Single-Electron-Transfer-Induced C(sp3)-N Couplings via C-C Bond Cleavage of Cycloketoxime Esters

Article abstract of DOI:10.1021/acs.joc.9b01338

A practical single-electron-transfer-induced selective C(sp³)-N coupling of cycloketoximes with anilines via C-C bond cleavage under copper-catalytic and synergetic photoredox/copper-catalytic reaction systems has been uncovered. These two powerful and simple protocols demonstrated excellent selectivity and good functional group compatibility without any base or ligand control. Preliminary mechanistic experiments indicated that a radical-mediated process was involved in these transformations.

Full text of DOI:10.1021/acs.joc.9b01338

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Article
Single-Electron-Transfer-Induced C(sp3)-N Couplings
via C-C Bond Cleavage of Cycloketoxime Esters
Binlin Zhao, Minyan Wang, and Zhuangzhi Shi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01338 • Publication Date (Web): 17 Jul 2019
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The Journal of Organic Chemistry
Single-Electron-Transfer-Induced C(sp3)-N Couplings via C-C Bond
Cleavage of Cycloketoxime Esters
1
2
3
4
5
Binlin Zhao,a,b Minyan Wang,a* and Zhuangzhi Shia*
a State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing, 210093, China
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9
b College of Science, Nanjing Forestry University, Nanjing 210037, China
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cat [Cu]
with or without [PC]
NC
SET
+
R
R
ABSTRACT: A practical single-electron-transfer-induced selective C(sp3)N coupling of cycloketoximes with anilines via CC
bond cleavage under copper catalytic and synergetic photoredox/copper catalytic reaction systems has been uncovered. These two
powerful and simple protocols demonstrated excellent selectivity and good functional groups compatibility without any base or
ligand control. Preliminary mechanistic experiments indicated a radical-mediated process was involved in these transformations.
■ INTRODUCTION
Amines and the derivatives are a privileged class of compounds with wide applications from pharmaceuticals, agrochemicals and
material science to diverse mediates for the synthesis of functional molecules.1 The development of amine chemistry is urgently
required, especially to construst varieties of carbon-nitrogen (CN) bond. Conventional, the alkylation of amines with readily
available alkyl halides and alcohols were well developed accompanying with overalkylation and poor functional group compatibility,
3
which seriously hampered its industrial application. Moreover, Buchwald-Hartwig and Ullman-type cross-coupling reactions
provided alternative practical pathways for the construction of alkyl or aryl amines in the presence of copper or palladium catalyst, 4
which provided a straightforward protocol to synthesize diaryl amines, while the alkyl arylamines were limited owing to the β-
elimination of a metal alkyl intermediate. Furthermore, reductive amination of amines with carbonyl compounds is also a classical
popular strategy to obtain variable protected amines in the presence of reductants. 5 In spite of these remarkable developments, it is
highly desirable and significant to develop an effective mild approach achieving the direct construction of C(sp3)N bonds. In recent
years, the photo-induced copper-catalyzed Ullman CN coupling reactions were detailed studied, which mainly proceed via
photoexcitation of copper-amine complexes with a reductive potential triggering a single-electron-transfer event. 6, 7, 8
The synergetic photoredox and transition-metal catalyst is a novel catalytic system9 for the efficient formation of C(sp3)N bond.
The group of Hu has recently developed a decarboxylative amination of alkyl redox-active esters with arylamines enabled by tandem
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10
photoredox and copper catalyst (Scheme 1a).
Meanwhile, MacMillan and co-workers achieved decarboxylative C(sp3) N
1
2
3
4
5
6
couplings from active iodonium carboxylates and anilines via dual copper and photoredox catalyst (Scheme 1b). 11 The key point of
these transformations is that the copper salts can cooperate well with the photoredox catalyst to accomplish the catalyzed cycle
Scheme 1. Single-Electron-Transfer-Induced Selective C(sp3)-N Couplings.
7
8
a) Hu's strategy:
9
R'
N
R'
N
O
O
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60
cat [Cu]/[PC]
R
H
R
+
2018
O N
Ar
Ar
Blue LEDs
O
b) MacMillan's strategy:
O
O
O
R'
N
R
Mes
O
O
MesI(OAc)2
cat [Cu]/[PC]
2018
R
I
R
Ar
Blue LEDs
R'
OH
N
R
H
Ar
c) This work:
O
Ar
R'
N
cat [Cu]
R'
O
N
CN
with or without [PC]
N
+
H
Ar
with or without Blue LEDs
Ar
under the irradiation of visible light via single electron transfer process. As a sequence, with our ongoing interest in the research of
CC bond cleavage. Herein, we disclosed a C(sp3)N cross coupling reaction of anilines with cycloketoximes to generate
12
cyanoalkylated anilines in the presence of copper catalyst with or without synergetic photoredox under mild reaction conditions
(Scheme 1c). In this transformation, the non-toxic and stable cycloketoximes were used as presursor of cyano at ambient condition.
A wide range of cycloketoximes and anilines are well tolerated to furnish varieties of mono-alkylated products and di-alkylated
products in good to excellent yields, respectively.
■ RESULTS AND DISCUSSION
Cycloketoxime derivatives13-21 were good precursors to achieve cyanoalkylation of diverse radical acceptors via the C-C bond
cleavage. Initially, we operated the reaction employing cyclobutanone O-benzoyl oxime (1a) and aniline (2a) under our previous
reported reaction conditions (Table 1).12a As we expected, the desired product 4-(phenylamino)butanenitrile (3aa) was obtained in 26%
yield (entry 1). After a brief screening of solvents, DMF performed better than other solvents for this conversion (entry 4). When the
temperature was reduced to 80 oC, the yield of 3aa was improved to 49% (entry 5). Further lowering the temperature would suppress
the reaction (entry 6). What’s more, different copper salts showed different efficiencies for this transformation, a good yield of 3aa
was isolated in the presence of copper bis(dipivaloylmethanate) (5 mol%) (entry 8). Moreover, the isolated yield of product was
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improved to 85% with an increasing amount of cyclobutanone O-benzoyl oxime (1a) to 1.5 equivalent (entry 9). Furthermore, single
3aa was detected in 90% yield eventhough the amount of 1a was improved to 3.0 equivalent (entry 10). The copper-catalyzed reaction
system was limited to the formation of mono-functionalizated aniline 3aa. Furthermore, the synergetic photoredox and copper-
catalytic condition was investigated under the irradiation of visible light. Surprisingly, when cycloketoxime (1a’)
Table 1. Screening of Conditionsa
1
2
3
4
5
6
7
8
9
NH2
NC
N
CN
HN
CN
NOX
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[Cu] / [PC]
+
+
Conditions
1
4aa
2a
3aa
Yield (%)b
[Cu]
(mol%)
[PC]
(mol%)
T
Entry
X
Solvent
(oC)
3aa
4aa
1
2
PhCO (1a)
PhCO (1a)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
1,4-dioxane
PhCF3
100
100
26
31
0
0
3
4
PhCO (1a)
PhCO (1a)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
CuTc (5)
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100
100
80
60
80
80
80
80
80
rt
38
41
0
0
5
PhCO (1a)
49
0
6
PhCO (1a)
45
0
7
PhCO (1a)
69
0
8
PhCO (1a)
Cu(tmhd)2 (5)
Cu(tmhd)2 (5)
Cu(tmhd)2 (5)
Cu(tmhd)2 (5)
Cu(tmhd)2 (5)
Cu(tmhd)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
81 (75)
93 (85)
90
0
9c
PhCO (1a)
0
10d
11c
12
13
14
15
16
17e
18
19e,f
PhCO (1a)
0
4-CF3PhCO (1a’)
4-CF3PhCO (1a’)
4-CF3PhCO (1a’)
4-CF3PhCO (1a’)
4-CF3PhCO (1a’)
4-CF3PhCO (1a’)
4-CF3PhCO (1a’)
PhCO (1a)
88
0
fac-Ir(ppy)3 (1)
fac-Ir(ppy)3 (1)
fac-Ir(ppy)3 (1)
15
5
rt
52
10
rt
65
12
Ir (ppy)2
(dtbbpy)PF6 (1)
rt
57
7
Ru(bpy)2PF6(1)
fac-Ir(ppy)3 (1)
fac-Ir(ppy)3 (1)
fac-Ir(ppy)3 (1)
rt
25
5
rt
7
80 (73)
rt
0
0
0
4-CF3PhCO (1a’)
rt
trace
a Standard conditions, [Cu]: 1a (0.2 mmol), 2a (0.4 mmol), [Cu] 5 mol% in solvent (0.2 M) under Ar for 12 h; [Cu]+[PC]: 1a’ (0.2
mmol), 2a (0.4 mmol), [Cu] 20 mol%, [PC] 1 mol% in solvent (0.2 M) at room temperature under irradiation of 12 w/m × 5 m blue
LEDs for 12 h. b GC-MS yield using dodecane as internal standard, isolated yield was in parenthesis. c1 (0.3 mmol), 2a (0.2 mmol).
d1a (0.6 mmol), 2a (0.2 mmol). 1a’ (0.6 mmol), 2a (0.2 mmol). Without blue LEDs irradiation. tmhd = 2,2,6,6-tetramethyl-3,5-
e
f
heptanedionato.
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and free aniline (2a) were treated with extra addition of fac-Ir(ppy)3 (1 mol%) under the irradiation of 12 w/m × 5 m blue LEDs at
room temperature, the N, N-dialkylanilines 4aa was detected in GC-MS, albeit with 5% yield (entry 12). According to MacMillan’s
and Hu’s conditions, increasing amount of copper salt to 20 mol% resulted in a sudden improvement yield of 3aa to 52% with
furnishing 4aa in 10% yield (entry 13). Other photocatalysts were also investigated providing significantly lower yields of amine
Table 2. Anilines scope of copper-catalyzed selective C(sp3)-N cross-coupling.a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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NH2
HN
Ar
CN
1
2
3
4
NOBz
[Cu] (5 mol%)
+
Ar
Solvent, 80 °C, 12 h
1a
2
3
5
6
7
8
9
CN
HN
CN
NH
1
CN
CN
HN
HN
OMe
2
6
5
10
11
12
13
14
15
16
17
18
19
20
21
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51
R
3
Cl
Br
MeO
4
O
OCF3
NO2
3ka
F
3ba
3ca
R = 4-Me,
, 89%
3ia
3ja
, 70%
, 73%
, 78%
t
R = 4- Bu,
, 93%
CN
HN
3da
, 83%
R = 4-F,
CN
HN
CN
HN
3ea
R = 4-CF3,
, 58%
, 64%
3ga
MeO
F
3fa
R = 2-I,
R = 4-OMe,
Me
N
H
, 78%
3ha
O
R = 4-CH2CN,
, 73%
3na
, 75%
3la
3ma
, 85%
, 79%
CN
CN
HN
HN
CN
HN
CN
HN
OH
OH
N
3pa
, 64%
3qa
3ra
, 55%
, 72%
3oa
, 80%
CN
HN
CN
HN
CN
HN
CN
HN
O
NH
COOH
, 48%
NHPh
O
NHMe
Me
3va
, 87%
3sa
3ta
3ua
, 71%
, 73%
CN
HN
CN
HN
CN
HN
CN
HN
Me
Et
NH2
O
NH
F
O
N
O
O
O
Me
O
3za
, 91%
3wa
3xa
, 46%
, 58%
3ya
, 87%
a Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), 5 mol% of Cu(tmhd)2 in DMF (0.2 M) under Ar at 80 °C for 12 h, isolated yields.
52
53
54
55
56
57
58
59
60
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products (entries 15-16). When Cu(tmhd)2 was changed to Cu(OTf)2 with an improving amount of cycloketoxime (1a’) to 3.0
equivalents, the yield of N, N-disubstituted aniline (4aa) was dramatically improved to 80% (entry 17). It was noteworthy that the
reaction was inhibited completely in the absence of light (entry 16).
1
2
3
4
5
6
7
8
With the optimized reaction conditions in hand, firstly we tested the substrate scope of copper-catalyzed C (sp3)N cross-couplings
and the results were summarized in Table 2. We turned our attention to investigate the applicability of the optimized conditions with
various anilines in the presence of Cu(tmhd)2 (5 mmol%). The results showed that anilines with varieties of functional groups were
transformed into the corresponding products smoothly. Several mono-substituted anilines bearing 4-Me, 4-tBu, 4-F, 4-CF3, 2-I, 4-
OMe, and 4-CH2CN on aryl rings were perfectly tolerated giving the cyanoalkylation products in good to excellent yields (3ba-3ha).
Moreover, a wide range of multi-substituted anilines containing different kinds of substituents on different substituted positions
showed good efficiency to afford the desired products in good yields (3ia-3la). It is worthy to note when 1H-indol-4-amine (2m)
containing both a primary amine and an active indole nitrogen was investigated under the optimized conditions, the corresponding
product 4-((1H-indol-4-yl)amino)butanenitrile (3ma) was formed with high selectivity in 85% yield. What’s more, 1-(2-
aminophenyl)ethan-1-one (3n) performed well to provide the alkyl amination product 3na in 75% yield. Meanwhile, naphthalene and
quinolone-substituted amines reacted with cyclobutanone O-benzoyl oxime (1a) effectively to produce the cyanoalkylation products
in 64-80% yields (3oa-3pa). Alcohol, phenol, benzoic acid, and their derivatives were also compatible well with this mild copper-
catalyzed protocol, only C (sp3)-N coupling products were observed in moderate to good yields without the detection of any other
products (3qa-3sa). In addition, other active anilines including secondary amine, N-methylbenzamide, and acetamide also reacted
with cyclobutanone O-benzoyl oxime (1a) to give the single products (3ta-3wa) in 58-87% yields. Importantly, some natural products
and functional amines could also proceed well to furnish the cyanoalkylation products (3xa-3za) in 46-91% yields. However, the
alkylamines were not good candidates for this copper-catalyzed C(sp3)-N coupling, neither phenylmethanamine nor N-methyl-1-
phenylmethanamine could provide the desired product under the optimized conditions.
9
10
11
12
13
14
15
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17
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34
35
36
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42
43
44
45
46
47
48
49
50
51
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53
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59
60
Following these satisfied results with aniline substrates, we further explored the scope of cyclobutanone O-benzoyl oximes shown
in Table 3. Lowering the amount of oximes to 1.0 equivalent and increasing amount of aniline to 2.0 equivalent, a range of substituted
cyclobutanone O-benzoyl oximes could generate the diverse 4-(phenylamino)butanenitriles smoothly in the presence of copper
catalyst. The mono-substituted cyclobutanone O-benzoyl oximes bearing Ph, Bn, and OBn participated in this alkylamination
furnishing the products (3ab-3ad) in yields of 44-72%. Furthermore, di-substituted oximes showed good performance under the
optimized conditions (3ae-3af). This reaction was also amenable to the spirocyclic cyclobutanone O-benzoyl oxime (1g) to afford
the cycloketoximes under standard conditions. 2-Phenyl cyclobutan-1-one oxime (1h) was also a good candidate for the preparation
of amine product (3ah). As shown in Table 3, a diverse set of cyclopentanone oxime derivatives (1i-1o) and cycloheptyl ketoxime
derivative (1p) could produce the corresponding products (3ai-3ap) in moderate to good yields.
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Table 3. Cycloketoximes scope of copper-catalyzed selective C(sp3)-N cross-coupling.
1
2
3
4
5
NH2
HN
CN
NOBz
[Cu] (5 mol%)
+
Solvent, 80 °C, 12 h
6
7
1
2a
3
8
9
Variation of strained cycloketoxime motifs a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
CN
HN
CN
CN
HN
HN
CN
HN
Ph
Bn
OBn
Ph
3ab
, 65%
3ac
3ad
3ae
, 61%
, 72%
, 44%
OAc
CN
Ph
CN
HN
CN
HN
Boc
N
HN
Me
b
3ah
, 42%
NH
3af
3ag
, 52%
, 58%
Variation of less-strained cycloketoxime motifs b
Ph
Ph
Ph
Ph
NH
NH
NH
CN
CN
CN
CN
tBu
F
Ph
3ai
3aj
3ak
3al
, 66%
, 53%
, 60%
, 50%
Ph
Ph
Ph
Ph
NH
NH
NH
NH
CN
CN
CN
CN
S
MeO
MeO
3ap
, 51%
3ao
, 48%
3am
3an
, 52%
, 70%
a Reaction conditions A: 1 (0.2 mmol), 2a (0.4 mmol), 5 mol% of Cu(tmhd)2 in DMF (0.2 M) under Ar at 80 °C for 12 h, isolated
yields. bReaction conditions B: 1 (0.2 mmol), 2a (0.4 mmol), 5 mol% of Cu(OTf)2 in 1,4-dioxane (0.2 M) under Ar at 80 °C for 12
h, isolated yields.
To further prove the potential application of dual copper and photoredox catalyst reaction system, we explored the scope of free
anilines and N-alkyl anilines (Table 4). A broad range of free anilines were examined, the dialkylfunctionalization products bearing
4-tBu, 4-OMe, 4-Fluro groups (4ba-4da) were generated in good yields. 4-Methyl-3-bromo aniline was also transformed to
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Table 4. Substrate scope of photoredox/copper-catalyzed selective C(sp3)-N cross-coupling.
1
2
3
4
R
R
NH
N
CN
fac-[Ir(ppy)3] (1.0 mol%)
NOBz (4-CF3)
Cu(OTf)2 (20 mol%)
+
Ar
DMF, rt, Blue LEDs
5
6
7
1a'
4
2
8
9
R = H a
NC
CN
NC
CN
N
N
NC
CN
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tBu
OMe
F
4ba
4ca
4da
, 78%
, 85%
, 52%
NC
CN
N
NC
CN
N
NC
CN
N
Br
OH
OH
Me
4ea
4fa
4ga
, 52%
, 68%
N
, 62%
N
NC
CN
NC
CN
NC
CN
N
F
Et
O
NH
N
Me
NH
O
O
O
4ha
, 90%
4ia
, 65%
4ja
, 66%
R = Alkyl groups b
Me
CN
N
4ka
R = Me, R2 = H,
R = Bn, R2 = H,
R = iPr, R2 = H,
R = Allyl, R2 = H,
, 78%
R1
N
CN
4la
, 68%
4ma
, 55%
4na
, 72%
OMe
4oa
, 74%
HO
N
CN
CN
N
N
N
CN
4pa
, 65%
4ra
, 59%
4qa
, 80%
a Reaction conditions A: 1a’ (0.6 mmol), 2 (0.2 mmol), 1 mol% of fac-Ir(ppy)3, and 20 mol% of Cu(OTf)2 in DMF (0.2 M) under Ar
at room temperature under irradiation of 12 w/m × 5 m blue LEDs for 12 h. b Reaction conditions B: 1a’ (0.3 mmol), 2 (0.2 mmol),
1 mol% of fac-Ir(ppy)3 and 20 mol% of Cu(OTf)2 in DMF (0.2 M) under Ar at room temperature under irradiation of 12 w/m × 5 m
blue LEDs for 12 h.
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N, N-dialkyl aniline (4ea) in 52% yield. Meanwhile, the anilines containing aliphatic hydroxyl group, phenolic hydroxyl group, and
amide reacted with 1a’ smoothly to afford the desired products (4fa-4ha) in 62% to 90% yield. The functional natural products were
also compatible with the reaction conditions delivering the products (4ia-4ja) in moderate yields. Notably, N-alkyl aniline could not
afford the desired product under the single copper-catalytic reaction conditions. However, under the dual copper and photoredox
catalyst reaction conditions, the coupling of varieties of N-alkyl anilines with cycloketoxime (1a’) could be conducted smoothly. N-
methyl, benzyl, isopropyl, and allyl anilines all performed well to give the corresponding amines (4ka-4na) in good yields. 4-((4-
Methoxyphenyl)(methyl)amino)butanenitrile (4ao) was also obtained in 74% yield. Synthetically useful functional group such as free
alcohol was well compatible and the aniline product (4pa) was prepared in 65% yield under the optimized conditions. Furthermore,
indoline was also a suitable amine substrate producing 4-(indolin-1-yl)butanenitrile (4qa) in 80% yield. In addition, the alkylated
heteroindoline (4ra) was generated in 59% yield. However, no desired product was observed when alkylamine such as
phenylmethanamine or N-methyl-1-phenylmethanamine was investigated under the optimized photoredox/copper-catalytic
conditions.
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To further demonstrate the potential application of this transformation, we operated the copper-catalyzed C(sp3)-N coupling
reaction on a 5.0 mmol scale, 82% yield of the desired product 3aa was isolated (Scheme 2). Meanwhile, the corresponding amide
products 10 and 11 were prepared in excellent to good yields when 3aa were treated with cold H2SO4 and hot H2SO4, respectively.
Moreover, 3aa reacted with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate smoothly to furnish the aryl product 12 in 85% yield
in the presence of KF.
Scheme 2. Further Transformations
NH2
CN
HN
NOBz
Cu
+
5.0 mmol-scale
82%
3aa
1a
2a
TMS
OTf
Cold
H2SO4
Hot
H2SO4
KF
N
NH2
Ph
CN
HN
O
N
O
10
11
12
, 85%
, 93%
, 71%
In order to understand the possible mechanism of copper-catalyzed and synergetic catalyzed selective C(sp3)N coupling, TEMPO
trapping experiments were operated with an extra addition of TEMPO. The distal carbon-TEMPO adduct 5 were formed in 83% and
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70% yield respectively, with no observation of alkylated products 3aa and 4aa (Scheme 3a), indicating that a radical-mediated
pathway was involved in this reaction. To our delight, multi-component radical cascade reactions could also be realized affording
products (7, 9) in modest yields when styrenes (6, 8) were added to the copper-catalytic reaction system (Scheme 3b). To evaluate
the possibility of association between photoredox catalyst and copper salt, a series of photo-induced experiments were operated.
When fac-Ir(ppy)3 (1 mol%) was employed in the absence of copper salts, we didn’t detect any alkylation product. Meanwhile, copper
salt performed hypodynamic transformation in the absence of photoredox catalyst (Scheme 3c). These results indicated that the
combination of photoredox catalyst and copper catalyst under the irradiation of blue LEDs was crucial to achieve the C(sp3)N
couplings.
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Scheme 3. Mechanistic Experiments
a) TEMPO trapping experiment
Me
Me
N
NH2
CN
HN
Cu
NOBz
O
CN
+
+
Me
Me
TEMPO (2.0 equiv)
1a
1.5 equiv
1
2a
1.0 equiv
3aa
, ND
5
, 83% ( H NMR based on
1a
)
Me
Me
N
NH2
NC
CN
N
NOBz (4-CF3)
Cu
TEMPO (4.0 equiv)
PC
O
CN
+
+
Me
Me
1a'
3.0 equiv
2a
1.0 equiv
1
4aa
, ND
5
, 70% ( H NMR
1a'
based on
)
b) Multi-component reaction experiments
Ar
NH2
Cu(OTf)2 (5 mol%)
1,4-dioxane, 80 °C
NOBz
CN
HN
+
R
1a
2a
7,
R = H, 35%
6
R = H,
9,
R = OMe, 55%
8
R = OMe,
c) Photo-induced experiments
NH2
CN
NC
CN
HN
N
NOBz (4-CF3)
fac-[Ir(ppy)3] (1.0 mol%)
+
+
DMF, rt
Blue LEDs
3aa
, ND
1a'
2a
4aa
, ND
NH2
CN
NC
CN
HN
N
NOBz (4-CF3)
Cu(OTf)2 (20 mol%)
DMF, rt
+
+
1a'
2a
3aa
4aa
with or without light
ND
with or without light
trace
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The Journal of Organic Chemistry
Scheme 4. Plausible Mechanism
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4
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6
7
8
Ar
NC
NC
1A''
Copper catalytic cycle
-H
Cun+1
Cun
R
NOBz
Ar
NC
R
R = Ar
1A'
1A
1
9
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Cun+1
Cun
3aa
NH2
Ph
NHPh
2a
Ar
NC
3ah,
Ar = Ph
CN
Cu
HN
Ph
Cun+1
n+2
N
H
Ph
1B
1C
1A
R = H
Copper and photoredox catalytic cycle
4
CN
2D
R
Cun
Cun+2
N
PC
H
Ar
N
Ar
R
2'
SET
PC*
NOBz(4-CF3)
R
N
R
1a'
Cun
Ar
Ar
N
PC+
Cun+1
2B
NC
NC
1A
2C
1A
Based on the experimental results and previous reports, plausible mechanisms including copper catalytic cycle and dual
photoredox-copper catalytic cycle were shown in Scheme 4. For copper-catalyzed selective C(sp3)N couplings, initially a distal
radical 1A was formed in the presence of copper via a SET reduction and β-scission of iminyl radical process with a release of
Cun+1species. Radical 1A (R = H) was trapped by a copper amido complex 1B, which generated from an incorporation of aniline (2)
with Cun+1, to give a high-valent copper alkyl amido complex 1C. Then the desired mono-alkylated product was formed along with
the regeneration of a low-valent copper catalyst. When α-aryl cycloketoximes was employed, a highly reductive potential intermediate
1A (R = Ar) would be oxidized to generate a benzyl cation species 1A’. Then the corresponding product 3ah would be formed through
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nucleophilic attack of anilines along with the generation of the β-H elimination byproduct. For copper and photoredox catalytic cycle,
the photoredox catalyst fac-[Ir(ppy)3] was excited under the light irradiation producing a long-lived triplet excited state (PC*), which
has a reductive potential to promote cyclo ketoximes (1a’) producing a distal radical 1A via an known process. Concurrently, the
aniline 2’ coordinated with a low-valent copper catalyst formed a copper amido complex 2B. Subsequently, the active radical 1A was
captured by complex 2B to produce complex 2C. Then a high-valent copper alkyl amido complex 2D was obtained via a single-
electron oxidation between PC+ and complex 2C with a regeneration of PC.22 Finally, complex 2D was expected to yield the amine
product 4 through a reductive elimination to complete the cycle.
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■ CONCLUSIONS
In conclusion, we have reported a single-electron-transfer-induced selective C(sp3)N coupling of cycloketoximes with anilines
via CC bond cleavage. Both copper catalytic and synergetic photoredox/copper catalytic protocols were developed for the efficient
preparation of varieties of mono-alkylamination products and di-alkylamination products, respectively. These amines containing
cynao groups are of great importance in organic synthesis of functional molecules. These two mild and operationally simple
approaches complementing each other were suitable for the modification of different anilines and exhibited good functional group
tolerance. This work provided practical strategy for the C(sp3)N couplings.
■ EXPERIMENTAL SECTION
All new compounds were fully characterized. NMR-spectra were recorded on Bruker ARX-400 MHz or ARX-500 MHz Associated.
Mass spectra were conducted at Micromass Q-Tof instrument (ESI) and Agilent Technologies 5973N (EI). All reactions were carried
out in flame-dried reaction vessels with Teflon screw caps under argon. Cu(tmhd)2 and Cu(OTf)2 were purchased from TCI, fac-
[Ir(ppy)3] was purchased from Acros. All of the cyclobutanone O-acyl oximes 1 were synthesized from the corresponding
cycloketones and carboxylic acids according to the literatures.12a-c All of the NMR spectra of the know compounds were in full
accordance with the data in the literature. Unless otherwise noted, materials obtained from commercial suppliers were used without
further purification.
o
Characterization of New Starting Materials. 2-Phenylcyclobutan-1-one O-benzoyl oxime (1h). A brown soild, mp 76-78 C
(5.0 mmol scale, 420.2 mg, 41%): 1H NMR (500 MHz, CDCl3) δ 8.10 – 8.03 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz,
2H), 7.42 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.27 – 7.25 (m, 1H), 4.70 – 4.66 (m, 1H), 3.28 – 3.08 (m, 2H), 2.70 – 2.55 (m,
1H), 2.35 – 2.15 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 170.8, 163.9, 138.7, 133.2, 129.6, 129.0, 128.6, 128.4, 127.1, 127.0, 49.6,
-1
29.5, 23.3; ATR-FTIR (cm ):1739, 1650, 1544, 1463, 1259, 1119, 710; HRMS m/z (ESI) calcd for C17H15NNaO2 (M + Na)+
288.0995, found 288.0998.
2-Phenylcyclopentan-1-one O-benzoyl oxime (1i). A white soild, mp 82-84 oC (5.0 mmol scale, 749.6 mg, 53%): 1H NMR (400
MHz, CDCl3) δ 8.07 (d, J = 7.1 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.34 – 7.33 (m, 4H), 7.26 – 7.22 (m, 1H),
4.05 (t, J = 7.2 Hz, 1H), 2.98 – 2.78 (m, 2H), 2.36 – 2.29 (m, 1H), 2.09 – 1.79 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 177.5, 163.7,
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The Journal of Organic Chemistry
140.3, 133.1, 129.5, 129.1, 128.5, 128.4, 127.8, 126.7, 49.0, 34.6, 29.8, 22.4; ATR-FTIR (cm-1): 1739, 1599, 1450, 1266, 710; HRMS
m/z (ESI) calcd for C18H18NO2 (M + H)+ 280.1332, found 280.1336.
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2-(4-(tert-Butyl)phenyl)cyclopentan-1-one O-benzoyl oxime (1j). A white soild, mp 102-104 oC (5.0 mmol scale, 838.5 mg, 50%):
1H NMR (400 MHz, CDCl3) δ 8.07 – 8.05 (m, 1H), 7.58 – 7.41 (m, 2H), 7.37 – 7.32 (m, 3H), 7.27 – 7.19 (m, 2H), 7.14 – 7.12 (m,
1H), 4.07 – 4.03 (m, 1H), 2.97 – 2.75 (m, 2H), 2.44 – 2.26 (m, 1H), 2.09 – 1.74 (m, 3H), 1.30 – 1.29 (m, 9H); 13C NMR (101 MHz,
CDCl3) δ 177.8, 175.9, 163.9, 163.8, 149.5, 149.4, 138.6, 137.2, 133.1, 132.8, 129.54, 129.49, 129.3, 128.8, 128.4, 128.0, 127.5,
126.8, 125.6, 125.5, 48.6, 48.3, 36.7, 34.5, 34.4, 33.1, 31.4 31.3, 29.9, 23.8, 22.5; ATR-FTIR (cm -1): 1739, 1650, 1550, 1454, 1260,
712; HRMS m/z (ESI) calcd for C22H25NNaO2 (M + Na)+ 358.1778, found 358.1780.
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2-(4-Fluorophenyl)cyclopentan-1-one O-benzoyl oxime (1k). A white soild, mp 85-87 oC (5.0 mmol scale, 628.2 mg, 42%): 1H
NMR (400 MHz, CDCl3) δ 8.07 – 8.05 (m, 2H), 7.60 – 7.56 (m, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.31 – 7.28 (m, 2H), 7.04 – 7.00 (m,
2H), 4.02 (t, J = 7.6 Hz, 1H), 2.99 – 2.74 (m, 2H), 2.36 – 2.29 (m, 1H), 2.04 – 1.81 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 177.3,
163.8, 161.71 (d, J = 245.0 Hz), 135.9 (d, J = 2.8 Hz), 133.2, 129.5, 129.4 (d, J = 8.0 Hz), 129.1, 128.5, 115.4 (d, J = 21.4 Hz), 48.5,
34.8, 29.8, 22.4; 19F NMR (376 MHz, CDCl3) δ -116.3; ATR-FTIR (cm -1): 2245, 1738, 1644, 1495, 1454, 1266, 708; HRMS m/z
(ESI) calcd for C18H16FNNaO2 (M + Na)+ 320.1057, found 320.1060.
2-([1,1'-Biphenyl]-4-yl)cyclopentan-1-one O-benzoyl oxime (1l). A white soild, mp 134-136 oC (5.0 mmol scale, 837.8 mg, 47%):
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.1 Hz, 1H), 7.61 – 7.40 (m, 10H), 7.36 – 7.33 (m, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.21 –
7.17 (m, 1H), 4.18 – 4.09 (m, 1H), 3.00 – 2.79 (m, 2H), 2.50 – 2.32 (m, 1H), 2.14 – 1.80 (m, 3H); 13C NMR (101 MHz, CDCl3) δ
177.6, 175.5, 163.9, 163.8, 140.9, 140.8, 140.7, 139.7, 139.5, 139.4, 133.2, 132.9, 129.6, 129.5, 128.8, 128.7, 128.5, 128.3, 128.1,
127.6, 127.5, 127.3, 127.2, 127.1, 127.0, 126.9, 48.9, 48.4, 36.7, 34.7, 33.1, 29.9, 23.8, 22.5; ATR-FTIR (cm -1): 1742, 1732, 1654,
1501, 1454, 1266, 708; HRMS m/z (ESI) calcd for C24H22NO2 (M + H)+ 356.1645, found 356.1650.
2-(4-Methoxyphenyl)cyclopentan-1-one O-benzoyl oxime (1m). A white soild, mp 125-127 oC (5.0 mmol scale, 821.5 mg, 53%):
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.4 Hz, 1.51H), 7.58 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.26 – 7.24 (m, 2H), 7.12
(d, J = 8.5 Hz, 0.5H), 6.88 – 6.84 (m, 2H), 4.10 – 3.99 (m, 1H), 3.79 (s, 3H), 2.94 – 2.76 (m, 2H), 2.37 – 2.27 (m, 1H), 2.04 – 1.80
(m, 3H); 13C NMR (101 MHz, CDCl3) δ 177.7, 175.9, 163.8, 158.4, 158.2, 133.8, 133.1, 132.9, 132.2, 129.52, 129.45, 129.2, 128.8,
128.4, 128.11, 128.09, 114.1, 114.0, 55.3, 55.2, 48.4, 47.7, 36.7, 34.6, 32.9, 29.8, 23.6, 22.4; ATR-FTIR (cm -1): 1740, 1640, 1451,
1263, 708; HRMS m/z (ESI) calcd for C19H20NO3 (M + H)+ 310.1438, found 310.1441.
2-(Naphthalen-2-yl)cyclopentan-1-one O-benzoyl oxime (1n). A white soild, mp 130-132 oC (5.0 mmol scale, 958.6 mg, 58%):
1H NMR (400 MHz, CDCl3) δ 8.09 – 8.07 (m, 1H), 7.84 – 7.78 (m, 3H), 7.75 – 7.68 (m, 1H), 7.61 – 7.42 (m, 4H), 7.34 – 7.28 (m,
1H), 7.24 – 7.22 (m, 1H), 6.96 – 6.93 (m, 1H), 4.30 – 4.22 (m, 1H), 3.03 – 2.83 (m, 2H), 2.51 – 2.34 (m, 1H), 2.21 – 1.81 (m, 3H);
13C NMR (101 MHz, CDCl3) δ 177.4, 175.4, 163.84, 163.77, 139.1, 137.7, 133.5, 133.4, 133.1, 132.8, 132.4, 132.1, 129.6, 129.3,
129.2, 128.7, 128.51, 128.45, 128.3, 127.9, 127.8, 127.6, 127.52, 127.47, 126.4, 126.3, 126.1, 126.0, 125.7, 125.6, 125.4, 36.6, 34.5,
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33.1, 29.9, 23.8, 22.5; ATR-FTIR (cm -1): 1739, 1651, 1545, 1464, 1260, 1120, 711; HRMS m/z (ESI) calcd for C22H19NNaO2 (M +
Na)+ 352.1308, found 352.1305.
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6
7
8
9
2-(Benzo[b]thiophen-5-yl)cyclopentan-1-one O-benzoyl oxime (1o). A yellow soild, mp 135-137 oC (5.0 mmol scale, 754.2 mg,
45%): 1H NMR (400 MHz, CDCl3) δ 8.08 – 8.06 (m, 1H), 7.84 (dd, J = 8.4, 1.8 Hz, 1H), 7.77 – 7.67 (m, 1H), 7.61 – 7.56 (m, 0.5H),
7.48 – 7.42 (m, 2H), 7.38 – 7.24 (m, 3H), 7.20 (dd, J = 8.3, 1.7 Hz, 0.5H), 7.07 – 7.03 (m, 1H), 4.25 – 4.17 (m, 1H), 3.02 – 2.82 (m,
2H), 2.50 – 2.33 (m, 1H), 2.16 – 1.80 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 177.6, 175.6, 163.9, 163.8, 140.0, 139.9, 138.2, 137.9,
136.5, 133.1, 132.8, 129.6, 129.4, 129.2, 128.6, 128.5, 128.0, 127.1, 126.7, 124.4, 123.8, 123.7, 123.6, 122.9, 122.7, 122.6, 122.0,
49.1, 48.7, 37.0, 34.9, 33.1, 29.9, 23.8, 22.5; ATR-FTIR (cm -1): 1738, 1625, 1593, 1454, 1259, 707; HRMS m/z (ESI) calcd for
C20H17NNaO2S (M +Na)+ 358.0872, found 358.0877.
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2-(4-Methoxyphenyl)cycloheptan-1-one O-benzoyl oxime (1p). A white soild, mp 84-86 oC (3.0 mmol scale, 633.9 mg, 63%). 1H
NMR (400 MHz, CDCl3) δ 8.07 – 8.05 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.87 (d, J
= 8.7 Hz, 2H), 4.09 – 4.05 (m, 1H), 3.78 (s, 3H), 3.14 – 3.10 (m, 1H), 2.39 – 2.32 (m, 1H), 2.11 – 2.05 (m, 1H), 1.98 – 1.88 (m, 4H),
1.63 – 1.57 (m, 1H), 1.46 – 1.39 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 173.2, 164.0, 158.5, 133.1, 132.7, 129.5, 129.4, 128.5,
128.3, 113.9, 55.2, 47.6, 31.0, 30.8, 27.4, 26.2, 25.4; ATR-FTIR (cm-1): 2222, 1692, 1480, 1371, 1276, 1174, 758; HRMS m/z (ESI)
calcd for C21H23NNaO3 (M + Na)+ 360.1570, found 360.1573.
General Procedure A of Copper-Catalyzed Selective C (sp3)-N Cross-Couplings.
Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone oxime 1a (56.7 mg, 0.3 mmol), aniline 2a (18.6 mg, 0.2 mmol),
Cu(tmhd)2 (4.3 mg, 5 mol%), and absolute dry DMF (1.0 mL) were added under Ar. The formed mixture was stirred at 80 ºC with
the heating mantle under Ar for 12 h as monitored by TLC. The solution was then cooled to room temperature, the mixture was
extracted with EA and saturated NaHCO3 solution, dried (MgSO4) and concentrated to give a crude product. The crude product was
purified by flash column chromatography on silica gel (PE : EA = 8 : 1) to afford 3aa.
4-(Phenylamino)butanenitrile (3aa). A yellow oil (27.1 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 7.20 (t, J = 7.9 Hz, 2H), 6.75
(t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 2H), 3.72 (br s, 1H), 3.32 (t, J = 6.6 Hz, 2H), 2.47 (t, J = 7.1 Hz, 2H), 2.07 – 1.89 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 147.5, 129.3, 119.3, 117.9, 112.8, 42.2, 25.2, 14.7; ATR-FTIR (cm -1): 2245, 1596, 1452, 1385, 1267,
1115, 1071, 741; HRMS m/z (ESI) calcd for C10H13N2 (M + H)+ 161.1073, found 161.1076.
4-(p-Tolylamino)butanenitrile (3ba). A yellow oil (30.9 mg, 89%): 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 8.0 Hz, 2H), 6.57
– 6.54 (m, 2H), 3.57 (br s, 1H), 3.29 (t, J = 6.6 Hz, 2H), 2.47 (t, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.99 – 1.92 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 145.2, 129.8, 127.1, 119.4, 113.0, 42.6, 25.2, 20.3, 14.7; ATR-FTIR (cm -1): 2247, 1550, 1446, 1381, 1267, 1060,
749; HRMS m/z (ESI) calcd for C11H15N2 (M + H)+ 175.1230, found 175.1229.
1
4-((4-(tert-Butyl)phenyl)amino)butanenitrile (3ca). A yellow oil (40.3 mg, 93%): H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.4
Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 3.31 (t, J = 6.5 Hz, 2H), 2.48 (t, J = 7.1 Hz, 2H), 1.97 – 1.90 (m, 2H), 1.31 (s, 9H); 13C NMR (126
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MHz, CDCl3) δ 145.1, 140.6, 126.1, 119.4, 112.5, 42.4, 33.8, 31.4, 25.3, 14.7; ATR-FTIR (cm ): 2246, 1603, 1462, 1378, 1123,
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751; HRMS m/z (ESI) calcd for C14H21N2 (M + H)+ 217.1699, found 217.1702.
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4-((4-Fluorophenyl)amino)butanenitrile (3da). A yellow oil (29.6 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 6.90 – 6.86 (m, 2H),
6.58 – 6.52 (m, 2H), 3.26 (t, J = 6.6 Hz, 2H), 2.47 (t, J = 7.1 Hz, 2H), 1.98 – 1.91 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 155.9 (d,
J = 235.5 Hz), 143.8, 119.3, 115.7 (d, J = 22.4 Hz), 113.7 (d, J = 7.4 Hz), 42.9, 25.1, 14.7; 19F NMR (376 MHz, CDCl3) δ -127.5;
ATR-FTIR (cm -1): 2245, 1719, 1452, 1385, 1267, 1115, 1071, 741; HRMS m/z (ESI) calcd for C10H12FN2 (M + H)+ 179.0979, found
179.0978.
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4-((4-(Trifluoromethyl)phenyl)amino)butanenitrile (3ea). A yellow oil (26.3 mg, 58%): 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J
= 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 4.13 (br s, 1H), 3.37 – 3.32 (m, 2H), 2.47 (t, J = 7.0 Hz, 2H), 2.04 – 1.94 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 145.0, 126.7 (q, J = 3.7 Hz), 124.8 (q, J = 270.3 Hz), 119.3 (q, J = 32.7 Hz), 119.1, 111.9, 41.8, 24.9, 14.7; 19
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NMR (471 MHz, CDCl3) δ -61.1; ATR-FTIR (cm -1): 2246, 1550, 1459, 1383, 1223, 1050, 736; HRMS m/z (ESI) calcd for
C11H12F3N2 (M + H)+ 229.0947, found 229.0950.
4-((2-Iodophenyl)amino)butanenitrile (3fa). A yellow oil (36.3 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 7.8, 1.4
Hz, 1H), 7.24 – 7.20 (m, 1H), 6.59 (dd, J = 8.1, 1.0 Hz, 1H), 6.48 (td, J = 7.7, 1.4 Hz, 1H), 4.18 (br s, 1H), 3.39 – 3.34 (m, 2H), 2.49
(t, J = 7.1 Hz, 2H), 2.04 – 1.97 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 146.4, 139.2, 129.5, 119.2, 119.1, 110.5, 85.7, 42.4, 24.9,
14.8; ATR-FTIR (cm -1): 2248, 1505, 1452, 1378, 1236, 1125, 756; HRMS m/z (ESI) calcd for C10H12IN2 (M + H)+ 287.0040, found
287.0043.
4-((4-Methoxyphenyl)amino)butanenitrile (3ga). A yellow oil (29.7 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 6.85 – 6.74 (m,
2H), 6.65 – 6.54 (m, 2H), 3.75 (s, 3H), 3.25 (t, J = 6.6 Hz, 2H), 2.47 (t, J = 7.1 Hz, 2H), 1.97 – 1.90 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 152.4, 141.7, 119.4, 114.9, 114.2, 55.7, 43.2, 25.3, 14.8; ATR-FTIR (cm -1): 2247, 1596, 1505, 1378, 1264, 1120, 1069,
750; HRMS m/z (ESI) calcd for C11H15N2O (M + H)+ 191.1179, found 191.1182.
4-((4-(Cyanomethyl)phenyl)amino)butanenitrile (3ha). A yellow oil (28.9 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J =
8.6 Hz, 2H), 6.69 – 6.53 (m, 2H), 3.88 (br s, 1H), 3.62 (s, 2H), 3.30 (t, J = 6.6 Hz, 2H), 2.47 (t, J = 7.0 Hz, 2H), 1.99 – 1.92 (m, 2H);
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13C NMR (101 MHz, CDCl3) δ 147.2, 129.0, 119.3, 118.53, 118.47, 113.1, 42.1, 25.0, 22.7, 14.7; ATR-FTIR (cm ): 2247, 1590,
1509, 1378, 1220, 1116, 746; HRMS m/z (ESI) calcd for C12H14N3 (M + H)+ 200.1182, found 200.1185.
4-((3-Bromo-4-(trifluoromethoxy)phenyl)amino)butanenitrile (3ia). A yellow oil (47.3 mg, 73%): 1H NMR (500 MHz, CDCl3)
δ 7.10 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 6.51 (dd, J = 8.9, 2.7 Hz, 1H), 3.88 (br s, 1H), 3.31 – 3.26 (m, 2H), 2.48 (t, J =
7.0 Hz, 2H), 2.00 – 1.94 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 147.0, 137.8, 123.6, 120.6 (q, J = 257.8 Hz), 119.0, 117.3, 116.5,
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112.3, 42.3, 24.8, 14.8; 19F NMR (471 MHz, CDCl3) δ -58.2; ATR-FTIR (cm ): 2248, 1603, 1545, 1372, 1246, 752; HRMS m/z
(ESI) calcd for C11H11BrF3N2O (M + H)+ 323.0001, found 323.0006.
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4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)butanenitrile (3ja). A yellow oil (49.8 mg, 78%): 1H NMR (400 MHz, CDCl3)
δ 7.36 – 7.30 (m, 1H), 7.22 – 7.18 (m, 2H), 7.03 – 6.96 (m, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 6.43 (dd, J = 8.8,
2.8 Hz, 1H), 5.02 (s, 2H), 3.22 (t, J = 6.6 Hz, 2H), 2.45 (t, J = 7.1 Hz, 2H), 1.95 – 1.89 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 162.8
(d, J = 245.9 Hz), 146.2, 143.1, 139.6 (d, J = 7.3 Hz), 130.0 (d, J = 8.2 Hz), 124.7, 122.6 (d, J = 2.4 Hz), 119.3, 117.1, 114.7, 114.6
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(d, J = 21.1 Hz), 114.1 (d, J = 22.1 Hz), 111.9, 71.4, 42.7, 25.0, 14.7; 19F NMR (376 MHz, CDCl3) δ -112.9; ATR-FTIR (cm ):
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2246, 1603, 1460, 1372, 1264, 1056, 753; HRMS m/z (ESI) calcd for C17H17ClFN2O (M + H)+ 319.1008, found 319.1012.
4-((2,5-Dimethoxy-4-nitrophenyl)amino)butanenitrile (3ka) . A yellow oil (36.9 mg, 70%): 1H NMR (400 MHz, CDCl3) δ 7.51
(s, 1H), 6.13 (s, 1H), 5.13 (t, J = 5.5 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.44 (q, J = 6.6 Hz, 2H), 2.51 (t, J = 6.9 Hz, 2H), 2.08 – 2.02
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 152.8, 144.5, 139.1, 126.4, 118.9, 107.2, 92.7, 56.8, 56.0, 41.2, 24.9, 14.8; ATR-FTIR (cm
-1): 2248, 1598, 1505, 1382, 1265, 1125, 1068, 753; HRMS m/z (ESI) calcd for C12H16N3O4 (M + H)+ 266.1135, found 266.1137.
4-((2-Fluoro-6-methoxyphenyl)amino)butanenitrile (3la). A yellow oil (32.8 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 6.64 (dd,
J = 8.3, 5.0 Hz, 1H), 6.35 – 6.29 (m, 2H), 4.39 (br s, 1H), 3.81 (s, 3H), 3.28 (t, J = 5.7 Hz, 2H), 2.47 (t, J = 7.1 Hz, 2H), 2.02 – 1.95
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 158.2 (d, J = 235.9 Hz), 142.8, 138.6 (d, J = 10.9 Hz), 119.2, 109.7 (d, J = 10.1 Hz), 101.3
(d, J = 23.0 Hz), 97.4 (d, J = 28.2 Hz), 55.8, 41.8, 25.0, 14.7; 19F NMR (376 MHz, CDCl3) δ -121.9; ATR-FTIR (cm -1): 2248, 1601,
1505, 1380, 1265, 1065, 752; HRMS m/z (ESI) calcd for C11H14FN2O (M + H)+ 209.1085, found 209.1087.
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4-((1H-indol-4-yl)amino)butanenitrile (3ma). A brown oil (33.8 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 8.16 (br s, 1H), 7.12 –
7.07 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.45 (t, J = 2.2 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 4.01 (br s, 1H), 3.47 (t, J = 6.6 Hz, 2H), 2.50
(t, J = 7.1 Hz, 2H), 2.09 – 2.02 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 140.6, 136.4, 123.4, 122.2, 119.6, 116.8, 101.8, 99.3, 98.4,
42.3, 25.3, 14.8; ATR-FTIR (cm -1): 2248, 1603, 1506, 1452, 1372, 1265, 1123, 1068, 755; HRMS m/z (ESI) calcd for C12H14N3 (M
+ H)+ 200.1182, found 200.1185.
4-((3-Acetylphenyl)amino)butanenitrile (3na). A brown oil (30.4 mg, 75 %). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.28 (m, 2H),
7.23 – 7.19 (m, 1H), 6.85 – 6.82 (m, 1H), 4.04 (br s, 1H), 3.37 (t, J = 6.6 Hz, 2H), 2.59 (s, 3H), 2.50 (t, J = 7.1 Hz, 2H), 2.03 – 1.96
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 198.6, 147.7, 138.1, 129.4, 119.3, 118.2, 117.6, 111.2, 42.1, 26.7, 25.0, 14.7; ATR-FTIR
(cm -1): 2247, 1736, 1605, 1460, 1379, 1256, 1120, 752; HRMS m/z (ESI) calcd for C12H15N2O (M + H)+ 203.1179, found 203.1182.
4-(Naphthalen-2-ylamino)butanenitrile (3oa). A yellow oil (33.5 mg, 80 %). 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.60 (m, 3H),
7.39 – 7.34 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.83 (dd, J = 8.8, 2.3 Hz, 1H), 6.78 (d, J = 1.7 Hz, 1H), 3.85 (br s, 1H), 3.34 (t, J = 6.6
Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 1.99 – 1.92 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 145.1, 135.0, 129.0, 127.6, 126.4, 125.9, 122.2,
119.4, 117.8, 104.3, 42.2, 24.9, 14.7; ATR-FTIR (cm -1): 2248, 1601, 1505, 1462, 1380, 1127, 1065, 751; HRMS m/z (ESI) calcd for
C14H15N2 (M + H)+ 211.1230, found 211.1235.
4-(Quinolin-6-ylamino)butanenitrile (3pa) . A yellow oil (26.8 mg, 64%): 1H NMR (400 MHz, CDCl3) δ 8.61 (dd, J = 4.2, 1.4
Hz, 1H), 7.90 (dd, J = 18.1, 8.5 Hz, 2H), 7.26 – 7.25 (m, 1H), 7.07 (dd, J = 9.0, 2.6 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 4.19 (br s, 1H),
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3.40 (t, J = 6.6 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H), 2.06 – 1.99 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 146.3, 145.5, 143.1, 133.9,
130.2, 130.0, 121.5, 121.3, 119.2, 103.0, 42.2, 24.8, 14.8; ATR-FTIR (cm -1): 2246, 1595, 1464, 1380, 1265, 1132, 1066, 749; HRMS
m/z (ESI) calcd for C13H14N3 (M + H)+ 212.1182, found 212.1179.
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4-((3-(Hydroxymethyl)phenyl)amino)butanenitrile (3qa) . A colorless oil (27.5 mg, 72%): H NMR (400 MHz, CDCl3) δ 7.15 (t,
J = 7.8 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.62 (s, 1H), 6.53 (dd, J = 8.0, 1.8 Hz, 1H), 4.58 (s, 2H), 3.28 (t, J = 6.5 Hz, 2H), 2.43 (t, J
= 7.0 Hz, 2H), 1.96 – 1.89 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 147.8, 142.2, 129.4, 119.5, 116.2, 111.8, 111.2, 65.1, 42.1, 25.0,
14.6; ATR-FTIR (cm -1): 2247, 1605, 1466, 1378, 1250, 1065, 762; HRMS m/z (ESI) calcd for C11H15N2O (M + H)+ 191.1179, found
191.1182.
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4-((3-Hydroxyphenyl)amino)butanenitrile (3ra) . A colorless oil (19.4, 55%). 1H NMR (400 MHz, CDCl3) δ 7.01 (t, J = 8.0 Hz,
1H), 6.26 – 6.14 (m, 2H), 6.10 (s, 1H), 4.55 (br s, 1H), 3.20 (t, J = 6.7 Hz, 2H), 2.40 (t, J = 7.1 Hz, 2H), 1.91 – 1.85 (m, 2H); 13
C
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NMR (101 MHz, CDCl3) δ 157.0, 149.1, 130.3, 119.6, 105.7, 105.0, 99.8, 42.2, 25.0, 14.6; ATR-FTIR (cm ): 2246, 1709, 1506,
1446, 1378, 1264, 1069, 735; HRMS m/z (ESI) calcd for C10H13N2O (M + H)+ 177.1022, found 177.1025.
3-((3-Cyanopropyl)amino)benzoic acid (3sa). A white solid, mp 157-159 oC (19.7 mg, 48%). 1H NMR (400 MHz, DMSO) δ 7.20
– 7.11 (m, 3H), 6.80 – 6.77 (m, 1H), 5.97 (br s, 1H), 3.16 – 3.06 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 1.86 – 1.79 (m, 2H); 13C NMR
(101 MHz, DMSO) δ 167.9, 148.7, 131.5, 129.1, 120.6, 116.8, 116.1, 112.6, 41.4, 24.4, 14.1; ATR-FTIR (cm -1): 2246, 1728, 1631,
1565, 1511, 1263, 1096, 850; HRMS m/z (ESI) calcd for C11H13N2O2 (M + H)+ 205.0972, found 205.0970.
4-((4-(Phenylamino)phenyl)amino)butanenitrile (3ta). A yellow oil (36.4 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 7.22 – 7.17
(m, 2H), 7.04 – 7.01 (m, 2H), 6.87 – 6.84 (m, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.63 – 6.59 (m, 2H), 5.43 (br s, 1H), 3.30 (t, J = 6.6 Hz,
2H), 2.49 (t, J = 7.1 Hz, 2H), 2.00 – 1.93 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 145.9, 143.5, 133.3, 129.2, 123.5, 119.4, 118.9,
114.9, 113.8, 42.8, 25.3, 14.8; ATR-FTIR (cm -1): 2246, 1590, 1452, 1377, 1265, 1123, 1068, 746; HRMS m/z (ESI) calcd for
C16H18N3 (M + H)+ 252.1495, found 252.1493.
4-((3-Cyanopropyl)amino)-N-methylbenzamide (3ua). A yellow oil (30.9 mg, 71%): 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J =
8.5 Hz, 2H), 6.55 (d, J = 8.5 Hz, 2H), 6.32 (br s, 1H), 4.32 (br s, 1H), 3.31 (t, J = 6.6 Hz, 2H), 2.94 (d, J = 4.6 Hz, 3H), 2.45 (t, J =
7.0 Hz, 2H), 1.97 – 1.91 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 168.0, 150.2, 128.6, 123.1, 119.3, 111.7, 41.7, 26.6, 24.9, 14.7;
ATR-FTIR (cm -1): 2247, 1715, 1509, 1450, 1383, 1264, 1150, 1069, 735; HRMS m/z (ESI) calcd for C12H16N3O (M + H)+ 218.1288,
found 218.1289.
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N-(4-((3-Cyanopropyl)amino)phenyl)acetamide (3va). A yellow oil (37.6 mg, 87%): H NMR (500 MHz, CDCl3) δ 7.62 (br s,
1H), 7.28 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H), 3.26 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 7.0 Hz, 2H), 2.12 (s, 3H), 1.97 – 1.90 (m,
2H); 13C NMR (126 MHz, CDCl3) δ 168.5, 144.6, 128.6, 122.4, 119.4, 112.9, 42.5, 25.1, 24.1, 14.7; ATR-FTIR (cm -1): 2248, 1732,
1605, 1553, 1381, 1259, 1115, 742; HRMS m/z (ESI) calcd for C12H16N3O (M + H)+ 218.1288, found 218.1290.
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3-((3-Cyanopropyl)amino)-4-methylbenzamide (3wa). A white oil (25.1 mg, 58%): 1H NMR (400 MHz, DMSO) δ 7.79 (br s, 1H),
7.14 (br s, 1H), 7.07 – 6.99 (m, 3H), 5.04 (br s, 1H), 3.20 (t, J = 6.6 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.11 (s, 3H), 1.93 – 1.86 (m,
2H); 13C NMR (101 MHz, DMSO) δ 168.6, 146.0, 132.9, 129.4, 125.6, 120.8, 115.3, 107.9, 41.7, 24.3, 17.7, 14.2; ATR-FTIR (cm -
1): 2246, 1729, 1603, 1455, 1379, 1129, 1032, 733; HRMS m/z (ESI) calcd for C12H16N3O (M + H)+ 218.1288, found 218.1289.
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4-((4-Methyl-2-oxo-2H-chromen-7-yl)amino)butanenitrile (3xa). A yellow oil (22.4 mg, 46%). H NMR (400 MHz, CDCl3) δ
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2.33 (d, J = 1.1 Hz, 3H), 2.06 – 1.97 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 161.9, 155.8, 153.1, 151.0, 125.7, 119.1, 110.9, 110.0,
109.6, 98.4, 41.8, 24.7, 18.5, 14.8; ATR-FTIR (cm -1): 2248, 1725, 1556, 1463, 1382, 1263, 1036, 752; HRMS m/z (ESI) calcd for
C14H15N2O2 (M + H)+ 243.1128, found 243.1132.
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4-((3-Fluoro-4-morpholinophenyl)amino)butanenitrile (3ya). A yellow oil (45.7 mg, 87%): 1H NMR (400 MHz, CDCl3) δ 6.82
(t, J = 9.2 Hz, 1H), 6.41 – 6.28 (m, 2H), 3.84 – 3.82 (m, 4H), 3.64 (br s, 1H), 3.23 (t, J = 6.6 Hz, 2H), 2.94 – 2.93 (m, 4H), 2.45 (t, J
= 7.1 Hz, 2H), 1.96 – 1.89 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 156.9 (d, J = 245.1 Hz), 144.2 (d, J = 10.2 Hz), 131.0 (d, J = 9.8
Hz), 120.3 (d, J = 4.5 Hz), 119.2, 108.2 (d, J = 2.8 Hz), 101.5 (d, J = 24.5 Hz), 67.0, 51.7, 51.6, 42.5, 25.0, 14.7; 19F NMR (376 MHz,
CDCl3) δ -122.4; ATR-FTIR (cm -1): 2246, 1559, 1456, 1380, 1264, 1120, 1065, 749; HRMS m/z (ESI) calcd for C14H19FN3O (M +
H)+ 264.1507, found 264.1505.
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4-((4-(4-Ethyl-2,6-dioxopiperidin-4-yl)phenyl)amino)butanenitrile (3za). A yellow oil (54.7 mg, 91%): H NMR (400 MHz,
CDCl3) δ 8.47 (br s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 3.28 (t, J = 6.6 Hz, 2H), 2.61 – 2.50 (m, 1H), 2.47 (t, J =
7.1 Hz, 2H), 2.44 – 2.38 (m, 1H), 2.32 – 2.27 (m, 1H), 2.14 (td, J = 13.7, 4.6 Hz, 1H), 2.02 – 1.83 (m, 4H), 0.83 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 175.7, 172.9, 146.7, 127.2, 127.1, 119.3, 112.9, 50.0, 42.0, 32.8, 29.2, 26.7, 25.0, 14.7, 8.9; ATR-
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FTIR (cm ): 2248, 1729, 1515, 1460, 1379, 1123, 1065, 752; HRMS m/z (ESI) calcd for C17H22N3O2 (M + H)+ 300.1707, found
300.1709.
General Procedure B of Copper-Catalyzed Selective C (sp3)-N Cross-Couplings.
Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone oxime 1b (53.0 mg, 0.2 mmol), aniline 2a (37.2 mg, 0.4 mmol),
Cu(tmhd)2 (4.3 mg, 5 mol%), and absolute dry DMF (1.0 mL) were added under Ar. The formed mixture was stirred at 80 ºC with
heating mantle under Ar for 12 h as monitored by TLC. The solution was then cooled to room temperature, the mixture was extracted
with EA and saturated NaHCO3 solution, dried (MgSO4) and concentrated to give a crude product. The crude product was purified
by flash column chromatography on silica gel (PE : EA = 8 : 1) to afford 3ab.
3-Phenyl-4-(phenylamino)butanenitrile (3ab). A yellow oil (30.6 mg, 65%): 1H NMR (500 MHz, CDCl3) δ 7.45 (t, J = 7.4 Hz,
2H), 7.39 (t, J = 7.1 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 8.1 Hz, 2H), 3.73
(br s, 1H), 3.63 (dd, J = 13.1, 6.9 Hz, 1H), 3.49 (dd, J = 13.1, 7.3 Hz, 1H), 3.40 – 3.33 (m, 1H), 2.84 – 2.73 (m, 2H); 13C NMR (126
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MHz, CDCl3) δ 147.2, 139.3, 129.4, 129.1, 128.0, 127.3, 118.3, 118.1, 113.0, 47.9, 41.3, 22.1; ATR-FTIR (cm -1): 2247, 1550, 1452,
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1380, 1126, 1066, 755; HRMS m/z (ESI) calcd for C16H17N2 (M + H)+ 237.1386, found 237.1388.
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3-Benzyl-4-(phenylamino)butanenitrile (3ac). A colorless oil (36.1 mg, 72%): H NMR (500 MHz, CDCl3) δ 7.38 (t, J = 7.4 Hz,
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2H), 7.32 – 7.29 (m, 1H), 7.26 – 7.20 (m, 4H), 6.77 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 2H), 3.83 (br s, 1H), 3.34 (dd, J = 13.8,
5.3 Hz, 1H), 3.24 (dd, J = 13.7, 7.9 Hz, 1H), 2.92 (dd, J = 13.8, 5.9 Hz, 1H), 2.76 (dd, J = 13.8, 8.1 Hz, 1H), 2.50 (td, J = 6.8, 3.3 Hz,
1H), 2.40 – 2.34 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 147.4, 138.1, 129.3, 128.9, 128.7, 126.8 118.3 117.8, 112.8 46.6, 37.7, 37.2,
19.4; ATR-FTIR (cm -1): 2247, 1602, 1556, 1377, 1123, 1069, 748; HRMS m/z (ESI) calcd for C17H19N2 (M + H)+ 251.1543, found
251.1540.
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3-(Benzyloxy)-4-(phenylamino)butanenitrile (3ad). A yellow oil (23.4 mg, 44%): 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.32 (m,
5H), 7.20 – 7.16 (m, 2H), 6.75 (t, J = 7.3 Hz, 1H), 6.60 – 6.58 (m, 2H), 4.71 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 11.6 Hz, 1H), 4.00 –
3.94 (m, 1H), 3.91 (br s, 1H), 3.43 – 3.28 (m, 2H), 2.68 (d, J = 5.9 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 147.4, 137.0, 129.4,
128.7, 128.3, 128.0, 118.2, 117.3, 113.1, 73.0, 72.3, 46.3, 21.2; ATR-FTIR (cm -1): 2247, 1556, 1453, 1380, 1262, 1133, 1020, 753;
HRMS m/z (ESI) calcd for C17H19N2O (M + H)+ 267.1492, found 267.1496.
3-Methyl-3-phenyl-4-(phenylamino)butanenitrile (3ae). A yellow oil 30.5 mg, 61%): 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.31
(m, 5H), 7.20 – 7.13 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H), 3.53 – 3.48 (m, 1H), 3.44 – 3.39 (m, 1H), 3.30 (br s,
1H), 2.85 (s, 2H), 1.63 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.8, 142.0, 129.3, 129.1, 127.5, 125.8, 118.1, 118.0, 113.2, 53.5,
41.5, 28.4, 24.3; ATR-FTIR (cm -1): 2248, 1603, 1556, 1455, 1382, 1265, 1075, 736; HRMS m/z (ESI) calcd for C17H19N2 (M + H)+
251.1543, found 251.1543.
4-Cyano-3-methyl-3-((phenylamino)methyl)butyl acetate (3af). A yellow oil (30.3 mg, 58%): 1H NMR (400 MHz, CDCl3) δ 7.21
– 7.17 (m, 2H), 6.76 – 6.72 (m, 1H), 6.69 – 6.66 (m, 2H), 4.24 – 4.12 (m, 2H), 3.84 (br s, 1H), 3.14 (s, 2H), 2.44 (s, 2H), 2.06 (s,
3H), 1.84 (t, J = 6.7 Hz, 2H), 1.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.9, 148.1, 129.3, 118.1, 117.9, 113.1, 60.3, 51.5, 36.9,
35.3, 27.0, 22.7, 20.9; ATR-FTIR (cm -1): 2248, 1726, 1559, 1446, 1377, 1269, 1125, 1067, 739; HRMS m/z (ESI) calcd for
C15H21N2O2 (M + H)+ 261.1598, found 261.1596.
tert-Butyl 4-(cyanomethyl)-4-((phenylamino)methyl)piperidine-1-carboxylate (3ag). A yellow oil (34.1 mg, 52%). 1H NMR (400
MHz, CDCl3) δ 7.22 – 7.17 (m, 2H), 6.77 – 6.72 (m, 1H), 6.70 – 6.68 (m, 2H), 3.70 – 3.60 (m, 2H), 3.30 – 3.21 (m, 4H), 2.53 (s,
2H), 1.66 – 1.60 (m, 4H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 154.6, 148.0, 129.4, 118.3, 117.6, 113.2, 80.0, 50.6, 36.4,
32.3, 28.4, 23.7; ATR-FTIR (cm -1): 2247, 1726, 1562, 1463, 1378, 1259, 1036, 759; HRMS m/z (ESI) calcd for C19H28N3O2 (M +
H)+ 330.2176, found 330.2173.
General Procedure C of Copper-Catalyzed Selective C (sp3)-N Cross-Couplings.
Flame-dried 25 mL Schlenk tube filled with argon, 2-phenylcyclobutan-1-one O-benzoyl oxime 1h (53.0 mg, 0.2 mmol), aniline
2a (37.2 mg, 0.4 mmol), Cu(OTf)2 (3.6 mg, 5 mol%), and absolute dry 1,4-dioxane (1.0 mL) were added under Ar. The formed
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mixture was stirred at 80 ºC under Ar for 12 h as monitored by TLC. The solution was then cooled to room temperature, the mixture
was extracted with EA and saturated NaHCO3 solution, dried (MgSO4) and concentrated to give a crude product. The crude product
was purified by flash column chromatography on silica gel (PE : EA = 7 : 1) to afford 3ah.
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4-Phenyl-4-(phenylamino)butanenitrile (3ah). A yellow oil (19.7 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.31 (m, 4H),
7.30 – 7.27 (m, 1H), 7.15 – 7.09 (m, 2H), 6.72 – 6.66 (m, 1H), 6.59 – 6.57 (m, 2H), 4.51 (t, J = 7.0 Hz, 1H), 4.05 (br s, 1H), 2.52 –
2.32 (m, 2H), 2.25 – 2.08 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 146.5, 141.6, 129.3, 129.0, 127.8, 126.3, 119.3, 118.2, 113.7, 56.9,
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33.6, 14.5; ATR-FTIR (cm ): 2245, 1601, 1524, 1451, 1383, 1207, 1062, 750; HRMS m/z (ESI) calcd for C16H17N2 (M + H)+
237.1386, found 237.1385.
5-Phenyl-5-(phenylamino)pentanenitrile (3ai). A yellow oil (26.5 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.33 (m, 4H),
7.27 – 7.24 (m, 1H), 7.12 – 7.08 (m, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 7.8 Hz, 2H), 4.36 (t, J = 6.8 Hz, 1H), 4.05 (br s, 1H),
2.35 (td, J = 7.0, 1.6 Hz, 2H), 2.03 – 1.93 (m, 2H), 1.85 – 1.77 (m, 1H), 1.72 – 1.66 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 146.9,
142.9, 129.2, 128.8, 127.3, 126.2, 119.3, 117.6, 113.3, 57.4, 37.3, 22.4, 17.1; ATR-FTIR (cm -1): 2246, 1556, 1454, 1380, 1209, 1065,
745; HRMS m/z (ESI) calcd for C17H19N2 (M + H)+ 251.1543, found 251.1540.
5-(4-(tert-Butyl)phenyl)-5-(phenylamino)pentanenitrile (3aj). A yellow oil (36.7 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.36
– 7.34 (m, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.13 – 7.10 (m, 2H), 6.67 (t, J = 7.3 Hz, 1H), 6.60 – 6.47 (m, 2H), 4.35 (t, J = 6.8 Hz, 1H),
2.34 (td, J = 7.1, 2.2 Hz, 2H), 2.00 – 1.92 (m, 2H), 1.83 – 1.78 (m, 1H), 1.71 – 1.65 (m, 1H), 1.31 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 150.1, 147.0, 139.7, 129.1, 125.9, 125.6, 119.4, 117.4, 113.2, 56.9, 37.2, 34.4, 31.3, 22.4, 17.0; ATR-FTIR (cm -1): 2247,
1560, 1446, 1383, 1216, 1032, 746; HRMS m/z (ESI) calcd for C21H27N2 (M + H)+ 307.2169, found 307.2170.
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5-(4-Fluorophenyl)-5-(phenylamino)pentanenitrile (3ak). A yellow oil (26.9 mg, 50%): H NMR (400 MHz, CDCl3) δ 7.32 –
7.28 (m, 2H), 7.12 – 7.08 (m, 2H), 7.02 (t, J = 8.6 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.51 (d, J = 7.7 Hz, 2H), 4.35 (t, J = 6.8 Hz, 1H),
2.36 (td, J = 7.0, 1.8 Hz, 2H), 1.98 – 1.88 (m, 2H), 1.82 – 1.77 (m, 1H), 1.72 – 1.64 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 161.9
(d, J = 245.4 Hz), 146.7, 138.6 (d, J = 3.1 Hz), 129.2, 127.7 (d, J = 8.1 Hz), 119.2, 117.8, 115.6 (d, J = 21.4 Hz), 113.4, 56.8, 37.4,
22.3, 17.0; 19F NMR (376 MHz, CDCl3) δ -115.3; ATR-FTIR (cm -1): 2246, 1602, 1507, 1427, 1318, 1223, 1157, 752; HRMS m/z
(ESI) calcd for C17H18FN2 (M + H)+ 269.1449, found 269.1447.
5-([1,1'-Biphenyl]-4-yl)-5-(phenylamino)pentanenitrile (3al) . A yellow oil (42.9 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 7.56
– 7.53 (m, 4H), 7.45 – 7.30 (m, 5H), 7.10 (t, J = 7.9 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 7.9 Hz, 2H), 4.39 (t, J = 6.8 Hz,
1H), 4.09 (br s, 1H), 2.36 – 2.30 (m, 2H), 2.01 – 1.93 (m, 2H), 1.85 – 1.76 (m, 1H), 1.75 – 1.66 (m, 1H); 13C NMR (101 MHz, CDCl3)
δ 146.9, 142.0, 140.6, 140.2, 129.2, 128.7, 127.5, 127.2, 127.0, 126.7, 119.3, 117.6, 113.3, 57.1, 37.3, 22.3, 17.0; ATR-FTIR (cm -1):
2246, 1559, 1450, 1377, 1223, 1113, 1068, 751; HRMS m/z (ESI) calcd for C23H23N2 (M + H)+ 327.1856, found 327.1860.
5-(4-Methoxyphenyl)-5-(phenylamino)pentanenitrile (3am). A yellow oil (39.4 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.27 –
7.19 (m, 2H), 7.12 – 7.04 (m, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.64 (t, J = 7.3 Hz, 1H), 6.55 – 6.48 (m, 2H), 4.29 (t, J = 6.8 Hz, 1H),
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4.02 (br s, 1H), 3.76 (s, 3H), 2.29 (td, J = 7.0, 1.5 Hz, 2H), 1.99 – 1.82 (m, 2H), 1.79 – 1.69 (m, 1H), 1.69 – 1.57 (m, 1H); 13C NMR
(101 MHz, CDCl3) δ 158.9, 146.9, 134.8, 129.1, 127.3, 119.3, 117.4, 114.1, 113.3, 56.7, 55.2, 37.3, 22.3, 17.0; ATR-FTIR (cm -1):
2246, 1604, 1508, 1313, 1245, 1177, 831; HRMS m/z (ESI) calcd for C18H21N2O (M + H)+ 281.1648, found 281.1654.
5-(Naphthalen-2-yl)-5-(phenylamino)pentanenitrile (3an). A yellow oil (31.4 mg, 52%): 1H NMR (400 MHz, CDCl3) δ 7.87 –
7.77 (m, 4H), 7.51– 7.45 (m, 3H), 7.12– 7.08 (m, 2H), 6.67 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.7 Hz, 2H), 4.53 (t, J = 6.8 Hz, 1H), 4.17
(br s, 1H), 2.34 (td, J = 7.0, 2.4 Hz, 2H), 2.08 – 1.98 (m, 2H), 1.87 – 1.79 (m, 1H), 1.74 – 1.67 (m, 1H); 13C NMR (101 MHz, CDCl3)
δ 146.9, 140.4, 133.3, 132.8, 129.1, 128.7, 127.7, 127.6, 126.2, 125.8, 125.1, 124.2, 119.3, 117.6, 113.4, 57.6, 37.2, 22.3, 17.0;ATR-
FTIR (cm -1): 2246, 1601, 1552, 1455, 1315, 1125, 1069, 752; HRMS m/z (ESI) calcd for C21H21N2 (M + H)+ 301.1699, found
301.1696.
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5-(Benzo[b]thiophen-5-yl)-5-(phenylamino)pentanenitrile (3ao). A yellow oil (29.5 mg, 48%). H NMR (400 MHz, CDCl3) δ
7.84 (d, J = 8.3 Hz, 1H), 7.80 – 7.79 (m, 1H), 7.45 (d, J = 5.4 Hz, 1H), 7.34 – 7.26 (m, 2H), 7.11 – 7.07 (m, 2H), 6.66 (t, J = 7.3 Hz,
1H), 6.56 (d, J = 7.7 Hz, 2H), 4.48 (t, J = 6.8 Hz, 1H), 4.14 (br s, 1H), 2.35 (td, J = 7.0, 2.1 Hz, 2H), 2.08 – 1.95 (m, 2H), 1.86 – 1.76
(m, 1H), 1.76 – 1.63 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 146.9, 139.9, 139.3, 138.7, 129.2, 127.0, 123.8, 122.9, 122.7, 121.2,
119.3, 117.7, 113.4, 57.5, 37.6, 22.4, 17.1; ATR-FTIR (cm -1): 2245, 1600, 1545, 1320, 1151, 1071, 750; HRMS m/z (ESI) calcd for
C19H19N2S (M + H)+ 307.1263, found 307.1258.
7-(4-Methoxyphenyl)-7-(phenylamino)heptanenitrile (3ap). A yellow oil (31.3 mg, 51%): 1H NMR (400 MHz, CDCl3) δ 7.24 (d,
J = 8.6 Hz, 2H), 7.08 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.73 – 6.58 (m, 1H), 6.51 (d, J = 8.5 Hz, 2H), 4.26 (t, J = 6.8 Hz,
1H), 4.01 (br s, 1H), 3.78 (s, 3H), 2.30 (t, J = 7.0 Hz, 2H), 1.84 – 1.72 (m, 2H), 1.67 – 1.58 (m, 2H), 1.50 – 1.42 (m, 3H), 1.36 – 1.30
(m, 1H); 13C NMR (101 MHz, CDCl3) δ 158.5, 147.3, 135.8, 129.1, 127.3, 119.6, 117.2, 114.0, 113.3, 57.4, 55.2, 38.4, 28.5, 25.5,
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25.2, 17.0; ATR-FTIR (cm ): 2246, 1603, 1455, 1380, 1221, 1119, 1063, 752; HRMS m/z (ESI) calcd for C20H25N2O (M + H)+
309.1961, found 309.1958.
General Procedure A of Dual Photoredox and Copper-Catalyzed Selective C (sp3)-N Cross-Couplings.
Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime 1a’ (154.2 mg, 0.6 mmol),
aniline 2a (18.6 mg, 0.2 mmol), fac-Ir(ppy)3 (1.3 mg, 1 mol%), Cu(OTf)2 (14.4 mg, 20 mol%), and absolute DMF (1.0 mL) were
added under Ar. The formed mixture was stirred into a crystallizing basin equipped with a 5 m length blue LED strips (12 w/m) under
constant irradiation at room temperature for 12 h as monitored by TLC. The mixture was extracted with EA and saturated NaHCO3
solution, dried (MgSO4) and concentrated to give a crude product. The crude product was purified by flash column chromatography
on silica gel (PE : EA = 4 : 1) to afford 4aa.
4,4'-(Phenylazanediyl)dibutanenitrile (4aa) . A yellow oil (33.1 mg, 73%): 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.23 (m, 2H),
6.82 – 6.74 (m, 3H), 3.48 – 3.41 (m, 4H), 2.39 (t, J = 7.0 Hz, 4H), 1.97 – 1.90 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 147.0, 129.6,
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119.2, 118.2, 114.1, 50.2, 23.0, 14.7; ATR-FTIR (cm -1): 2245, 1598, 1503, 1325, 1112, 780; HRMS m/z (ESI) calcd for C14H18N3
(M + H)+ 228.1495, found 228.1496.
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4,4'-((4-(tert-Butyl)phenyl)azanediyl)dibutanenitrile (4ba). A yellow oil (44.3 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 7.28 (d,
J = 8.9 Hz, 2H), 6.73 – 6.71 (m, 2H), 3.40 (t, J = 7.1 Hz, 4H), 2.39 (t, J = 7.0 Hz, 4H), 1.98 – 1.89 (m, 4H), 1.29 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ 144.8, 141.3, 126.3, 119.3, 114.2, 50.5, 33.8, 31.4, 23.1, 14.7;ATR-FTIR (cm -1): 2246, 1601, 1550, 1335, 1118,
1069, 753; HRMS m/z (ESI) calcd for C18H26N3 (M + H)+ 284.2121, found 284.2126.
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4,4'-((4-Methoxyphenyl)azanediyl)dibutanenitrile (4ca) . A yellow oil (43.7 mg, 85%): H NMR (400 MHz, CDCl3) δ 6.85 (s,
4H), 3.77 (s, 3H), 3.25 (t, J = 6.8 Hz, 4H), 2.39 (t, J = 7.0 Hz, 4H), 1.86 – 1.79 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 154.2, 141.7,
119.6, 119.4, 114.9, 55.6, 52.1, 23.2, 14.7; ATR-FTIR (cm -1): 2246, 1602, 1505, 1336, 1121, 1067, 751; HRMS m/z (ESI) calcd for
C15H20N3O (M + H)+ 258.1601, found 258.1603.
4,4'-((4-Fluorophenyl)azanediyl)dibutanenitrile (4da). A yellow oil. ( 25.4 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 7.00 – 6.94
(m, 2H), 6.80 – 6.73 (m, 2H), 3.35 (t, J = 7.0 Hz, 4H), 2.39 (t, J = 6.9 Hz, 4H), 1.91 – 1.84 (m, 4H); 13C NMR (101 MHz, CDCl3) δ
156.8 (d, J = 239.0 Hz), 143.9, 119.2, 117.4 (d, J = 7.5 Hz), 116.1 (d, J = 22.2 Hz), 51.3, 23.0, 14.7; 19F NMR (376 MHz, CDCl3) δ
-124.9;ATR-FTIR (cm -1): 2245, 1605, 1509, 1332, 1220, 1109, 1026, 752; HRMS m/z (ESI) calcd for C14H17FN3 (M + H)+ 246.1401,
found 246.1400.
4,4'-((3-Bromo-4-methylphenyl)azanediyl)dibutanenitrile (4ea). A yellow oil (33.1 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 7.09
(d, J = 8.4 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.64 (dd, J = 8.4, 2.6 Hz, 1H), 3.40 (t, J = 7.0 Hz, 4H), 2.38 (t, J = 7.0 Hz, 4H), 2.29 (s,
3H), 1.96 – 1.88 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 146.2, 131.4, 127.5, 125.9, 119.1, 118.0, 113.7, 50.4, 23.0, 21.6, 14.7;
ATR-FTIR (cm ): 2246, 1545, 1446, 1378, 1230, 1121, 1065, 752; HRMS m/z (ESI) calcd for C15H19BrN3 (M + H)+ 320.0757,
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4,4'-((3-(Hydroxymethyl)phenyl)azanediyl)dibutanenitrile (4fa). A yellow oil (34.8 mg, 68%): H NMR (400 MHz, CDCl3) δ
7.26 – 7.21 (m, 1H), 6.80 (s, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.67 (dd, J = 8.2, 2.4 Hz, 1H), 4.65 (s, 2H), 3.47 (t, J = 7.1 Hz, 4H), 2.39
(t, J = 7.0 Hz, 4H), 1.98 – 1.91 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 147.3, 142.5, 129.8, 119.2, 116.7, 113.0, 112.3, 65.5, 50.1,
23.1, 14.7; ATR-FTIR (cm ): 2246, 1550, 1446, 1336, 1228, 1109, 1066, 739; HRMS m/z (ESI) calcd for C15H20N3O (M + H)+
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4,4'-((3-Hydroxyphenyl)azanediyl)dibutanenitrile (4ga). A yellow oil (30.3 mg, 62%): 1H NMR (400 MHz, CDCl3) δ 7.09 (t, J =
8.1 Hz, 1H), 6.33 – 6.21 (m, 3H), 5.69 (br s, 1H), 3.53 – 3.30 (m, 4H), 2.38 (t, J = 7.0 Hz, 4H), 1.96 – 1.89 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 157.1, 148.5, 130.5, 119.3, 106.0, 105.0, 100.6, 50.0, 23.0, 14.6; ATR-FTIR (cm -1): 2247, 1617, 1579, 1503, 1375,
1165, 759; HRMS m/z (ESI) calcd for C14H18N3O (M + H)+ 244.1444, found 244.1443.
N-(4-(Bis(3-cyanopropyl)amino)phenyl)acetamide (4ha). A yellow oil (50.9 mg, 90%): 1H NMR (400 MHz, CDCl3) δ 7.51 (br s,
1H), 7.35 (d, J = 8.9 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H), 3.37 (t, J = 7.0 Hz, 4H), 2.36 (t, J = 6.9 Hz, 4H), 2.11 (s, 3H), 1.88 (p, J = 7.1
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Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 168.4, 144.1, 129.4, 122.2, 119.3, 115.2, 50.5, 24.2, 22.9, 14.6; ATR-FTIR (cm -1): 2246,
1732, 1661, 1519, 1420, 1372, 1265, 1062, 818; HRMS m/z (ESI) calcd for C16H21N4O (M + H)+ 285.1710, found 285.1715.
4,4'-((3-Fluoro-4-morpholinophenyl)azanediyl)dibutanenitrile (4ia). A yellow oil (42.7 mg, 65%). 1H NMR (500 MHz, CDCl3)
δ 6.88 (t, J = 9.4 Hz, 1H), 6.57 – 6.45 (m, 2H), 3.91 – 3.80 (m, 4H), 3.36 (t, J = 7.0 Hz, 4H), 3.00 – 2.98 (m, 4H), 2.38 (t, J = 7.0 Hz,
4H), 1.93 – 1.87 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 156.8 (d, J = 245.7 Hz), 143.7 (d, J = 9.5 Hz), 131.9 (d, J = 9.4 Hz), 120.2
(d, J = 4.6 Hz), 119.1, 110.6 (d, J = 2.7 Hz), 103.7 (d, J = 24.4 Hz), 67.1, 51.52 (d, J = 2.4 Hz), 50.7, 23.1, 14.7; 19F NMR (471 MHz,
CDCl3) δ -121.1; ATR-FTIR (cm -1): 2245, 1629, 1518, 1452, 1301, 1238, 737; HRMS m/z (ESI) calcd for C18H24FN4O (M + H)+
331.1929, found 331.1930.
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4, 4'-((4-(3-Ethyl-2,6-dioxopiperidin-3-yl)phenyl)azanediyl)dibutanenitrile (4ja). A yellow oil (50.4 mg, 66%): H NMR (400
MHz, CDCl3) δ 8.07 (br s, 1H), 7.14 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 3.45 (t, J = 7.2 Hz, 4H), 2.62 – 2.55 (m, 1H), 2.50
– 2.43 (m, 1H), 2.39 (t, J = 6.9 Hz, 4H), 2.35 – 2.29 (m, 1H), 2.17 (td, J = 13.7, 4.6 Hz, 1H), 2.03 – 1.84 (m, 6H), 0.85 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 175.4, 172.5, 146.0, 127.5, 119.1, 113.6, 50.1, 40.0, 32.8, 29.3, 26.7, 22.9, 14.7, 9.0; ATR-FTIR
(cm -1): 2246, 1699, 1520, 1461, 1355, 1192, 819; HRMS m/z (ESI) calcd for C21H26N4NaO2 (M + Na)+ 389.1948, found 389.1951.
General Procedure B of Dual Photoredox and Copper-Catalyzed Selective C (sp3)-N Cross-Couplings.
Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime 1a’ (77.1 mg, 0.3 mmol),
aniline 2k’ (21.4 mg, 0.2 mmol), fac-Ir(ppy)3 (1.3 mg, 1 mol%), Cu(OTf)2 (14.4 mg, 20 mol%), and absolute DMF (1.0 mL) were
added under Ar. The formed mixture was stirred into a crystallizing basin equipped with a 5 m length blue LED strips (12 w/m) under
constant irradiation at room temperature for 12 h as monitored by TLC. The mixture was extracted with EA and saturated NaHCO3
solution, dried (MgSO4) and concentrated to give a crude product. The crude product was purified by flash column chromatography
on silica gel (PE : EA = 8 : 1) to afford 4ka.
4-(Methyl(phenyl)amino)butanenitrile (4ka) . A yellow oil (27.2 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.24 (m, 2H),
6.82 – 6.66 (m, 3H), 3.47 (t, J = 6.9 Hz, 2H), 2.96 (s, 3H), 2.40 (t, J = 7.1 Hz, 2H), 2.00 – 1.93 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 148.9, 129.3, 119.4, 117.0, 112.5, 51.2, 38.7, 23.1, 14.7; ATR-FTIR (cm -1): 2245, 1605, 1450, 1339, 1220, 1067, 752; HRMS m/z
(ESI) calcd for C11H15N2 (M + H)+ 175.1230, found 175.1228.
4-(Benzyl(phenyl)amino)butanenitrile (4la). A yellow oil (33.8 mg, 68%): 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.25 (m, 2H),
7.25 – 7.15 (m, 5H), 6.73 – 6.65 (m, 3H), 4.52 (s, 2H), 3.55 – 3.41 (m, 2H), 2.32 (t, J = 7.1 Hz, 2H), 1.98 – 1.91 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 148.0, 138.3, 129.4, 128.6, 127.0, 126.6, 119.2, 117.2, 112.9, 55.1, 49.6, 23.2, 14.7; ATR-FTIR (cm -1): 2246,
1595, 1505, 1378, 1229, 1108, 1066, 750; HRMS m/z (ESI) calcd for C17H19N2 (M + H)+ 251.1543, found 251.1543.
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4-(Isopropyl(phenyl)amino)butanenitrile (4ma) . A yellow oil (22.1 mg, 55%): H NMR (400 MHz, CDCl3) δ 7.30 – 7.22 (m,
2H), 6.87 – 6.75 (m, 3H), 4.02 – 3.95 (m, 1H), 3.29 – 3.21 (m, 2H), 2.39 (t, J = 7.0 Hz, 2H), 1.92 – 1.85 (m, 2H), 1.19 (d, J = 6.7
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Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 148.4, 129.2, 119.6, 118.2, 116.0, 51.1, 41.8, 24.1, 20.0, 14.6; ATR-FTIR (cm ): 2246,
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1602, 1552, 1377, 1121, 1069, 748; HRMS m/z (ESI) calcd for C13H19N2 (M + H)+ 203.1543, found 203.1545.
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4-(Allyl(phenyl)amino)butanenitrile (4na). A yellow oil. ( 28.7 mg, 72%). H NMR (400 MHz, CDCl3) δ 7.36 – 7.17 (m, 2H),
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6.83 – 6.68 (m, 3H), 5.92 – 5.83 (m, 1H), 5.22 – 5.18 (m, 2H), 3.96 (dt, J = 5.0, 1.6 Hz, 2H), 3.63 – 3.41 (m, 2H), 2.43 (t, J = 7.1
Hz, 2H), 2.03 – 1.96 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 147.8, 133.7, 129.3, 119.3, 117.0, 116.6, 112.7, 53.9, 49.1, 23.4, 14.7;
ATR-FTIR (cm -1): 2245, 1559, 1462, 1338, 1208, 1105, 1059, 739; HRMS m/z (ESI) calcd for C13H17N2 (M + H)+ 201.1386, found
201.1384.
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4-((4-Methoxyphenyl)(methyl)amino)butanenitrile (4oa). A yellow oil (30.4 mg, 74%). H NMR (400 MHz, CDCl3) δ 6.87 –
6.82 (m, 2H), 6.78 – 6.72 (m, 2H), 3.76 (s, 3H), 3.34 (t, J = 6.8 Hz, 2H), 2.86 (s, 3H), 2.40 (t, J = 7.1 Hz, 2H), 1.95 – 1.88 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 152.4, 144.1, 119.5, 115.5, 114.8, 55.7, 52.5, 39.6, 23.1, 14.7; ATR-FTIR (cm -1): 2246, 1606, 1556,
1339, 1216, 1108, 1065, 752; HRMS m/z (ESI) calcd for C12H17N2O (M + H)+ 205.1335, found 205.1336.
4-((2-Hydroxyethyl)(phenyl)amino)butanenitrile (4pa). A yellow oil (26.5 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.07
(m, 2H), 7.00 – 6.47 (m, 3H), 3.79 (t, J = 5.7 Hz, 2H), 3.51 – 3.47 (m, 4H), 2.39 (t, J = 7.0 Hz, 2H), 1.99 – 1.89 (m, 2H), 1.89 (br s,
1H); 13C NMR (101 MHz, CDCl3) δ 147.6, 129.4, 119.4, 117.8, 113.6, 59.9, 54.0, 50.3, 22.9, 14.7; ATR-FTIR (cm -1): 2245, 1595,
1545, 1463, 1378, 1125, 1066, 750; HRMS m/z (ESI) calcd for C12H17N2O (M + H)+ 205.1335, found 205.1336.
4-(Indolin-1-yl)butanenitrile (4qa). A yellow oil (29.7 mg, 80%): 1H NMR (400 MHz, CDCl3) δ 7.10 (t, J = 7.8 Hz, 2H), 6.70 (t,
J = 7.3 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 3.34 (t, J = 8.3 Hz, 2H), 3.21 (t, J = 6.6 Hz, 2H), 3.00 (t, J = 8.3 Hz, 2H), 2.50 (t, J = 7.1
Hz, 2H), 2.01 – 1.95 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 152.2, 129.8, 127.3, 124.5, 119.5, 118.0, 106.9, 53.5, 48.1, 28.5, 23.9,
14.6; ATR-FTIR (cm -1): 2245, 1615, 1546, 1339, 1228, 1068, 746; HRMS m/z (ESI) calcd for C12H15N2 (M + H)+ 187.1230, found
187.1224.
4-(2, 3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)butanenitrile (4ra). A yellow oil (22.1 mg, 59%): 1H NMR (400 MHz, CDCl3) δ
7.10 (t, J = 7.8 Hz, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 3.34 (t, J = 8.3 Hz, 4H), 3.21 (t, J = 6.6 Hz, 2H), 3.00 (t, J
= 8.3 Hz, 2H), 2.50 (t, J = 7.1 Hz, 2H), 2.05 – 1.98 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 163.2, 145.7, 131.0, 122.9, 119.7, 112.7,
50.2, 44.8, 26.0, 24.0, 14.8; ATR-FTIR (cm -1): 2245, 1608, 1556, 1382, 1208, 1121, 1069, 755; HRMS m/z (ESI) calcd for C11H14N3
(M + H)+ 188.1182, found 188.1185.
TEMPO Trapping Experiments
(a) Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone oxime 1a (56.7 mg, 0.3 mmol), aniline 2a (18.6 mg, 0.2
mmol), Cu(tmhd)2 (4.3 mg, 5 mol%), TEMPO (62.5 mg, 0.4 mmol), and absolute dry DMF (1.0 mL) were added under Ar. The
formed mixture was stirred at 80 ºC under Ar for 12 h as monitored by TLC. The solution was then cooled to room temperature, the
reaction mixture was analyzed by GC-MS and 1H NMR. The yield of 5 was determined by 1H NMR using CH2Br2 as internal standard
based on 1a.
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(b) Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime 1a’ (77.1 mg, 0.3
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mmol), aniline 2a (18.6 mg, 0.2 mmol), fac-Ir(ppy)3 (1.3 mg, 1 mol%), Cu(OTf)2 (14.4 mg, 20 mol%), TEMPO (125.0 mg, 0.8
mmol), and absolute DMF (1.0 mL) were added under Ar. The formed mixture was stirred into a crystallizing basin equipped with a
5 m length blue LED strips (12 w/m) under constant irradiation at room temperature for 12 h as monitored by TLC. the reaction
mixture was analyzed by GC-MS and 1H NMR. The yield of 5 was determined by 1H NMR using CH2Br2 as internal standard based
on 1a’.
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Multi-component Reaction Experiments
(a) Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone oxime 1a (56.7 mg, 0.3 mmol), aniline 2a (18.6 mg, 0.2
mmol), styrene 6 (41.6 mg, 0.4 mmol), Cu(OTf)2 (3.6 mg, 5 mol%), and absolute 1,4-dioxane (1.0 mL) were added under Ar. The
formed mixture was stirred at 80 ºC under Ar for 12 h as monitored by TLC. The solution was then cooled to room temperature, the
mixture was extracted with EA and saturated NaHCO3 solution, dried (MgSO4) and concentrated to give a crude product. The crude
product was purified by flash column chromatography on silica gel (from PE : EA = 7 : 1) to afford 18.4 mg (35%) of 7 as a yellow
oil: 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.32 (m, 4H), 7.25 – 7.21 (m, 1H), 7.11 – 7.07 (m, 2H), 6.65 (t, J = 7.3 Hz, 01H), 6.54 –
6.50 (m, 12H), 4.32 (t, J = 6.8 Hz, 1H), 4.06 (br s, 1H), 2.37 – 2.29 (m, 2H), 1.90 – 1.79 (m, 2H), 1.69 – 1.57 (m, 3H), 1.53 – 1.42
(m, 1H); 13C NMR (101 MHz, CDCl3) δ 147.1, 143.5, 129.1, 128.7, 127.1, 126.3, 119.5, 117.4, 113.3, 57.8, 37.9, 25.5, 25.2, 17.1;
ATR-FTIR (cm -1): 2246, 1601, 1560, 1452, 1382, 1123, 1059, 753; HRMS m/z (ESI) calcd for C18H21N2 (M + H)+ 265.1699, found
265.1700.
(b) Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone oxime 1a (56.7 mg, 0.3 mmol), aniline 2a (18.6 mg, 0.2
mmol), 4-methoxystyrene 6 (53.6 mg, 0.4 mmol), Cu(OTf)2 (3.6 mg, 5 mol%), and absolute 1,4-dioxane (1.0 mL) were added under
Ar. The formed mixture was stirred at 80 ºC under Ar for 12 h as monitored by TLC. The solution was then cooled to room temperature,
the mixture was extracted with EA and saturated NaHCO3 solution, dried (MgSO4) and concentrated to give a crude product. The
crude product was purified by flash column chromatography on silica gel (from PE : EA = 5 : 1) to afford 32.4 mg (55%) of 9 as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 7.11 – 7.08 (m, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.65 (t, J = 7.3 Hz,
1H), 6.55 – 6.51 (m, 2H), 4.28 (t, J = 6.8 Hz, 1H), 4.03 (br s, 1H), 3.79 (s, 3H), 2.31 (td, J = 7.0, 1.3 Hz, 2H), 1.89 – 1.82 (m, 1H),
1.80 – 1.73 (m, 1H), 1.70 – 1.64 (m, 2H), 1.60 – 1.54 (m, 1H), 1.50 – 1.40 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 158.6, 147.1,
135.4, 129.1, 127.3, 119.5, 117.3, 114.0, 113.3, 57.2, 55.2, 37.8, 25.5, 25.2, 17.0; ATR-FTIR (cm -1): 2246, 1602, 1559, 1380, 1209,
1128, 1066, 753; HRMS m/z (ESI) calcd for C19H23N2O (M + H)+ 295.1805, found 295.1802.
Photo-induced Experiments
(a) Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime 1a’ (77.1 mg, 0.3
mmol), aniline 2a (18.6 mg, 0.2 mmol), fac-Ir(ppy)3 (1.3 mg, 1 mol%), and absolute DMF (1.0 mL) were added under Ar. The formed
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mixture was stirred into a crystallizing basin equipped with a 5 m length blue LED strips (12 w/m) under constant irradiation at room
temperature for 12 h as monitored by TLC. the reaction mixture was analyzed by GC-MS.
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(b) Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime 1a’ (77.1 mg, 0.3
mmol), aniline 2a (18.6 mg, 0.2 mmol), Cu (OTf)2 (14.4 mg, 20 mol%), and absolute DMF (1.0 mL) were added under Ar. The
formed mixture was stirred into a crystallizing basin equipped with a 5 m length blue LED strips (12 w/m) under constant irradiation
at room temperature for 12 h as monitored by TLC. the reaction mixture was analyzed by GC-MS.
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(c) Flame-dried 25 mL Schlenk tube filled with argon, cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime 1a’ (77.1 mg, 0.3
mmol), aniline 2a (18.6 mg, 0.2 mmol), Cu (OTf)2 (14.4 mg, 20 mol%), and absolute DMF (1.0 mL) were added under Ar. The stirred
mixture was wrapped up in tinfoil to avoid light at room temperature for 12 h as monitored by TLC. the reaction mixture was analyzed
by GC-MS.
Functional Group Transformations
Reaction on 5.0 mmol scale: Flame-dried 100 mL Schlenk tube filled with argon, cyclobutanone oxime 1a (1.4 g, 7.5 mmol),
aniline 2a (465.6 mg, 5.0 mmol), Cu(tmhd)2 (107.5 mg, 5 mol%), and absolute dry DMF (25.0 mL) were added under Ar. The formed
mixture was stirred at 80 ºC in an oil bath under Ar for 12 h as monitored by TLC. The solution was then cooled to room temperature,
the mixture was extracted with EA and saturated NaHCO3 solution, dried (MgSO4) and concentrated to give a crude product. The
crude product was purified by flash column chromatography on silica gel (PE : EA = 8 : 1) to afford 652.8 mg (82%) of 3aa as a
yellow oil.
4-(Phenylamino)butanamide (10) To a solution of 3aa (32.0 mg, 0.2 mmol) in toluene (1.0 mL) was added a cooled solution of
conc. sulfuric acid in H2O (100.0 μL H2SO4/16.0 μL) (The ratio of toluene to acid/H2O is very important and should be followed
strictly). Stir the biphasic mixture at room temperature for 0.5 h and warm to 35°C and stir for 22 h. The reaction was cooled to room
temperature and quenched with 68.7 mg of Na2CO3 in water (add slowly some foaming). Separate the organic and extract 2 × EtOAc.
Combine all the organics and wash the organics with brine, dry over MgSO4, filter and concentrate to afford 33.1 mg (93%) of 10 as
a white solid, mp 63-65 oC: 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.14 (m, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 7.7 Hz, 2H),
5.69 (br s, 1H), 5.57 (br s, 1H), 3.18 (t, J = 6.7 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 2.00 – 1.93 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 175.1, 148.2, 129.2, 117.3, 112.7, 43.3, 33.2, 24.9; ATR-FTIR (cm -1): 3389, 1650, 1600, 1505, 1376, 1206, 1067, 740; HRMS
m/z (ESI) calcd for C10H14N2NaO (M + Na)+ 201.0998, found 201.0999.
1-Phenylpyrrolidin-2-one (11) A mixture of 3aa (32.0 mg, 0.2 mmol) in absolute ethanol (0.5 mL), concentrated sulfuric acid 66.7
(μL) was stirred under reflux for 12 h. The excess alcohol removed by distillation and the residue was diluted with water, basified
with Na2CO3 solution (1.0 mL, 30%) and extracted with ether. The ethereal layer was separated, washed with water and dried over
MgSO4. The solvent was evaporated under vacuum to give a crude product. The crude product was purified by flash column
chromatography on silica gel (PE : EA = 3 : 1) to afford 22.9 mg (71%) of 11 as a white solid, mp 65-67 oC: 1H NMR (400 MHz,
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CDCl3) δ 7.72 – 7.50 (m, 2H), 7.42 – 7.28 (m, 2H), 7.13 (t, J = 7.4 Hz, 1H), 3.84 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 8.1 Hz, 2H), 2.17 –
2.10 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 174.1, 139.3, 128.7, 124.4, 119.8, 48.7, 32.7, 17.9; ATR-FTIR (cm -1): 1675, 1555,
1462, 1383, 1236, 1128, 1067, 756; HRMS m/z (ESI) calcd for C10H11NNaO (M + Na)+ 184.0733, found 184.0738.
4-(Diphenylamino)butanenitrile (12) To a 25 mL flame-dried schlenk tube was added KF (34.8 mg, 0.6 mmol) and 18-crown-6
(158.4 mg, 0.6 mmol) jin a glove box. The mixture was dissolved in THF (1.0 mL) under argon atmosphere. 3aa (32.0 mg, 0.2 mmol)
was added under argon atmosphere. To the stirred solution, 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (89.4 mg, 0.3 mmol)
was added. Then the reaction mixture was allowed to react at 30 ºC for 12 h. After 12 h, the reaction was stopped, the solvent was
evaporated and the crude product was purified by flash column chromatography on silica gel (PE : EA = 10 : 1) to afford 40.2 mg
(85%) of 12 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.23 (m, 4H), 7.01 – 6.94 (m, 6H), 3.85 (t, J = 7.1 Hz, 2H), 2.41
(t, J = 7.1 Hz, 2H), 2.04 – 1.97 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 147.6, 129.4, 121.9, 121.1, 119.3, 50.5, 23.5, 14.7; ATR-
FTIR (cm -1): 2246, 1605, 1556, 1465, 1380, 1267, 1109, 1067, 752; HRMS m/z (ESI) calcd for C16H16N2Na (M + Na)+259.1206,
found 259.1210.
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■ASSOCIATED CONTENT
Supporting Information
Full spectroscopic data for all new compounds. The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.xxxxxxx
■AUTHOR INFORMATION
Corresponding Authors
*Email: shiz@nju.edu.cn; wangmy@nju.edu.cn
Notes
The authors declare no competing financial interest.
■ACKNOWLEDGMENTS
We thank the “1000-Youth Talents Plan”, the “Jiangsu Specially-Appointed Professor Plan”, the National Natural Science Foundation of
China (grant 21672097), and National Natural Science Foundation of Jiangsu Province (BK 20170632) for financial support. This work was
also supported by a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and the
program A for Outstanding PhD candidate of Nanjing University.
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