.05 (m, 2 H), 3.87–3.79 (m, 1
H), 2.33–2.09 (m, 12 H), 2.06–2.02 (m, 2 H), 1.82–1.71 (m, 2 H), 1.29
(d, J = 6.0 Hz, 4 H), 1.14 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.0, 141.3, 130.2, 130.0, 129.6,
127.0, 126.1, 125.6, 121.4, 113.6, 112.6, 107.8, 78.1, 74.9, 60.1, 56.7,
56.0, 53.0, 32.1, 29.9, 28.5, 26.8, 21.8, 20.3, 20.2, 18.0.
IR (KBr): 3041, 2970, 2910, 2849, 1595, 1545, 1490, 1359, 1184, 805,
734 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 9.2 Hz, 2 H), 6.58 (d, J = 8.8
Hz, 2 H), 4.60–4.56 (m, 1 H), 4.40–4.37 (m, 1 H), 4.24–4.19 (m, 1 H),
3.50–3.45 (m, 1 H), 3.24–3.16 (m, 1 H), 2.19–2.08 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 144.8, 132.3, 113.6, 109.3, 75.6, 57.5,
48.3, 29.4, 22.8.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H18N2O2Na: 257.1265;
found: 257.1267.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H13BrN2O2Na: 307.0057;
found: 307.0061.
[5-(Nitromethyl)-1-phenylpyrrolidin-2-yl]methanol (2m)
Yellow oil; yield: 0.17 g (73%); 1:1.1 mixture of diastereomers.
IR (neat): 3386, 3058, 2959, 2921, 2877, 1595, 1545, 1501, 1353,
2-(Nitromethyl)-1-phenylpiperidine (2i)
Yellow oil; yield: 0.07 g (32%).
1036, 751, 690 cm–1
.
IR (neat): 3058, 3041, 2970, 2915, 2844, 1595, 1545, 1501, 1359,
1184, 997, 751, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.27 (m, 3 H), 6.86–6.78 (m, 5 H),
4.68–4.56 (m, 2 H), 4.48–4.39 (m, 2 H), 4.15–4.05 (m, 1 H), 3.98–3.95
(m, 2 H), 3.82–3.77 (m, 1 H), 3.69–3.61 (m, 2 H), 3.55–3.51 (m, 1 H),
2.51 (s, 2 H), 2.35–2.25 (m, 1 H), 2.19–2.10 (m, 4 H), 2.05–1.97 (m, 2
H).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.29 (m, 2 H), 7.02–7.00 (m, 2 H),
6.94–6.90 (m, 1 H), 4.62–4.57 (m, 2 H), 4.51–4.46 (m, 1 H), 3.46–3.43
(m, 1 H), 2.96–2.89 (m, 1 H), 1.99–1.92 (m, 1 H), 1.86–1.64 (m, 5 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
G. A. Rao, M. Periasamy
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 146.5, 143.4, 129.9, 129.6, 118.3,
117.7, 113.9, 112.7, 77.9, 77.5, 77.2, 76.9, 74.5, 62.4, 61.8, 61.5, 60.1,
58.6, 57.1, 28.6, 27.2, 26.4, 26.1.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.21 (m, 1 H), 6.72 (d, J = 7.6 Hz, 1
H), 6.56 (s, 2 H), 4.48–4.46 (m, 1 H), 3.52–3.48 (m, 1 H), 3.43–3.37 (m,
1 H), 2.46–2.44 (m, 1 H), 2.41 (s, 3 H), 2.36–2.22 (m, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H17N2O3: 237.1240; found:
13C NMR (100 MHz, CDCl3): δ = 145.4, 139.3, 129.4, 119.4, 119.2,
237.1243.
113.5, 110.0, 49.1, 47.5, 31.6, 24.1, 21.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H15N2: 187.1236; found:
187.1230.
1-(Nitromethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (2n)
Brown solid; yield: 0.24 g (91%); mp 92–94 °C.
1-(3,5-Dimethylphenyl)pyrrolidine-2-carbonitrile (3d)
Colorless liquid; yield: 0.19 g (95%).
IR (KBr): 3063, 3030, 2964, 2915, 1605, 1545, 1496, 1380, 1003, 899,
756 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.18 (m, 5 H), 7.13 (d, J = 6.8 Hz, 1
H), 6.98 (d, J = 8.0 Hz, 2 H), 6.85 (t, J = 7.2 Hz, 1 H), 5.55 (t, J = 7.0 Hz, 1
H), 4.95–4.85 (m, 1 H), 4.59–4.54 (m, 1 H), 3.79–3.59 (m, 2 H), 3.21–
3.05 (m, 1 H), 2.87–2.78 (m, 1 H).
IR (neat): 3041, 2975, 2921, 2855, 2230, 1605, 1479, 1381, 1222,
1184, 1036, 822, 685 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.55 (s, 1 H), 6.38 (s, 2 H), 4.46 (d, J =
6.0 Hz, 1 H), 3.51–3.46 (m, 1 H), 3.41–3.38 (m, 1 H), 2.44–2.42 (m, 1
H), 2.36 (s, 6 H), 2.31–2.20 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.5, 135.3, 133.0, 130.0, 129.2,
128.2, 127.0, 126.7, 119.5, 115.2, 78.8, 58.2, 42.1, 26.5.
13C NMR (100 MHz, CDCl3): δ = 145.5, 139.1, 120.3, 119.5, 110.8, 49.2,
47.5, 31.6, 24.0, 21.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H17N2: 201.1392; found:
α-Aminonitriles 3; General Procedure
A mixture of the arylamine (1 mmol), T-HYDRO (0.41 mL, 3 mmol), t-
BuOK (0.17 g, 1.5 mmol), and TMSCN (0.19 mL, 1.5 mmol) in MeCN (5
mL) was stirred for 24 h at 80 °C. After completion of the reaction, the
solvent was evaporated. EtOAc (10 mL) and H2O (5 mL) were added
and the organic layer was washed with brine (10 mL), dried over an-
hydrous sodium sulfate, filtered and concentrated. The residue was
purified by column chromatography [silica gel, EtOAc–hexane
(7:100)] to afford the α-aminonitriles 3a–r.
201.1390.
1-(4-Fluorophenyl)pyrrolidine-2-carbonitrile (3e)
Colorless liquid; yield: 0.16 g (86%).
IR (neat): 3058, 2975, 2937, 2871, 2225, 1611, 1512, 1463, 1364,
1222, 1162, 964, 816 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.05–7.01 (m, 2 H), 6.66–6.63 (m, 2 H),
4.41–4.39 (m, 1 H), 3.43–3.34 (m, 2 H), 2.42–2.26 (m, 4 H).
1-Phenylpyrrolidine-2-carbonitrile (3a)
13C NMR (100 MHz, CDCl3): δ = 157.4, 155.0 (d, JC–F = 236.6 Hz),
141.91, 141.90 (d, JC–F = 1.4 Hz), 119.2, 116.0, 115.8 (d, JC–F = 22.7 Hz),
113.7, 113.6 (d, JC–F = 7.4 Hz), 49.6, 47.9, 31.5, 24.0.
Colorless liquid; yield: 0.15 g (89%).
IR (neat): 3044, 2951, 2874, 2853, 2227, 1596, 1501, 1359, 1186,
1158, 993 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H12FN2: 191.0985; found:
1H NMR (400 MHz, CDCl3): δ = 7.35 (t, J = 8.0 Hz, 2 H), 6.88 (t, J = 7.4
Hz, 1 H), 6.74 (d, J = 8.4 Hz, 2 H), 4.48–4.46 (m, 1 H), 3.52–3.48 (m, 1
H), 3.43–3.38 (m, 1 H), 2.48–2.41 (m, 1 H), 2.36–2.19 (m, 3 H).
191.0981.
1-(4-Chlorophenyl)pyrrolidine-2-carbonitrile (3f)
White solid; yield: 0.18 g (89%); mp 78–80 °C.
13C NMR (100 MHz, CDCl3): δ = 145.3, 129.5, 119.3, 118.3, 112.8, 49.1,
47.5, 31.6, 24.0.
IR (KBr): 2981, 2948, 2932, 2860, 2205, 1600, 1496, 1364, 1189, 1151,
1096, 970, 811, 718 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H13N2: 173.1079; found:
1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.8 Hz, 2 H), 6.63 (d, J = 8.8
Hz, 2 H), 4.43–4.41 (m, 1 H), 3.47–3.34 (m, 2 H), 2.48–2.43 (m, 1 H),
2.41–2.21 (m, 3 H).
173.1071.
1-(p-Tolyl)pyrrolidine-2-carbonitrile (3b)
13C NMR (100 MHz, CDCl3): δ = 143.8, 129.3, 123.3, 118.9, 113.9, 49.2,
Colorless liquid; yield: 0.17 g (93%).
47.7, 31.6, 24.1.
IR (neat): 3036, 2926, 2855, 2207, 1616, 1518, 1463, 1364, 1184, 910,
800, 734 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H12ClN2: 207.0690; found:
1H NMR (400 MHz, CDCl3): δ = 7.14–7.12 (m, 2 H), 6.65–6.63 (m, 2 H),
4.45–4.43 (m, 1 H), 3.47–3.35 (m, 2 H), 2.46–2.39 (m, 1 H), 2.32–2.25
(m, 4 H), 2.24–2.19 (m, 2 H).
207.0681.
1-(4-Bromophenyl)pyrrolidine-2-carbonitrile (3g)
13C NMR (100 MHz, CDCl3): δ = 143.1, 130.1, 127.5, 119.4, 112.8, 49.4,
Light brown solid; yield: 0.23 g (90%); mp 75–77 °C.
IR (KBr): 2974, 2861, 2234, 1594, 1492, 1359, 1186, 909, 805, 730 cm–1
.
47.6, 31.5, 23.9, 20.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H14N2Na: 209.1054;
found: 209.1053.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.38 (m, 2 H), 6.61–6.57 (m, 2 H),
4.42–4.41 (m, 1 H), 3.47–3.33 (m, 2 H), 2.48–2.40 (m, 1 H), 2.38–2.21
(m, 3 H).
1-(m-Tolyl)pyrrolidine-2-carbonitrile (3c)
13C NMR (100 MHz, CDCl3): δ = 144.2, 132.2, 118.9, 114.4, 110.4, 49.1,
Colorless liquid; yield: 0.18 g (96%).
47.7, 31.6, 24.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H12BrN2: 251.0185; found:
251.0187.
IR (neat): 3037, 2919, 2859, 2239, 1603, 1582, 1495, 1455, 1359,
1178, 1023, 837, 767 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
G. A. Rao, M. Periasamy
Paper
Synthesis
1-Phenylpiperidine-2-carbonitrile (3h)
13C NMR (100 MHz, CDCl3): δ = 150.1, 131.9, 131.6, 130.1, 120.9,
118.53, 118.50 (d, JC–F = 3.6 Hz), 116.8, 114.9, 114.86 (d, JC–F = 4.0 Hz),
51.5, 46.4, 29.1, 25.1, 20.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H13F3N2Na: 277.0928;
found: 277.0921.
Colorless liquid; yield: 0.14 g (75%).
IR (neat): 3063, 2942, 2860, 2816, 2225, 1595, 1490, 1447, 1375,
1244, 1162, 1025, 915, 855, 762, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.33 (m, 2 H), 7.05–7.01 (m, 3 H),
4.66 (s, 1 H), 3.48 (d, J = 12.0 Hz, 1 H), 3.11–3.04 (m, 1 H), 2.09–2.00
(m, 2 H), 1.90–1.88 (m, 2 H), 1.75–1.70 (m, 2 H).
1-(4-Fluorophenyl)piperidine-2-carbonitrile (3m)
White solid; yield: 0.15 g (71%); mp 98–100 °C.
13C NMR (100 MHz, CDCl3): δ = 149.8, 129.4, 122.2, 118.3, 117.2, 52.0,
IR (KBr): 3081, 2945, 2929, 2859, 2227, 1505, 1434, 1343, 1207, 1121,
46.6, 29.3, 25.2, 20.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H15N2: 187.1236; found:
187.1231.
1030, 924, 828, 727 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.05–6.98 (m, 4 H), 4.52 (s, 1 H), 3.32–
3.29 (m, 1 H), 3.07–3.00 (m, 1 H), 2.05–2.01 (m, 2 H), 1.88–1.86 (m, 2
H), 1.75–1.67 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 157.3 (d, JC–F = 241.8 Hz), 146.3,
120.6, 120.5 (d, JC–F = 8.0 Hz), 117.0, 116.1, 115.8 (d, JC–F = 22.3 Hz),
53.3, 47.1, 29.3, 25.1, 20.1.
1-(p-Tolyl)piperidine-2-carbonitrile (3i)
Colorless liquid; yield: 0.16 g (78%).
IR (neat): 3025, 2939, 2854, 2818, 2224, 1616, 1515, 1444, 1374,
1303, 1247, 1167, 914, 813 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H14FN2: 205.1142; found:
205.1141.
1H NMR (400 MHz, CDCl3): δ = 7.17–7.15 (m, 2 H), 6.98–6.94 (m, 2 H),
4.60 (s, 1 H), 3.42–3.34 (m, 1 H), 3.08–3.03 (m, 1 H), 2.34 (s, 3 H),
2.07–2.01 (m, 2 H), 1.88–1.87 (m, 2 H), 1.78–1.70 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 147.6, 131.8, 130.1, 119.1, 118.6,
117.3, 52.7, 46.2, 29.3, 25.2, 20.6, 20.2.
1-(4-Chlorophenyl)piperidine-2-carbonitrile (3n)
White solid; yield: 0.17 g (77%); mp112–114 °C.
IR (KBr): 2970, 2950, 2854, 2808, 2231, 1596, 1485, 1384, 1308, 1242,
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H17N2: 201.1392; found:
201.1383.
1217, 1116, 914, 833, 752 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.27 (m, 2 H), 6.96–6.94 (m, 2 H),
4.59 (s, 1 H), 3.42–3.39 (m, 1 H), 3.04–2.98 (m, 1 H), 2.07–1.97 (m, 2
H), 1.89–1.86 (m, 2 H), 1.75–1.67 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 145.6, 126.5, 124.4, 116.8, 114.1, 49.2,
43.8, 26.3, 22.2, 17.2.
1-(m-Tolyl)piperidine-2-carbonitrile (3j)
Colorless liquid; yield: 0.15 g (73%).
IR (neat): 2955, 2914, 2855, 2236, 1601, 1581, 1500, 1439, 1253,
1157, 949, 773 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H13ClN2Na: 243.0664;
found: 243.0658.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.21 (m, 1 H), 6.83 (d, J = 6.4 Hz, 3
H), 4.65 (s, 1 H), 3.46 (d, J = 12.4 Hz, 1 H), 3.07–3.01 (m, 1 H), 2.36 (s, 3
H), 2.08–1.97 (m, 2 H), 1.89–1.86 (m, 2 H), 1.75–1.68 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 149.8, 139.1, 129.2, 123.0, 119.1,
117.2, 115.4, 52.1, 46.6, 29.3, 25.2, 21.7, 20.2.
1-(4-Bromophenyl)piperidine-2-carbonitrile (3o)
White solid; yield: 0.18 g (69%); mp 109–111 °C.
IR (KBr): 2950, 2919, 2854, 2227, 1591, 1485, 1434, 1404, 1298, 1237,
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H17N2: 201.1392; found:
201.1394.
1126, 995, 813, 798, 742 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.42 (m, 2 H), 6.92–6.89 (m, 2 H),
4.61 (s, 1 H), 3.43–3.40 (m, 1 H), 3.05–2.99 (m, 1 H), 2.09–1.98 (m, 2
H), 1.89–1.86 (m, 2 H), 1.73–1.68 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.9, 132.3, 120.1, 116.9, 114.8, 51.8,
46.6, 29.1, 25.0, 20.0.
1-(3,5-Dimethylphenyl)piperidine-2-carbonitrile (3k)
Colorless liquid; yield: 0.19 g (87%).
IR (neat): 2955, 2919, 2864, 2823, 2228, 1591, 1455, 1374, 1232,
1162, 1070, 955, 919, 843, 737 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H14BrN2: 265.0341; found:
265.0337.
1H NMR (400 MHz, CDCl3): δ = 6.67 (d, J = 8.0 Hz, 3 H), 4.65 (s, 1 H),
3.46 (d, J = 12.0 Hz, 1 H), 3.04 (t, J = 11.7 Hz, 1 H), 2.33 (s, 6 H), 2.08–
1.98 (m, 2 H), 1.89–1.82 (m, 2 H), 1.76–1.68 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 149.9, 138.9, 124.0, 117.3, 116.2, 52.2,
46.6, 29.3, 25.2, 21.6, 20.3.
5-Methyl-1-phenylpyrrolidine-2-carbonitrile (3p)
Colorless liquid; yield: 0.15 g (79%); 1:1.1 mixture of diastereomers.
IR (neat): 3061, 3040, 2970, 2929, 2874, 2232, 1596, 1505, 1465,
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H19N2: 215.1549; found:
215.1548.
1343, 1192, 1040, 747, 692 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.31 (m, 4 H), 6.88–6.83 (m, 2 H),
6.78–6.72 (m, 4 H), 4.57 (d, J = 6.8 Hz, 1 H), 4.39–4.36 (m, 1 H), 4.11–
3.97 (m, 2 H), 2.31–2.26 (m, 6 H), 2.01–1.93 (m, 1 H), 1.91–1.87 (m, 1
H), 1.37 (d, J = 6.4 Hz, 3 H), 1.22 (d, J = 6.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 143.8, 129.5, 129.4, 120.4,
119.0, 118.2, 118.1, 113.5, 113.3, 54.6, 53.4, 50.5, 49.4, 32.7, 31.5,
30.2, 29.2, 19.8, 19.3.
1-[3-(Trifluoromethyl)phenyl]piperidine-2-carbonitrile (3l)
Colorless liquid; yield: 0.17 g (68%).
IR (neat): 2955, 2859, 2823, 2231, 1616, 1586, 1495, 1455, 1354,
1167, 1121, 939, 793, 692 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44 (t, J = 7.7 Hz, 1 H), 7.29–7.18 (m, 3
H), 4.70 (s, 1 H), 3.52 (d, J = 10.8 Hz, 1 H), 3.12–3.06 (m, 1 H), 2.12–
2.01 (m, 2 H), 1.93–1.89 (m, 2 H), 1.81–1.68 (m, 2 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H15N2: 187.1236; found:
187.1230.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
G. A. Rao, M. Periasamy
Paper
Synthesis
5-Methyl-1-(p-tolyl)pyrrolidine-2-carbonitrile (3q)
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Org. Biomol. Chem. 2014, 12, 3123.
Colorless liquid; yield: 0.15 g (77%); 1:1 mixture of diastereomers.
IR (neat): 3035, 2970, 2919, 2869, 2229, 1621, 1571, 1515, 1455,
1348, 1157, 1020, 919, 803, 727 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 8.2 Hz, 4 H), 6.75–6.68 (m, 4
H), 4.57–4.56 (m, 1 H), 4.36–4.34 (m, 1 H), 4.07–3.97 (m, 2 H), 2.47–
2.39 (m, 4 H), 2.35 (s, 6 H), 2.34–2.27 (m, 2 H), 2.01–1.92 (m, 1 H),
1.89–1.86 (m, 1 H), 1.39–1.37 (m, 3 H), 1.25–1.23 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 142.9, 141.7, 130.1, 130.0, 127.4,
127.3, 120.7, 119.2, 113.8, 113.4, 54.8, 53.5, 50.8, 49.9, 32.8, 31.5,
30.2, 29.2, 20.4, 19.8, 19.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H17N2: 201.1392; found:
201.1384.
2-Phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (3r)
Pale yellow solid; 0.23 g (92%); mp 94–96 °C.
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2005, 70, 5420. (c) Periasamy, M.; Kishorebabu, S. N.;
Jayakumar, K. N. Tetrahedron Lett. 2003, 44, 8939.
IR (KBr): 3041, 2926, 2838, 1742, 1600, 1496, 1463, 1375, 1205, 1145,
1030, 942, 745, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.38 (m, 2 H), 7.35–7.26 (m, 4 H),
7.13 (d, J = 8.0 Hz, 2 H), 7.06 (t, J = 7.4 Hz, 1 H), 5.55 (s, 1 H), 3.83–3.78
(m, 1 H), 3.55–3.48 (m, 1 H), 3.23–3.14 (m, 1 H), 3.02–2.96 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 134.7, 129.6, 129.4, 128.8,
127.1, 126.9, 121.9, 117.8, 117.6, 53.2, 44.2, 28.6.
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X.-Z.; Yang, Y.-F.; Xia, X.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M. Org.
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Commun. 2011, 47, 2354. (f) Sakai, N.; Mutsuro, A.; Ikeda, R.;
Konakahara, T. Synlett 2013, 24, 1283. (g) Alagiri, K.; Kumara, G.
S. R.; Prabhu, K. R. Chem. Commun. 2011, 47, 11787.
(h) Ratnikov, M. O.; Xu, X.; Doyle, M. P. J. Am. Chem. Soc. 2013,
135, 9475.
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Lett. 2013, 15, 1092. (b) Nobuta, T.; Tada, N.; Fujiya, A.; Kariya,
A.; Miura, T.; Itoh, A. Org. Lett. 2013, 15, 574. (c) Hari, D. P.;
König, B. Org. Lett. 2011, 13, 3852. (d) Liu, L.; Wang, Z.; Fu, X.;
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Y.; Bao, X.; Wan, X. Chem. Eur. J. 2013, 19, 17917. (f) Shen, H.;
Zhang, X.; Liu, Q.; Pan, J.; Hu, W.; Xiong, Y.; Zhu, X. Tetrahedron
Lett. 2015, 56, 5628.
Funding Information
We are thankful to the SERB-DST, New Delhi for support (SB/S5/GC-
01/2014) to M.P. and for the DST support to the School of Chemistry
under the FIST and IRPHA programs. Support from CSIR-HRDG (No:
02/0176/14/EMR-II) to M.P. and from the UGC under the UPE and CAS
programs is also gratefully acknowledged. G.A.R. is grateful to the
UGC (New Delhi) for a fellowship.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590943.
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(11) (a) Neumann, M.; Zeitler, K. Org. Lett. 2012, 14, 2658. (b) Rusch,
F.; Unkel, L.-N.; Alpers, D.; Hoffmann, F.; Brasholz, M. Chem. Eur.
J. 2015, 21, 8336. (c) Prier, C. K.; MacMillan, D. W. C. Chem. Sci.
2014, 5, 4173.
(12) Rao, G. A.; Periasamy, M. Synlett 2015, 26, 2231.
(13) De La Mare, H. E. J. Org. Chem. 1960, 25, 2114.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H