Synthesis of α-aminonitriles via a FeSO4-mediated oxidative cyanation of tertiary amines with benzoyl cyanide and molecular oxygen or TBHP

Article abstract of DOI:10.1016/j.tet.2016.03.061

An iron-mediated oxidative cyanation of tertiary amines with benzoyl cyanide and molecular oxygen or TBHP has been achieved. This reaction furnished α-cyanated tertiary amines under mild reaction conditions in good to excellent yields (up to 94%) with gre

Full text of DOI:10.1016/j.tet.2016.03.061

Accepted Manuscript
Synthesis of α-Aminonitriles via a FeSO -Mediated Oxidative Cyanation of Tertiary
4
Amines with Benzoyl Cyanide and Molecular Oxygen or TBHP
Lianpeng Zhang, Xin Gu, Ping Lu, Yanguang Wang
PII:
S0040-4020(16)30190-9
10.1016/j.tet.2016.03.061
TET 27601
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 January 2016
Revised Date: 15 March 2016
Accepted Date: 17 March 2016
Please cite this article as: Zhang L, Gu X, Lu P, Wang Y, Synthesis of α-Aminonitriles via a FeSO -
4
Mediated Oxidative Cyanation of Tertiary Amines with Benzoyl Cyanide and Molecular Oxygen or TBHP,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.061.
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Synthesis of α-Aminonitriles via a FeSO4-
Mediated Oxidative Cyanation of Tertiary
Amines with Benzoyl Cyanide and
Molecular Oxygen or TBHP
Leave this area blank for abstract info.
Lianpeng Zhang, Xin Gu, Ping Lu*, and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China. pinglu@zju.edu.cn;
orgwyg@zju.edu.cn

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of α-Aminonitriles via a FeSO4-Mediated Oxidative Cyanation of Tertiary
Amines with Benzoyl Cyanide and Molecular Oxygen or TBHP
Lianpeng Zhang, Xin Gu, Ping Lu and Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An iron-mediated oxidative cyanation of tertiary amines with benzoyl cyanide and molecular
oxygen or TBHP has been achieved. This reaction furnished α-cyanated tertiary amines under
mild reaction conditions in good to excellent yields (up to 94%) with great diversity (19
examples). The cascade process involves an iron-catalyzed oxidation of tertiary amine. Our
protocol features safety cyanation reagent, acid-free conditions, inexpensive iron catalyst, and
aerobic oxidation.
Available online
Keywords:
iron catalysis
cyanation
2009 Elsevier Ltd. All rights reserved
.
oxidation
benzoyl cyanide
α-aminonitriles
lactam for the synthesis of fourth-generation antibiotics,16,17
Murahashi pioneered the development of RuCl3-catalyzed
oxidative cyanation of tertiary amines with sodium cyanides
using O2 or H2O2 in acid environment.18-20 Meanwhile, Li and co-
workers developed the CuBr-catalyzed cross-dehydrogenative
coupling between tetrahydroisoquinoline and manolonitrile in the
presence of TBHP under acid-free condition, which produced the
cyanated product in 36% yield.21 Afterwards, in order to have
high efficiency, high yield, and safe operation, several catalyst
systems based on various transition metals were disclosed,
including V2O5,22 FeCl2,23 polymer supported iron(II)
phthalocyanines,24 iron oligopyridine complexes,25 gold-
complex,26 and rhenium-complex.27 However, these transition
metal-catalyzed reactions all lead to by-product formation.
Taking N,N-dimethylaniline as an example, its oxidation could
produce N-methylformanilide15 and N-methylaniline,25,28 both of
them derived from the oxidation of tertiary amine.
1. Introduction
α-Aminonitriles are important building blocks in organic
synthesis because they can be readily converted into various
compounds with multifunctionalities, including α-amino acids
and 1,2-diamines. Preparation of α-aminonitriles by traditional
Streck reaction,1,2 a three-component reaction from carbonyl,
amine, and cyanide, has been well documented. Alternative
approach using α-cyanation of tertiary amines attracted much
attention since the late 1960s by using anodic oxidation of amine
to iminium and a sequential nucleophilic trap by Et4NCN3 or
NaCN.4 Since then, several chemical oxidation methods were
reported in the literature, such as chorine dioxide,5 hypervalent
iodine,6,7 and molecular iodine as well.8 By using visible-light,
photo-catalyzed oxidative cyanation of tertiary amines has
recently been realized with low organic dye loading.9-12 Beyond
electro-oxidation,
chem-oxidation,
and
photo-oxidation,
transition metal catalyzed oxidative cyanation of tertiary amines
becomes unique due to several advantages, such as controllable
reaction conditions, high catalytic efficiencies, simple facilities,
operational safety, and environmental benignity.13,14 In this
blooming field, several research groups made great contributions.
In 1993, Miura and co-workers reported a preliminary work
using FeCl3 as the catalyst and molecular oxygen as oxidant.15
However, only five 4-substituted N,N-dimethylanilines were
presented as starting materials, all of which contaminated with N-
methylformanilides in approximate 2:1 ratio. Keeping up with
In this paper, we would like to report an iron-mediated
oxidative cyanation of tertiary amines with benzoyl cyanide
using molecular oxygen or TBHP as oxidant. The reaction
furnished α-cyanated tertiary amines under mild reaction
conditions in good to excellent yields.
2. Results and discussion
Attracted by the thriving chemistry of transition metal-catalyzed
oxidative cyanation of tertiary amine13 and our previous work on
benzyl cyanide as the safe cyanating reagent,29,31 we primarily
the successful example of ruthenium-catalyzed oxidation of β-
———
Corresponding authors. Tel./fax: +86 571-87952543; e-mail addresses: pinglu@zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. G. Wang).

2
Tetrahedron
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designed the oxidative cyanation reaction of N,N-
found that the reaction largely depended upon the solvents and
dimethylaniline (1a) using the combination of “CuBr + t-BuOOH
TBHP) + PhCH2CN”.21 To our disappointment, no satisfied
results were obtained from benzyl cyanide. By altering benzyl
cyanide to benzoyl cyanide,32 the yields changed drastically. The
reaction of benzoyl cyanide with 1a in the presence of CuI and
TBHP provided the desired cyanated product 2a in 36% yield
(Table 1, entry 1), while Cu(OAc)2 and Pd(OAc)2 gave 2a in
10% and 62% yields, respectively (Table 1, entries 2 and 3).
oxidants. When 1,4-dioxane, dichloromethane, tetrahydrofuan or
toluene was used as solvent, on reaction was observed. DMSO
(Table 1, entry 20), acetonitrile (Table 1, entry 21) and ethanol
(Table 1, entry 22) provided 2a in 75%, 55% and 36% yields,
respectively. DMF (Table 1, entry 23) and isopropanol (Table 1,
entry 24) did not work. Without TBHP, the reaction could be
carried out under air, but presented poor yield (Table 1, entry 25).
Slightly improved yields were obtained when hydrogen peroxide
(Table 1, entry 26) or benzoyl peroxide (Table 1, entry 27) was
used as oxidant. The situation changed when molecular oxygen
was used. By screening other conditions under O2 (Table 1,
entries 29-31), the optimal reaction conditions were established.
When the mixture of 1a (0.5 mmol), PhCOCN (0.6 mmol), and
(5 mol % FeSO4•7H2O) in methanol (2.0 mL) reacted under O2 at
room temperature for 16 hours, 2a was prepared in 91% isolated
yield (Table 1, entry 29).
By changing the catalyst to various iron catalysts, FeSO4•7H2O
was found to be optimal in comparison with FeCl3, FeCl3•7H2O,
FeCl2, Fe2O3, Fe(NO3)3•9H2O, and Fe2(SO4)3 (Table 1, entries 4-
10). Yield of 2a increased to 84% (Table 1, entry 7). Optimal
amounts of FeSO4•7H2O, TBHP, and PhCOCN were found to be
0.05, 1.5, and 1.2 equivalents, respectively (Table 1, entries 11-
17). The suitable reaction temperature was determined to be at
room temperature (Table 1, entries 14, 18 and 19). It was also
Table 1
Optimization of the reaction conditionsa
Entry
1
2
3
4
5
6
7
8
Catalyst (equiv)
CuI (0.1)
Cu(OAc)2 (0.1)
Pd(OAc)2 (0.1)
FeCl3 (0.1)
FeCl3•7H2O (0.1)
FeCl2 (0.1)
FeSO4•7H2O (0.1)
Fe2O3 (0.1)
Fe(NO3)3•9H2O (0.1)
Fe2(SO4)3 (0.1)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.15)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.1)
FeSO4•7H2O (0.1)
FeSO4•7H2O (0.1)
FeSO4•7H2O (0.1)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
FeSO4•7H2O (0.05)
Oxidant (equiv)
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (2.5) / air
TBHP (1.0) / air
TBHP (1.5) / air
TBHP (2.0) / air
TBHP (1.5) / air
TBHP (1.5) / air
TBHP (1.5) / air
TBHP (1.5) / air
TBHP (1.5) / air
TBHP (1.5) / air
TBHP (1.5) / air
TBHP (1.5) / air
TBHP (1.5) / air
air
PhCOCN (equiv)
Solvent
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
DMSO
CH3CN
EtOH
Yield (%)b
36
10
62
63
52
69
84
35
30
65
86
82
83
88
86
75
88
38c
85d
75
55
36
0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
DMF
i-PrOH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
0
9
H2O2 (2.5) / air
(PhCOO)2 (2.5) / air
O2
O2
O2
15
12
91
91
91d
45c
O2
a
Reaction conditions: 1a (0.5 mmol), solvent (2 mL), room temperature, 16 h.
b Isolated yield.
c 0 oC.
d 50 oC.
With the optimal reaction conditions in our hand, we
investigated the substrate diversity and the results are
summarized in Table 2. It was found that reaction heavily relied
on the substrate structure. We thereby used the TLC to track each
reaction. Under the same conditions, 2b and 2c were obtained in
94% and 85% yields. With the methyl group occupied on the
ortho position of N,N-dimethylaniline, 2d was obtained in 83%
yield by raising the reaction temperature to reflux. With
bromomine atom occupied on the para-position of N,N-
dimethylaniline, 2e was obtained in 78% yield. For 4-chloro-
N,N-dimethylaniline, the cyanated product 2f was obtained in
50% yield when the reaction was carried out under O2. An
improved yield (65%) of 2f was obtained when the reaction was
performed using TBHP as oxidant. With fluorine atom occupied
on the para-position of N,N-dimethylaniline, 2g was obtained in
68% yield by refluxing for 24 h. When the para-position of N,N-

3
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Table 2.
Preparation of α-cyanated tertiary amines 2 a
Product
Reaction conditions
Yield (%)b
2a: R = H
O2, 5 mol % [Fe], rt, 16 h
91
88
94
89
85
83
78
50
65
68
41
82
53
1.5 equiv TBHP, 5 mol % [Fe], rt, 16 h
2b: R = 4-Me
O2, 5 mol % [Fe], rt, 16 h
1.5 equiv TBHP, 5 mol % [Fe], rt, 16 h
O2, 5 mol % [Fe], rt, 16 h
2c: R = 3-Me
2d: R = 2-Me
2e: R = 4-Br
2f: R = 4-Cl
O2, 5 mol % [Fe], reflux, 14 h
O2, 5 mol % [Fe], rt, 20 h
O2, 10 mol % [Fe], 35 oC, 36 h
1.5 equiv TBHP, 10 mol % [Fe], rt, 20 h
O2, 5 mol % [Fe], reflux, 24 h
O2, 10 mol % [Fe], reflux, 36 h
3 equiv TBHP, 20 mol % [Fe], reflux, 24 h
O2, 5 mol % [Fe], rt, 24 h
2g: R = 4-F
2h: R = 4-MeO
2i: R = 4-CO2Et
2j
2k: R = H
O2, 10 mol % [Fe], reflux, 24 h
70
68
45
20
80
35
68
51
2l: R = 4-MeO
2m: R = 4-CN
2n: X = CH2
O2, 10 mol % [Fe], reflux, 24 h
O2, 10 mol % [Fe], reflux, 24 h
O2, 20 mol % [Fe], reflux, 36 h
1.5 equiv TBHP, 20 mol % [Fe], rt, 24 h
O2, 20 mol % [Fe], 60 oC, 36 h (solvent-free)
1.5 equiv TBHP, 20 mol % [Fe], rt, 24 h
1.5 equiv TBHP, 20 mol % [Fe], rt, 36 h
2o: X= CH2CH2
2p
2q
1.5 equiv TBHP, 10 mol % [Fe], 60 oC, 24 h
34
2r: X = CH2
2s: X = CO
O2, 10 mol % [Fe], reflux, 30 h
9
3 equiv TBHP, 10 mol % [Fe], reflux, 30 h
3 equiv TBHP, 20 mol % [Fe], reflux, 24 h
80
70
a Reaction conditions: 1 (0.5 mmol), benzoyl cyanide (0.6 mmol), FeSO4•7H2O (5~20 mol %), CH3OH (2 mL).
b Isolated yield.

4
Tetrahedron
cyanation reagent, acid-free conditions, inexpensive iron catalyst,
ACCEPTED MANUSCRIPT
and aerobic oxidation.
dimethylaniline was substituted by methoxyl, a relatively lower
yield was observed. In this case, 2h was prepared in 41% yield
even when the catalyst amount was increased to 10 mol % and
the reaction mixture was refluxed for 36 hours. For ester group
substituted N,N-dimethylaniline, the desired product 2i was not
obtained under O2 condition. However, changing the oxidant to
TBHP led to successful preparation of 2i in 82% yield.
4. Experimental
4.1 General
Unless stated otherwise, commercially available reagents and
solvents were used as received. Flash column chromatography
was performed using 200-300 mesh silica gel. Visualization on
TLC was achieved by the use of UV light (254 nm). NMR
spectra were obtained at 400 MHz for 1H NMR and 100 MHz for
13C NMR. Chemical shifts were quoted relative to
tetramethylsilane (TMS) as internal standard and reported in
ppm. The following abbreviations were used to describe peak
splitting patterns when appropriate: s = singlet, d = doublet, t =
triplet, m = multiple. High-resolution mass spectra (HRMS) were
recorded using TOF-EI. Melting points were measured with a
micro melting point apparatus.
Regioselective oxidation was observed on N-Me instead of N-
Et in case of N-ethyl-N-methylaniline. For this case, 2j was
isolated in 53% yield. The cyclical amines were examined and
high regioselectivity was also observed. Thus, N-phenyl-
tetrahydroisoquinoline,
N-(p-methoxyphenyl)-tetrahydroiso-
quinoline and N-(p-cyanophenyl)-tetrahydroisoquinoline gave 2k,
2l and 2m in 70%, 68% and 45% yields, respectively. The
reaction of N-phenylpyrrolidine and N-phenylpiperidine under O2
conditions provided the corresponding products 2n and 2o in
relatively lower yields. When TBHP was used, the yields of 2n
and 2o were improved to 80% and 68% yields, respectively. N-
Both phenylmorpholine and N,N-Dimethylnaphthalen-1-amine
did not react under an oxygen atmosphere. Using TBHP as
oxidant, they offered the corresponding products 2p and 2q in
51% and 34% yields, respectively. 4,4'-Methylenebis(N,N-
dimethylaniline) furnished the bicyanated product 2r in 9% yield
under O2 even after refluxing for 30 hours. When 3.0 equivalents
of TBHP were used, we achieved 2r in 80% yield. Bis(4-
(dimethylamino)phenyl)methanone furnished the bicyanated
product 2s in 70% yield with excellent regioselectivity. So far,
we provided 19 examples with the nice substrate diversity in
yields varied from 20% to 94%.
4.2 Typical procedure for the synthesis of 2a
Method A: The mixture of FeSO4•7H2O (6.95 mg, 0.025 mmol),
N,N-dimethylaniline (60.55 mg, 0.5 mmol), benzoyl cyanide
(78.62 mg, 0.6 mmol) in CH3OH (2.0 mL) was stirred under an
oxygen atmosphere at room temperature for 16 hours. After the
tertiary amine was completely consumed (checked by TLC), the
reaction mixture was filtrated and concentrated under reduced
pressure. The residue was then purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 4:1)
to afford 2a (66.5 mg, 91% yield) as a yellow oil.
Method B: The mixture of FeSO4•7H2O (6.95 mg, 0.025 mmol),
N,N-dimethylaniline (60.55 mg, 0.5 mmol), benzoyl cyanide
(78.62 mg, 0.6 mmol), and TBHP (70% aqueous solution, 108 µL,
0.75 mmol) in CH3OH (2.0 mL) was stirred under air at room
temperature for 16 hours. After the tertiary amine was completely
consumed, the reaction mixture was filtrated and concentrated
under reduced pressure. The residue was then purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 4:1)
to afford 2a (64.3 mg, 88% yield) as a yellow oil.
Referring to the iron-oxo complexes in many non-heme iron
catalyzed oxidations33,34 and previous reports on transition metal-
catalyzed oxidation of tertiary amines,20,24,25 we postulated a
possible reaction mechanism (Scheme 1). The low valence
FeSO4•7H2O is oxidized into iron-oxo species (A) in the presence
of TBHP or oxygen. Followed by the electron and hydrogen
transfer, the iminium intermediate B is formed as the key
intermediate and subsequently trapped by the in situ generated
cyanide anion from benzoyl cyanide.
4.3 Characterization data
4.3.1. 2-(Methyl(phenyl)amino)acetonitrile (2a). (Method A, 66.5
1
mg, 91% yield); yellow oil; H NMR (400 MHz, CDCl3) δ 7.33-
7.25 (m, 2H), 6.90 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 2H),
4.10 (s, 2H), 2.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.9,
129.6, 120.2, 115.8, 115.0, 42.3, 39.3.
4.3.2. 2-(Methyl(p-tolyl)amino)acetonitrile (2b). (Method A, 75.2
mg, 94% yield); yellow solid; mp 55-56 oC; 1H NMR (400 MHz,
CDCl3) δ 7.01 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 3.97
(s, 2H), 2.82 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
145.9, 130.2, 129.9, 115.8, 115.5, 42.9, 39.6, 20.6.
Scheme 1. Possible reaction mechanism.
4.3.3. 2-(Methyl(m-tolyl)amino)acetonitrile (2c). (Method A,
68.0 mg, 85% yield); yellow oil; H NMR (400 MHz, CDCl3) δ
3. Conclusion
1
In conclusion, we have developed a feasible method for the
preparation of 2-cyanoamines from benzoyl cyanide and readily
available tertiary amines. More examples were presented with
nice diversity. The reaction proceeded in a cascade way,
including an iron-catalyzed oxidation of tertiary amine to
iminium ions and trapping them by cyanide anion. Several
features about this protocol should be mentioned: safety
7.11 (dd, J = 8.8, 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.58 (m,
2H), 4.04 (s, 2H), 2.89 (s, 3H), 2.26 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 148.1, 139.5, 129.5, 121.3, 115.9, 115.9, 112.3,
42.5, 39.4, 22.0.
4.3.4. 2-(Methyl(o-tolyl)amino)acetonitrile (2d). (Method A, 66.4
1
mg, 83% yield); yellow oil; H NMR (400 MHz, CDCl3) δ 7.23-

5
7.15 (m, 3H), 7.10-7.01 (m, 1H), 3.82 (s, 2H), 2.84 (s, 3H), 2.29
MHz, CDCl3) δ 155.8, 142.7, 134.5, 129.8, 129.6, 128.8, 127.2,
126.9, 121.1, 117.8, 114.9, 55.8, 55.7, 45.0, 28.8.
ACCEPTED MANUSCRIPT
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.8, 133.1, 131.6,
127.1, 125.2, 120.9, 115.9, 45.3, 41.2, 18.0.
4.3.13.
2-(4-Cyanophenyl)-1,2,3,4-tetrahydroisoquinoline-1-
4.3.5.
2-((4-Bromophenyl)(methyl)amino)acetonitrile
(2e).
carbonitrile (2m). (Method A, 58.3 mg, 45% yield); yellow solid;
o
1
(Method A, 87.4 mg, 78% yield); yellow solid; mp 35-36 oC; 1H
NMR (400 MHz, CDCl3) δ 7.38 (d, J = 9.2 Hz, 2H), 6.71 (d, J =
9.2 Hz, 2H), 4.12 (s, 2H), 2.96 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.0, 132.5, 116.6, 115.5, 112.7, 42.3, 39.5.
mp 153-155 C; H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 9.0
Hz, 2H), 7.39-7.31 (m, 3H), 7.29 (d, J = 7.1 Hz, 1H), 7.03 (d, J =
9.0 Hz, 2H), 5.60 (s, 1H), 3.90-3.79 (m, 1H), 3.68-3.52 (m, 1H),
3.19-3.06 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 150.9, 135.0,
134.2, 129.7, 129.5, 129.1, 127.7, 127.3, 119.7, 117.7, 115.0,
103.0, 50.5, 44.1, 28.5. HRMS (EI) Calcd. for
C17H13N3:259.1109([M]+), found: 259.1113.
4.3.6.
2-((4-Chlorophenyl)(methyl)amino)acetonitrile (2f).
(Method B, 58.5 mg, 65% yield); yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.24 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.12
(s, 2H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.6,
129.5, 125.4, 116.2, 115.5, 42.5, 39.6.
4.3.14. 1-Phenylpyrrolidine-2-carbonitrile (2n). (Method B, 68.8
mg, 80% yield); gray solid; mp 102-104 oC; 1H NMR (400 MHz,
CDCl3) δ 7.38 (t, J = 8.0 Hz, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.70
(d, J = 8.0 Hz, 2H), 4.55 (d, J = 6.4 Hz, 1H), 3.51-3.40 (m, 1H),
3.41-3.26 (m, 1H), 2.48-2.36 (m, 1H), 2.34-2.20 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 145.5, 129.8, 119.6, 118.6, 113.0,
49.4, 47.8, 31.9, 24.3.
4.3.7.
2-((4-Fluorophenyl)(methyl)amino)acetonitrile
(2g).
(Method A, 55.8 mg, 68% yield); brown oil; 1H NMR (400 MHz,
CDCl3) δ 7.04-6.98 (m, 2H), 6.86-6.83 (m, 2H), 4.02 (s, 2H),
2.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.7 (JC-F = 238.1
Hz), 144.6 (JC-F = 2.3 Hz), 117.2 (JC-F = 7.8 Hz), 116.2 (JC-F
=
22.2 Hz), 115.6, 43.5, 40.0.
4.3.15. 1-Phenylpiperidine-2-carbonitrile (2o). (Method B, 63.3
mg, 68% yield); yellow solid; mp 60-61 oC; 1H NMR (400 MHz,
CDCl3) δ 7.32 (dd, J = 8.8, 7.2 Hz, 2H), 7.00 (dd, J = 8.3, 7.7 Hz,
3H), 4.63 (t, J = 3.4 Hz, 1H), 3.44 (d, J = 12.0 z, 1H), 3.03 (ddd,
J = 12.1, 9.6, 2.5 Hz, 1H), 2.11-1.94 (m, 2H), 1.91-1.78 (m, 2H),
1.75-1.65 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 150.1, 129.7,
122.5, 118.6, 117.5, 52.3, 46.9, 29.5, 25.4, 20.5.
4.3.8. 2-((4-Methoxyphenyl)(methyl)amino)acetonitrile (2h).
(Method A, 36.1 mg, 41% yield); brown oil; 1H NMR (400 MHz,
CDCl3) δ 6.80 (s, 4H), 4.00 (s, 2H), 3.70 (s, 3H), 2.84 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 154.6, 142.4, 118.0, 115.7, 115.0,
55.8, 44.2, 40.2.
4.3.16. 4-Phenylmorpholine-3-carbonitrile (2p). (Method B, 48.0
1
mg, 51% yield); white solid; mp 96-98 oC; H NMR (400 MHz,
4.3.9. Ethyl 4-((cyanomethyl)(methyl)amino)benzoate (2i).
1
(Method B, 89.4 mg, 82% yield); yellow solid; mp 63-65 oC; H
CDCl3) δ 7.39-7.32 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.99 (d, J =
7.6 Hz, 2H), 4.43 (s, 1H), 4.16 (d, J = 11.5 Hz, 1H), 4.10 (d, J =
11.2 Hz, 1H), 3.91 (dd, J = 11.5, 2.9 Hz, 1H), 3.80-3.70 (m, 1H),
3.29 (dd, J = 7.9, 2.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
148.6, 129.9, 123.0, 117.6, 116.3, 68.4, 67.2, 51.4, 45.8.
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.9 Hz, 2H), 6.72 (d, J =
8.9 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.17 (s, 2H), 3.02 (s, 3H),
1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.7,
151.0, 131.6, 121.3, 115.5, 113.0, 60.8, 41.5, 39.3, 14.6.
4.3.17.
2-(Methyl(naphthalen-1-yl)amino)acetonitrile
(2q).
4.3.10. 2-(Ethyl(phenyl)amino)acetonitrile (2j). (Method A, 42.4
mg, 53% yield); yellow oil; H NMR (400 MHz, CDCl3) δ 7.23
(t, J = 7.6 Hz, 2H), 6.86-6.71 (m, 3H), 4.05 (s, 2H), 3.35 (q, J =
7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.0, 129.8, 120.0, 116.7, 115.1, 46.5, 39.7, 12.5.
(Method B, 33.3 mg, 34% yield); yellow oil; 1H NMR (400 MHz,
CDCl3) δ 8.11-8.05 (m, 1H), 7.84 (dd, J = 7.2, 2.2 Hz, 1H), 7.63
(d, J = 8.2 Hz, 1H), 7.54-7.45 (m, 2H), 7.45-7.39 (m, 1H), 7.30
(dd, J = 7.4, 0.9 Hz, 1H), 4.06 (s, 2H), 3.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 146.5, 135.0, 128.9, 128.8, 126.4, 126.4,
125.9, 125.6, 123.0, 117.4, 115.7, 46.3, 41.5.
1
4.3.11. 2-Phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile
(2k). (Method A, 81.9 mg, 70% yield); yellow solid; mp 95-96 oC;
1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.2 Hz, 2H), 7.25-7.14
(m, 4H), 7.01 (d, J = 7.6 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H), 5.44
(s, 1H), 3.74-3.64 (m, 1H), 3.41 (ddd, J = 12.4, 10.8, 4.0 Hz, 1H),
3.08 (ddd, J = 16.4, 10.8, 6.0 Hz, 1H), 2.89 (dt, J = 16.4, 3.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 148.7, 134.9, 129.9, 129.7,
129.1, 128.7, 127.4, 127.2, 122.2, 118.1, 117.9, 53.5, 44.5, 28.9.
4.3.18. 2,2'-((Methylenebis(4,1-phenylene))bis(methylazanediyl)-
)diacetonitrile (2r). (Method B, 121.7 mg, 80% yield); yellow
solid; mp 107-109 oC; 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J =
8.3 Hz, 4H), 6.80 (d, J = 8.4 Hz, 4H), 4.11 (s, 4H), 3.86 (s, 2H),
2.95 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 146.3, 133.5, 130.0,
115.9, 115.4, 42.7, 40.2, 39.6.
4.3.19. 2,2'-((Carbonylbis(4,1-phenylene))bis(methylazanediyl))-
diacetonitrile (2s). (Method B, 111.4 mg, 70% yield); yellow
solid; mp 183-185 oC; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J =
8.7 Hz, 4H), 6.83 (d, J = 8.8 Hz, 4H), 4.27 (s, 4H), 3.09 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 194.2, 150.6, 132.3, 128.9, 115.6,
4.3.12. 2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-1-
carbonitrile (2l). (Method A, 89.8 mg, 68% yield); white solid;
o
1
mp 107-108 C; H NMR (400 MHz, CDCl3) δ 7.35-7.19 (m,
4H), 7.09 (dd, J = 8.8, 4.4 Hz, 2H), 6.98-6.85 (m, 2H), 5.38 (s,
1H), 3.79 (s, 3H), 3.58 (dd, J = 11.5, 6.0 Hz, 1H), 3.51-3.36 (m,
1H), 3.21-3.06 (m, 1H), 2.93 (d, J = 16.4 Hz, 1H); 13C NMR (100

6
Tetrahedron
ACCEPTED MANUSCRIPT
33. Kaizer, J.; Klinker, E. J.; Oh, N. Y.; Rohde, J. -U.; Song, W. J.;
112.7, 41.3, 39.2. HRMS (EI) Calcd. for C19H1 N4O: 318.1481
8
([M]+), found: 318.1480.
Stubna, A.; Kim, J.; Munck, E.; Nam, W.; Jr, L. Q. J. Am. Chem.
Soc. 2004, 126, 472-473.
34. Mas-Ballesté, R.; Jr, L. Q. Science 2006, 312, 1885-1886.
Acknowledgements
We thank the National Nature Science Foundation of China
(Nos. 21272203 and J1210042) for financial support to this work.
Supplementary data
Copies of NMR spectra (1H and 13C) for 2a-2s and HRMS of 2m
and 2s. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.
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