Copper-Catalyzed Cyanoalkylation of Amines via C-C Bond Cleavage: An Approach for C(sp3)-N Bond Formations

Article abstract of DOI:10.1021/acs.joc.9b01084

The efficient copper-catalyzed cyanoalkylation of amines via C-C bond cleavage has been demonstrated. Distinctive features of this procedure involves mild conditions, broad range of nitrogen nucleophiles, high selectivity, and good functional group tolerance, thus providing a useful approach for the C(sp³)-N bond formations. Most importantly, this protocol is applicable to the late-stage functionalization of natural products, amino acid esters, and drugs. Mechanistic studies suggest that a radical intermediate was involved in this transformation.

Full text of DOI:10.1021/acs.joc.9b01084

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Article
Copper-Catalyzed Cyanoalkylation of Amines via C-C Bond
Cleavage: An Approach for C(sp3)-N Bond Formations
Lin Yang, Jia-Yu Zhang, Xin-Hua Duan, Pin Gao, Jiao Jiao, and Li-Na Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01084 • Publication Date (Web): 06 Jun 2019
Downloaded from http://pubs.acs.org on June 6, 2019
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Copper-Catalyzed Cyanoalkylation of Amines via C−C Bond Cleavage: An
3
Approach for C(sp )−N Bond Formations
a
a
Lin Yang, Jia-Yu Zhang, Xin-Hua Duan, Pin Gao, Jiao Jiao, and Li-Na Guo*
Department of Chemistry, School of Science, Xi'an Key Laboratory of Sustainable Energy Materials Chemistry,
and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong
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University, Xi’an 710049, China.
LG
R1
N
[Cu]
R1
+
HN
R
NC
N
R
visible light
or without light
R R3
2
R2 R3
(hetero)aromatic amines
aromatic N-heterocycles
sulfonamides
aliphatic amines & amino acid esters
natural products & drugs
>
75 examples
up to 93% yield
ABSTRACT
An efficient copper-catalyzed cyanoalkylation of amines via C−C bond cleavage has been
demonstrated. Distinctive features of this procedure involves mild conditions, broad range of
nitrogen nucleophiles, high selectivity and good functional group tolerance, thus providing a
3
useful approach for the C(sp )−N bond formations. Most importantly, this protocol is applicable to
late-stage functionalization of natural products, amino acid esters and drugs. Mechanistic studies
suggest that radical intermediate was involved in this transformation.
INTRODUCTION
Amines represent an important class of structural motifs, which exist widely in natural
1
products, pharmaceuticals, agrochemicals and materials. Thus, the construction of C−N
bonds has attracted much attention of chemists and has become a hot topic in organic
synthesis. In this field, transition-metal catalyzed cross coupling of aryl electrophiles with
2
amines has proven to be a powerful tool for the C(sp )−N bond formations, such as
2
Ullmann coupling, Buchwald-Hartwig reaction, and Chan-Lam amination. Apart from the
traditional S 2 alkylation of amines, olefin hydroamination, reductive aminations and
N
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others, transition-metal catalyzed amination of alkyl electrophiles (halides and pseudo
halides) has also been developed as an efficient method for the C(sp )−N bond formations.4
However, this method is still challenging due to the facile β-hydrogen elimination of metal
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alkyl intermediates and difficulty in C(sp )−N reductive elimination. Recently, the
combination of photoredox and copper catalysis has emerged as an excellent alternative for
the transition metal-catalyzed amination reactions.5,6 For instance, Fu and Peters et al
demonstrated several photoinduced, copper-catalyzed amination of alkyl halides using
carbazoles, carboxamides, indoles, carbamates, and aliphatic amines as nitrogen
5
nucleophiles (Scheme 1, route a). Moreover, they also reported an intramolecular
6a
decarboxylative amination of alkyl NHPI esters under this dual catalytic system. Very
recently, the groups of Hu and MacMillan disclosed the intermolecular decarboxylative
amination of alkyl NHPI esters and alkyl carboxylic acids via synergetic photoredox and
copper catalysis, respectively (Scheme 1, route b).6b-d In these C(sp )−N bond formation
reactions, alkyl halide, redox-active alkyl NHPI esters and iodonium carboxylates have
been developed as efficient alkyl sources. Although remarkable advances have been made,
it is still necessary and highly desirable to explore elegant catalytic systems, functionalized
3
3
Scheme 1 C(sp )−N Couplings via Synergetic Photoredox and Copper Catalysis
Fu and Peters et al.
[
Cu]
R
X (Br, I)
+
H N
R
R
N
H
(a)
(b)
2
hv
Hu and MacMillan et al.
[Ru] or [Ir]/[Cu]
R
COOA*
LG
+
H N
2
N
H
hv
N
This work
R1
[
Cu]
R1
NC
+
H2N
N
(c)
Blue LEDs
2
3 H
R R
R2 R3
Structural diversification
75 examples, 10 classes of N nucleophiles
Mono-cyanoalkylation
>
Mild conditions
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alkyl electrophiles as well as broad amine nucleophiles to achieve the structurally diverse
alkyl amine synthesis.
In recent years, the radical carbon-carbon bond cleavage of strained rings has become an
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efficient strategy for carbon-carbon and carbon-heteroatom bond formations. Since the
pioneering work of Forrester, Zard, Uemura et al.8 the iminyl radical-triggered
carbon-carbon bond cleavage of cycloketone oxime derivatives has become a powerful
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3
9,10
tool to construct C(sp )−C and C(sp )−Y (Y = O, S, Se, Te, X or B) bonds. In these
transformations, the reactive cyanoalkyl radicals generated in situ were trapped by a
variety of radical acceptors to deliver structurally diverse alkylnitriles through
transition-metal catalysis, photocatalysis, and even transition-metal free systems. Recently,
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we wondered whether the C(sp )−N bond formation can be accessible without recourse to
harsh conditions, complex catalytic systems or expensive metals. To achieve this, several
hurdles should be overcome simultaneously: (i) -hydride elimination of cyanoalkyl metal
11
10b-d
complex; (ii) fragmentation-rearrangement of cycloketone oxime esters;
(iii) neophyl
rearrangement, reduction and oxidation of cyanoalkyl radical.10e-f As our ongoing interest
3
in C−C bond cleavage, we set out to challenge the C(sp )−N bond coupling of cycloketone
oxime esters with amines, aiming at incorporating the important cyanoalkyl moieties into
structurally diverse nitrogen-containing molecules, especially bioactive natural products
12
5,6
and drugs (Figure 1). Inspired by the previous fascinating works, we herein describe a
room-temperature, copper-catalyzed C−C bond cleavage/amination of cycloketone oxime
esters (Scheme 1, route c). A variety of (hetero)aromatic amines, aromatic N-heterocycles,
sulfonamides and even aliphatic amines were amenable for this cyanoalkylation
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transformation. Furthermore, this protocol can be applied successfully to the late-stage
functionalization of some natural products, amino acid esters and drugs. It is worth noting
that visible-light irradiation was indispensable for the success of this reaction in some
cases.
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Fig. 1 Natural Products and Drugs Containing Alkylnitrile Moieties
CN
N
CN
N
Me
CN
NH
N
Me
N
CO Me
2
N
N
Me
N
H
OH
HO

-Amino nitriles alkaloids N-Cyanoalkylbenzomorphan
Ruxolitinib
RESULTS AND DISCUSSION
We commenced our study by evaluating the coupling of various cyclobutanone oxime esters 1
with aniline (2a) (see the Supporting Information for details). Primary optimization demonstrated
that treatment of cyclobutanone O-perfluorobenzoyl oxime (1a) with aniline (2a) in the presence
of 20 mol % Cu(OTf) in DMF under room temperature led to the desired mono-cyanoalkylated
2
aniline 3a in 82% yield (Table 1). Control experiment indicated that the copper catalyst was
essential for this transformation (entry 1). Thus, other copper catalysts such as Cu(OAc) , CuI and
2
CuOTf were tested. But all of them were less effective than Cu(OTf) , affording the product 3a in
2
3
7-66% yields (entries 2-4). The addition of bases did not improve the yield of 3a (entries 5-7).
Solvent screenings revealed that a mixture of DMF and H O (1:1) was superior to other solvents
2
(entries 8 and 9). Additionally, the reaction could give a comparable yield of 3a in the dark as in
ambient light, which indicates that light is unnecessary for the reaction of 1a with 2a (entry 10).
Notably, this reaction can be easily scaled up to 3 mmol with the high efficiency (entry 8). It is
worth mentioning that the pentafluorobenzoic acid could be recovered in 65% after the reaction,
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which would significantly reduce the costs and waste of this transformation.
a
Table 1. Optimization of the Reaction Conditions
OCOC F
6
5
N
Cu(OTf) (20 mol %)
2
+
H N
2
NC
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
DMF, rt, 16 h
H
Ph
Ph
1a
2a
3a, 82%
b
Entry
1
Deviation from above
no Cu(OTf)2
Yield (%)
n.r.c
2
3
4
5
6
7
8
9
Cu(OAc)
CuI instead of Cu(OTf)
CuOTf instead of Cu(OTf)
2
instead of Cu(OTf)
2
37
50
66
63
82
75
2
2
t
1.2 equiv LiO Bu added
1.2 equiv K
1.2 equiv DIPEA added
DMF:H O (1:1) instead of DMF
O instead of DMF
DMF:H O (1:1), in the dark
2 2 4 2
C O ·H O added
d
2
88 (76 )
H
2
10
85
1
0
2
aStandard conditions: 20 mol % of Cu(OTf)
mL), at room temperature for 16 h, under N
, 1a (0.20 mmol, 1.0 equiv), 2a (0.40 mmol, 2.0 equiv), DMF (2.0
2
b
c
d
2
. Yields of isolated product. n.r.= no reaction. The reaction was
scaled up to 3.0 mmol, and the pentafluorobenzoic acid was recovered in 65% yield.
With the optimal conditions in hand, we investigated the generality and limitations of this C−C
bond cleavage/C−N bond formation reaction. A variety of cyclobutanone oxime esters reacted
efficiently with aniline 2a to give the corresponding secondary amines 3b-o in moderate to good
yields (Scheme 2). 3-Substituted oxime esters bearing aryl, benzyl, alkyl or ether groups converted
smoothly to the target products 3b-k in moderate to excellent yields. Functional groups such as
CO Me, Br, BzO and OBn groups were well-tolerated. 3,3-Disubstituted substrates, even the
2
spirocyclic substrates (1m, 1n) also delivered the desired products 3l-n in good yields. The N-Boc
group in substrate was compatible with the reaction conditions (3m). Cyclobutanone oxime ester
1
o derived from simple cyclobutanone also furnished the product 3o in 82% yield. However, the
2,3-disubstitutedoximeester 1p failed to give the expected amine 3p, instead of the -hydrogen
elimination product 3p’ in 88% yield.11 The less strained norcamphor oxime ester 1q were
ineffective at the present conditions. Luckily, the anticipated product 3q could be obtained
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through copper catalysis upon visible-light irradiation, albeit in somewhat low yields.
Scheme 2 Scope of Cyclobutanone Oxime Esters
OCOC6F5
R1
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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Ph
Standard condition A
R1
+
PhNH2
NC
N
2
3 H
R R
R2 R3
1
2a
3
Cyclobutanone Oxime Estersa
Ph
NC
N
3b, R = 4-Me, 93%
3e, R = 4-CO Me, 60%
2
H
t
3c, R = 4- Bu, 89%
3f, R = 3-Me,
g, R = 3-Br,
65%
58%
3
R
3d, R = 4-Cl, 71%
Ph
Ph
Ph
Ph
NC
N
NC
N
NC
N
H
NC
N
H
H
H
Cl
OBn
Cl
BzO
3h, 55%
3i, 93%
3j, 60%
3k, 52%
Ph
NC
N
Ph
H
NC
N
Ph
H
Ph
Ph
NC
N
NC
N
H
H
Me Ph
N
Ph
Boc
3m, 79%
3l, 87%
3n, 86%, d.r. = 1:1
3o, 82%
Ph
OCOC6F5
H
N
NC
Ph
N
+
NC
Ph
Ph
Bn
Bn
1p
3p, trace
3p', 88%
Cyclopentanone Oxime Estersb
O
O
L3 =
Me
OCOC6F5
NC
N
CuOTf (20 mol %), L3 (10 mol %)
NH
Ph
3q, 28%, d.r. = 1:1
2
a, DIPEA (4.0 equiv), DMF, rt, 16 h
Blue LEDs
1q
Standard condition B
aStandard condition A: 20 mol % of Cu(OTf)
2
2
, 1 (0.2 mmol, 1.0 equiv), 2a (0.4 mmol, 2.0 equiv), DMF/H O (1:1,
b
2
mL), rt, 16 h, under N
2
, isolated yield. Standard condition B: 20 mol % of CuOTf, L3 (10 mol %), 1q (0.2
mmol, 1.0 equiv), 2a (0.4 mmol, 2.0 equiv), DIPEA (4.0 equiv), DMF (2 mL), rt, 10 W blue LEDs for 16 h, under
N
2
, isolated yield.
Then, we evaluated the scope of amine nucleophiles using 1o as cyanoalkylation reagent under
this copper catalytic system. Satisfactorily, a variety of aromatic amines bearing electron-rich at
ortho-, meta-, and para-position of the phenyl ring worked well with 1o to afford the desired
products 5a-g in moderate to good yields (Scheme 3). However, the electron-poor aromatic
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amines were less or inefficient under reaction conditions A. Treatment of oxime ester 1o with
Scheme 3 Scope of Aromatic Amines
OCOC6F5
N
A or B
Ar
Standard conditions
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
H N Ar
2
NC
N
,
H
1o
4
5
5
5
5
5
a, R = 2-Me, 88%a
OMe
b, R = 2-OMe, 89%a
c, R = 3-Me, 60%a
R
NC
N
d, R = 3-OMe, 31%a
H
NC
N
H
OMe
82%a
5e, R= 4-Me,
5f, R= 4-OMe, 65%a
5
g, 48%a
b
5
l, R = 4-F, 78% (28%)
F
b
R
5m, R = 4-Cl, 82% (29%)
b
NC
N
H
5n, R = 4-Br, 60% (27%)
NC
N
H
b
5
o, R = 4-I, 61% (30%)
b
5
5
5
5
h, R = 2-F, 65% (30%)
Me
b
5
p, R = 4-CN, 78% (0%)
b
i, R = 2-Br, 52% (38%)
b
b
5t, 52% (46%)
5q, R = 4-CF , 51% (0%)
b
3
j, R = 2-Ph, 80% (35%)
b
5r, R = 4-SO Me, 40% (0%)
b
2
k, R = 3-Cl, 75% (28%)
b
5s, R = 4-Bpin, 53% (0%)
Me
NC
N
CO Et
NC
N
2
NC
N
H
Ph
Ph
b
5v, 57%a
5w, 46%a
5
u, 42% (0%)
aStandard condition A: 20 mol % of Cu(OTf)
2
2
, 1o (0.2 mmol, 1.0 equiv), 4 (0.4 mmol, 2.0 equiv), DMF/H O (1:1,
b
2 mL), rt, 16 h, under N
2
, isolated yield. Standard condition B: 20 mol % of CuOTf, L3 (10 mol %), 1o (0.2
mmol, 1.0 equiv), 4 (0.4 mmol, 2.0 equiv), DIPEA (4.0 equiv), DMF (2 mL), rt, 10 W blue LEDs for 16 h, under
, isolated yield. The yields of 5h-u under condition A in parentheses.
N
2
4
-aminobenzonitrile 4p in the presence of 20 mol % of Cu(OTf) in DMF/H O only
2 2
furnished a trace amount of the desired product 5p. Increasing the reaction temperature to
o
8
0 C did not improve the yield of 5p. Other ligands or bases were also tested, but none of
them gave positive results. During optimization of the reaction conditions, unsaturated
nitriles and γ-carboxylated alkyl nitriles were observed as by-products in some cases (see
the Supporting Information for details).10,11 After many trials, we found that the reactions
proceeded efficiently in the presence of 20 mol % of CuOTf, 10 mol % of
2
-acetylcyclohexanone (L3)13 and 4.0 equiv of DIPEA under irradiation of 10 W blue
LEDs to give the desired amines 5h-u in moderate to good yields. It should be mentioned
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that the visible-light irradiation was necessary for good reaction efficiency of 1o with
electron-poor aromatic amines 4h-u (Scheme 3), while any exogenous photosensitizer was
not required. Notably, the synthetic important functional groups inlcuding Br, I, CN,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
SO Me and Bpin groups were survived well. Besides primary amines, the N-methylaniline
2
4v also gave the corresponding tertiary amine 5v in 57% yield. N-phenylglycine ethyl ester
4w was also suitable substrate, affording the desired product 5w in 46% yield. While the
diphenylamine was invalid under the present conditions (not shown).
Furthermore, a range of structurally diverse heteroaromatic amines and aromatic
N-heterocycles were subjected to this copper-catalyzed system (Scheme 4). Heteroaromatic
amines such as pyridin-2-amine, quinolin-8-amineand benzo[d]thiazol-6-amine were
efficient nitrogen nucleophiles, producing the secondary amines 7a-c in moderate yields.
In addition, weakly electrophilic aromatic N-heterocycles such as indole (6d), carbazole
(6e), phenothiazine (6f), benzo[d]imidazole (6g and 6h), pyrazole (6j) and indazole (6k)
were also efficient, furnishing the corresponding cyanoalkylated products in acceptable
yields under slightly modified reaction conditions. The theophylline 6i could also be
cyanoalkylated in 45% yield. In addition, the sulfonamide 6l also provided the desired
product 7l in moderate yield. Unexpectedly, the sulfadiazine 6m containing an amine
group and an amide group reacted chemoselectively to give the 7m as sole product in 30%
yield, which is probably attributed to the pyrimidine substituent.
3
Encouraged by above results, we hope to extend this C(sp )−N bond-forming procotol to
the more challenging aliphaticamines.4-6 So far, catalytic direct mono-alkylation of
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aliphatic amines has rarely been explored, mostly due to the issues of E2 side reactions and
5d
over-alkylation. Further investigation demonstrated that the cyanoalkylation of aliphatic
Scheme 4 Scope of Heteroaromatic Amines and Aromatic N-Heterocycles
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OCOC6F
5
N
Standard conditions B or C
+
RHN Het
NC
Het
N
R
1o
6
7
N
NC
NC
N
N
NC
N
H
NC
N
H
S
H
N
7
a, 32%a
7b, 58%a
7c, 40%a
NC
N
NC
N
N
S
Me
O
b
7e, 34%a
7f, 33%b
7
d, 72%
O
Me
N
N Me
NC
NC
N
NC
N
NC
N
N
Br
N
R
7g, R = H, 62%
7h, R = Cl, 44%b
O
N
b
i, 45%b
from Theophylline
7j, 40%b
7
O
O
O
O
S
S
N
N
N
NC
NC
N
Ph
H
N
N
NH2
Cl
7l, 40%b
7m, 30%a
from Sulfadiazine
7
k, 79%b
aStandard condition B: 20 mol % of CuOTf, L3 (10 mol %), 1o (0.2 mmol, 1.0 equiv), 4 (0.4 mmol, 2.0 equiv),
b
DIPEA (4.0 equiv), DMF (2 mL), rt, 10 W blue LEDs for 16 h, under N
2
, isolated yield. Standard condition C: 20
mol % of CuOTf, dtbpy (30 mol %), 1o (0.4 mmol, 2.0 equiv), 6 (0.2 mmol, 1.0 equiv), DIPEA (4.0 equiv),
DMSO (2 mL), rt, 10 W blue LEDs for 16 h, under N , isolated yield.
2
14
amines in the presence of 20 mol % of CuI, 30 mol % of bisoxazoline L7 and 4.0 equiv
of DIPEA under irradiation of 10 W blue LEDs, gave the corresponding secondary and
tertiary amines in moderate to good yields (For details, see the Supporting Information).
The addition of nitrogen-based ligands might be stabilize the LUMOs of photoactive
complexes and vary redox potentials and excited state lifetimes.14d,e The benzyl amine and
2-picolylamine reacted with 1o smoothly to give the desired products 9a and 9b in 92%
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and 60% yields, respectively (Scheme 5). Notably, primary aliphatic amines 8c-l furnished
the corresponding mono-cyanoalkylated products 9c-l in 34-84% yields. Secondary
Scheme 5 Scope of Aliphatic Amines, Natural Products and Drugsa
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OCOC6F5
N
O
O
R1
N
Standard condition D
1
2
NC
+
R R NH
N
R2
N
N
L7
Me
NC
Me
1o
8
9
NC
N
H
Ph
NC
N
N
H
H
N
9a, 92%
9b, 60%
9c, 84%
NH
NC
N
H
Ph
NC
NC
N
H
S
NC
N
H
9
d, 70%
9e, 82%
9f, 71%
NC
N
H
N
H
NC
N
H
O
9
g, 80%
9h, 78%
9i, 77%
9l, 68%
MeO C
2
N
H
CO Me
2
NC
N
H
NC
N
CO Me
2
NC
NC
H
N
H
9j, 34%
9k, 65%
N
NC
N
NC
CN
NC
N
N
O
9m, 65%
9n, 64%
9o, 70%
9p, 90%
Me
NC
HN
Me
Me
HN
H
NC
H
Me
9r, 40%
from Memantine
9
q, 76%
from Leelamine
Cl
N
N
O
N
N
NC
N
NC
Cl
9
s, 74%
9t, 45%
from Desloratadine
from Amoxapine
aStandard condition D: 20 mol % of CuI, L7 (30 mol %), 1o (0.4 mmol, 2.0 equiv), 8 (0.2 mmol, 1.0 equiv),
DIPEA (4.0 equiv), DMF (2 mL), rt, 10 W blue LEDs for 16 h, under N , isolated yield.
2
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aliphatic amines, cyclic as well as acyclic, both gave the expected tertiary amines 9m-p in 64-90%
yields. Notably, with tryptamine 8f and tryptophan methyl ester 8j, the cyanoalkylation reactions
occurred regioselectively, affording the products 9f and 9j in 71% and 34% yields, respectively.
Finally, several natural products and drugs such as Leelamine, Memantine, Desloartadine and
Amoxapine were also engaged in this cyanoalkylation reaction to afford the desired derivatives
9q-t in satisfied yields, which clearly highlighted the potential utility of this protocol for late-stage
modification of complex bioactive molecules. Satisfactorily, treatment of 2-phenylcyclopentanone
oxime ester 1r with benzyl amine 8a furnished the secondary amine 9u in 45% yield (eq 1).
Satisfactorily, treatment of 2-substituted cyclopentanone oxime esters 10a-d with benzyl amine 8a
furnished the secondary amine products 11a-d in moderate yields (Scheme 6). Unfortunately, the
use of 2-phenylcyclohexanone oxime in the reaction with 8a failed to give the desired product 11e
under the standard condition D. We also attempt to improve the yield of 11e by involving other
catalysts, ligands and bases, but were unsuccessful (for details, see SI). While the ring-unopened
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
product 11e’ was obtained in 80% yield when Fe(acac) was used as a catalyst, due to the
2
competitive direct coupling of oxime esters with amines.
Scheme 6 Scope of 2-Substituted Cyclopentanone and Cyclohexanone
Oxime Esters
OCOC6F5
N
H
Ar
Standard condition D
N
Ph
(1)
+
Ph
NH2
NC
Ar
10a-d
8a
1
1
1a, Ar = Ph, 45%; 11b, Ar = 2-MeC H , 68%
6
5
1c, Ar = 4-FC H , 40%; 11d, Ar = 2-naphthyl, 52%
6
5
OCOC6F5
Ph
N
Ph
Ph
Ph
N
Fe(acac) (20 mol %)
2
N
H
+
8a
NC
o
DMF (0.1 M), 80 C, 16h
N
Ph
n
H
n = 4
1
0e
11e, 0%
11e', 80%
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1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
To elucidate the reaction mechanism, several control experiments were performed (Scheme
7). First, radical trapping experiments by adding a radical scavenger, (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) to the reaction system were carried out. The
addition of 2.0 equiv of TEMPO inhibited the amination reaction completely and yielded
the TEMPO-adducts 12a and 12b in 48% and 52% yields, respectively (Scheme 7, a and
b), indicating that these transformations involved radical intermediates. Furthermore, the
radical clock substrate 13a reacted with 2a or 4p furnishing the cyclization/amination
product 14a and 14b in 35% and 51% yields, respectively (Scheme 7, c and d). These
results were consistent with a possible radical pathway. Furthermore, a series of UV-Vis
absorption spectra in Figure S1 showed that the mixture of amine 4p, CuOTf and ligand
L3 exhibited a strong visible light absorption tailing to the 390-520 nm region. These
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
observations suggest that a photo absorbing L Cu-NR R species might be involved in this
n
transformation (for details, see the Supporting Information).15 However, further
mechanistic studies will be needed to gain thorough understanding of the reaction
mechanism.16
Scheme 7 Mechanistic Investigation of the Cynoalkylation of Amines
OCOC6F5
N
Ph
H
H2N
Standard condition A
NC
N
N
(a)
+
NC
O
+
TEMPO (2.0 equiv)
Ph
12a, 48%
Ph
2a
3a, 0%
1a
OCOC6F5
+
N
H2N
H
Standard condition B
TEMPO (2.0 equiv)
NC
N
N
(b)
(c)
NC
O
+
CN
CN
1
o
4p
12b, 52%
5p, 0%
C6F5OCO
2
H N
H
Standard condition A
N
N
+
+
NC
13a
2a
4p
14a, 35% (dr = 1.8:1)
C6F5OCO
H2N
H
N
N
Standard condition B
(d)
NC
CN
CN
13a
14b, 51% (dr = 1.8:1)
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CONCLUSIONS
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In conclusion, we have developed a copper-catalyzed cyanoalkylation of amines via C−C bond
cleavage. The reactions proceeded under very mild conditions (room temperature, free of
exogenous photosensitizer) with exclusive selectivity and good functional group tolerance.
Furthermore, a variety range of nitrogen nucleophiles including (hetero)aromatic amines, aromatic
N-heterocycles, sulfonamides, and alkyl amines were amenable, thus providing a new and
efficient approach to structurally diverse cyanoalkylated amines. Especially, this protocol is also
applicable to late-stage functionalization of natural products, amino acid esters and drugs.
EXPERIMENTAL SECTION
General Methods. The reactions were conducted in oven-dried Schlenk-tube or the photoinduced
reactions were carried out in reaction tubes with Wattecs blue LEDs (10 W, 460-470 nm)
Irradiation Parallel Reactor under an atmosphere of nitrogen, the tube was placed 2 cm away from
the Irradiation Parallel Reactor, water cooling was enforced for effective thermal management to
maintain luminous efficiency and life expectancy of LED lights. Reactions were monitored by thin
layer chromatography (TLC) and visualized using UV light or a basic KMnO solution and heat.
4
1
Column chromatography purifications were carried out using 200-300 mesh silica gel. H NMR
and 13C NMR spectra were recorded on a Bruker Advance III-400 in solvents as indicated.
Chemical shift are reported in ppm from TMS with the solvent resonance as internal standard
1
13
1
13
(
CDCl : H NMR: δ = 7.26; C NMR: δ = 77.0; or DMSO-d6: H NMR: δ = 2.50; C NMR: δ =
3
39.52). Coupling constants are reported in Hz with multiplicities denoted as s (singlet), d (doublet),
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
t (triplet), q (quartet) and m (multiplet). FT-IR spectra were recorded on a Bruker V 70
-1
spectrometer and only major peaks are reported in cm . HRMS were obtained on a Q-TOF micro
spectrometer. Unless otherwise stated, all reagents were purchased from commercial sources and
used without further purification.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Note: if the amine, base or ligand is a liquid, its solution in solvent was used.
Starting Materials
All amines were purchased from commercial suppliers. All of cycloketone oxime esters 1 were
synthesized from the corresponding cycloketones and carboxylic acids according to the
11
9, 10f,
literature. The substituted cycloketones were prepared according to the reported procedure.
1
7a
All of the NMR spectra of the know compounds were in full accordance with the data in the
literatures.
Representative Procedure for the Reaction of Cyclobutanone Oxime Ester 1 with Aniline
2
a-p, 4a-g and 4v-w (Method A)
A 10 mL oven-dried Schlenk-tube equipped with a magnetic stirrer was charged with
cyclobutanone oxime ester 1 (0.2 mmol, 1.0 equiv), anilines 2a-p, 4a-g, 4v-w (0.4 mmol, 2.0
equiv), and Cu(OTf) (20 mol %). Then, the tube was evacuated and backfilled with nitrogen for
2
three times. Subsequently, 1.0 mL of DMF and 1.0mL H O were added by syringe under nitrogen.
2
The tube was then sealed and the mixture was stirred at room temperature for 16 h. After that, the
resulting mixture was quenched with H O and extracted with EtOAc (3 x 10 mL). The combined
2
organic phase was washed with brine (10 mL), dried over Na SO , and concentrated under
2
4
reduced pressure. The residue was purified by flash column chromatography on silica gel
(gradient eluent of petroleum ether/EtOAc/triethylamine: 100/20/3) to give the products 3a-p in
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Scheme 2, 5a-g, 5v-w in Scheme 3.
Representative Procedure for the Reaction of Cyclopentanone Oxime Esters 1q with Aniline
a, Cyclobutanone Oxime Ester 1o with Aromatic Amines 4h-u, Heteroaromatic Amines and
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Aromatic N-Heterocycles 6a-c, 6e, 6m (Method B)
A 10 mL oven-dried quartz reaction tube equipped with a magnetic stirrer was charged with
cyclopentanone oxime esters 1q (0.2 mmol, 1.0 equiv) with aniline 2a (0.4 mmol, 2.0 equiv) or
cyclobutanone oxime ester 1o (0.2 mmol, 1.0 equiv) with aromatic amines 4h-u (0.4 mmol, 2.0
equiv), heteroaromatic amines and aromatic N-heterocycles 6a-c, 6e, 6m (0.4 mmol, 2.0 equiv),
CuOTf (20 mol %), L3 (10 mol %) and DIPEA (0.8 mmol, 4.0 equiv). Then, the tube was
evacuated and backfilled with nitrogen for three times. Subsequently, 2.0 mL of DMF was added
by syringe under nitrogen. The tube was then sealed and the reactions were stirred with Wattecs
blue LEDs Irradiation Parallel Reactor at room temperature for 16 h. After that, the resulting
mixture was quenched with H O and extracted with EtOAc (3 x 10 mL). The combined organic
2
phase was washed with brine (10 mL), dried over Na SO , and concentrated under reduced
2
4
pressure. The residue was purified by flash column chromatography on silica gel to give the
products 3q in Scheme 2, 5h-u in Scheme 3, 7a-c, 7e and 7m in Scheme 4.
Representative Procedure for the Reaction of Cyclobutanone Oxime Ester 1o with
Heteroaromatic Amines and Aromatic N-Heterocycles 6d, 6f-l (Method C)
A 10 mL oven-dried quartz reaction tube equipped with a magnetic stirrer was charged with
cyclobutanone oxime ester 1o (0.4 mmol, 2.0 equiv), heteroaromatic amines or aromatic
N-heterocycles 6d, 6f-l (0.2 mmol, 1.0 equiv), CuOTf (20 mol %), dtbpy (30 mol %) and DIPEA
(0.8 mmol, 4.0 equiv). Then, the tube was evacuated and backfilled with nitrogen for three times.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Subsequently, 2.0 mL of DMSO was added by syringe under nitrogen. The tube was then sealed
and the reactions were stirred with Wattecs blue LEDs Irradiation Parallel Reactor at room
temperature for 16 h. After that, the resulting mixture was quenched with H O and extracted with
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EtOAc (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over
Na SO , and concentrated under reduced pressure. The residue was purified by flash column
2
4
chromatography on silica gel to give the products 7d, 7f-l in Scheme 4.
Representative Procedure for the Reaction of Cyclobutanone Oxime Ester 1o with Aliphatic
Amines 8 (Method D)
A 10 mL oven-dried quartz reaction tube equipped with a magnetic stirrer was charged with
cyclobutanone oxime ester 1o (0.4 mmol, 2.0 equiv), aliphatic amines 8 (0.2 mmol, 1.0 equiv),
CuI (20 mol %), L7 (30 mol %) and DIPEA (0.8 mmol, 4.0 equiv). Then, the tube was evacuated
and backfilled with nitrogen for three times. Subsequently, 2.0 mL of DMF was added by syringe
under nitrogen. The tube was then sealed and the reactions were stirred with Wattecs blue LEDs
Irradiation Parallel Reactor at room temperature for 16 h. After that, the resulting mixture was
quenched with H O and extracted with EtOAc (3 x 10 mL). The combined organic phase was
2
washed with brine (10 mL), dried over Na SO , and concentrated under reduced pressure. The
2
4
residue was purified by flash column chromatography on silica gel to give the products 9 in
Scheme 5.
Representative Procedure for the Reaction of 2-Substituted Cyclopentanone Oxime Ester
1
0a-d with Benzyl Amine 8a (Method D)
A 10 mL oven-dried quartz reaction tube equipped with a magnetic stirrer was charged with
2
-substituted cyclopentanone oxime ester 10a-d (0.4 mmol, 2.0 equiv), benzyl amine 8a (0.2
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mmol, 1.0 equiv), CuI (20 mol %), L7 (30 mol %) and DIPEA (0.8 mmol, 4.0 equiv). Then, the
tube was evacuated and backfilled with nitrogen for three times. Subsequently, 2.0 mL of DMF
was added by syringe under nitrogen. The tube was then sealed and the reaction was stirred with
Wattecs blue LEDs Irradiation Parallel Reactor at room temperature for 16 h. After that, the
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resulting mixture was quenched with H O and extracted with EtOAc (3 x 10 mL). The combined
2
organic phase was washed with brine (10 mL), dried over Na SO , and concentrated under
2
4
reduced pressure. The residue was purified by flash column chromatography on silica gel to give
the products 11a-d in Scheme 6.
Representative Procedure for the Reaction of 2-Phenyl Cyclohexanone Oxime Ester 10e with
Benzyl Amine 8a
A 10 mL oven-dried Schlenk-tube equipped with a magnetic stirrer was charged with 2-phenyl
cyclohexanone oxime ester 10e (0.4 mmol, 2.0 equiv), benzyl amine 8a (0.2 mmol, 1.0 equiv),
Fe(acac) (20 mol %) and L7 (30 mol %). Then, the tube was evacuated and backfilled with
2
nitrogen for three times. Subsequently, 2.0 mL of DMF was added by syringe under nitrogen. The
o
tube was then sealed and the mixture was stirred at 80 C for 16 h. After that, the resulting mixture
was quenched with H O and extracted with EtOAc (3 x 10 mL). The combined organic phase was
2
washed with brine (10 mL), dried over Na SO , and concentrated under reduced pressure. The
2
4
residue was purified by flash column chromatography on silica gel (gradient eluent of petroleum
ether/EtOAc/triethylamine: 100/20/3) to give the product 11e’ in Scheme 6.
Large Scale Procedure for the Synthesis of 3a: A 100 mL oven-dried Schlenk-tube equipped
with a magnetic stirrer was charged with cyclobutanone oxime ester 1a (1.07 g, 3.0 mmol, 1.0
equiv) and Cu(OTf) (0.22 g, 20 mol %). Then, the tube was evacuated and backfilled with
2
nitrogen for three times. Subsequently, aniline 2a (0.56 g, 6.0 mmol, 2.0 equiv), 15.0 mL of DMF
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and 15.0 mL H O were added by syringe under nitrogen. The tube was then sealed and the
2
mixture was stirred at room temperature for 16 h. After that, the resulting mixture was quenched
with H O and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with
2
brine (50 mL), dried over Na SO , and concentrated under reduced pressure. The residue was
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purified by flash column chromatography on silica gel (gradient eluent of petroleum
ether/EtOAc/triethylamine: 100/20/3) to give the product 3a (0.54 g, 76%), along with 65% of
pentafluorobenzoic acid recovered.
Characterization of Products 3
3
-Phenyl-4-(phenylamino)butanenitrile (3a): Following the Method A with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid (88%, 41.6 mg);
1
R 0.25 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.50 – 7.35 (m, 3H),
f
3
7.32 – 7.24 (m, 4H), 6.82 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 7.7 Hz, 2H), 3.83 – 3.72 (t, J = 6.0 Hz,
1
3
1
1
H), 3.64 – 3.54 (m, 1H), 3.49 – 3.43 (m, 1H), 3.36 – 3.30 (m, 1H), 2.81 – 2.68 (m, 2H); C{ H}
NMR (101 MHz, CDCl ) δ = 147.1, 139.2, 129.2, 128.9, 127.7, 127.1, 118.2, 117.8, 112.8, 47.7,
3
-1
41.1, 21.8 ppm; IR (neat): υmax 3399, 2924, 2246, 1731, 1602, 1508, 1257, 752, 697 cm ; HRMS
+
(
ESI) calcd for C H N [M+H] 237.1386, found 237.1394.
1
6
17
2
4-(Phenylamino)-3-(p-tolyl)butanenitrile (3b): Following the Method A with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid (93%, 46.5 mg);
1
R 0.25 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.25 – 7.12 (m, 6H),
f
3
6.76 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 3.67 (s, 1H), 3.57 (dd, J = 13.1, 6.9 Hz, 1H),
1
3
1
3
.42 (dd, J = 12.9, 7.4 Hz, 1H), 3.33 – 3.26 (m, 1H), 2.82 – 2.64 (m, 2H), 2.37 (s, 3H); C{ H}
NMR (101 MHz, CDCl ) δ = 147.2, 137.7, 136.2, 129.8, 129.3, 127.1, 118.3, 118.0, 113.0, 48.0,
3
4
0.9, 22.2, 21.0 ppm; IR (neat): υmax 3399, 2922, 2246, 1602, 1510, 1321, 1259, 816, 751, 693
-1
+
cm ; HRMS (ESI) calcd for C H N [M+H] 251.1543, found 251.1547.
1
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3-(4-Butylphenyl)-4-(phenylamino)butanenitrile (3c): Following the Method A with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
1
(
89%, 52.0 mg); R 0.3 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.46 –
f
3
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
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3
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3
4
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5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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8
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0
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4
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9
0
7
.36 (m, 2H), 7.23 – 7.14 (m, 4H), 6.75 (t, J = 7.3 Hz, 1H), 6.65 – 6.58 (m, 2H), 3.70 (s, 1H), 3.58
(dd, J = 13.1, 6.9 Hz, 1H), 3.44 (dd, J = 13.0, 7.3 Hz, 1H), 3.33 – 3.27 (m, 1H), 2.82 – 2.66 (m,
1
3
1
2H), 1.33 (s, 9H); C{ H} NMR (101 MHz, CDCl ) δ = 150.9, 147.2, 136.1, 129.3, 126.9, 126.0,
3
1
1
3
18.4, 118.0, 113.1, 48.0, 40.8, 34.5, 31.2, 22.2 ppm; IR (neat): υmax 2962, 2246 , 1602, 1508,
-1
+
260, 800, 693 cm ; HRMS (ESI) calcd for C H N [M+H] 293.2012, found 293.2013.
2
0
25
2
-(4-Chlorophenyl)-4-(phenylamino)butanenitrile (3d): Following the Method A with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
1
(71%, 38.4 mg); R 0.13 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.41 –
f
3
7
1
2
1
.35 (m, 2H), 7.22 – 7.18 (m, 4H), 6.76 (t, J = 7.3 Hz, 1H), 6.60 (dd, J = 8.5, 0.9 Hz, 2H), 3.66 (s,
H), 3.57 (dd, J = 12.9, 7.2 Hz, 1H), 3.42 (dd, J = 13.0, 7.3 Hz, 1H), 3.34 – 3.28 (m, 1H), 2.79 –
.67 (m, 2H); 13C{ H} NMR (101 MHz, CDCl ) δ = 146.9, 137.7, 133.9, 129.4, 129.3, 128.7,
1
3
18.3, 117.9, 113.0, 47.9, 40.8, 22.1 ppm; IR (neat): υmax 3399, 2924, 2247, 1602, 1493, 1259,
-1
+
1093, 752, 694 cm ; HRMS (ESI) calcd for C H ClN [M+H] 271.0997, found 271.1003.
1
6
16
2
Methyl 4-(1-cyano-3-(phenylamino)propan-2-yl)benzoate (3e): Following the Method A with
the corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow
1
liquid (60%, 35.3 mg); R 0.2 (EtOAc/petroleum ether = 1:3); H NMR (400 MHz, CDCl ): δ =
f
3
8
.09 – 8.01 (m, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.24 – 7.15 (m, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.60
(dd, J = 8.5, 0.9 Hz, 2H), 3.93 (s, 3H), 3.63 (dd, J = 24.4, 8.0 Hz, 2H), 3.50 – 3.38 (m, 2H), 2.84 –
1
2
.72 (m, 2H); 13C{ H} NMR (101 MHz, CDCl ) δ = 166.5, 146.9, 144.4, 130.4, 129.9, 129.4,
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127.4, 118.3, 117.8, 113.0, 52.2, 47.9, 41.3, 21.8 ppm; IR (neat): υmax 3397, 2959, 2247, 1719,
-
1
+
1
2
4
603, 1283, 1110, 753, 695 cm ; HRMS (ESI) calcd for C H N O [M+H] 295.1441, found
18 19 2 2
95.1444.
-(Phenylamino)-3-(m-tolyl)butanenitrile (3f): Following the Method A with the corresponding
0
1
2
3
4
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0
1
2
3
4
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8
9
0
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9
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9
0
cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid (65%, 32.5 mg);
1
R 0.3 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.33 – 7.23 (m, 2H), 7.21
f
3
–
3
7.13 (m, 2H), 7.06 (s, 2H), 6.75 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.9 Hz, 2H), 3.77 – 3.51 (m, 2H),
13
1
.43 (dd, J = 12.6, 7.5 Hz, 1H), 3.32 – 3.27 (m, 1H), 2.87 – 2.63 (m, 2H), 2.37 (s, 3H); C{ H}
NMR (101 MHz, CDCl ) δ = 147.2, 139.2, 138.9, 129.4, 129.0, 128.8, 128.0, 124.3, 118.1, 113.1,
3
9
9.6, 48.0, 41.3, 22.2, 21.4 ppm; IR (neat): υmax 3396, 2921, 2246, 1602, 1507, 1260, 791, 694
-1
+
cm ; HRMS (ESI) calcd for C H N [M+H] 251.1543, found 251.1548.
1
7
19
2
3
-(3-Bromophenyl)-4-(phenylamino)butanenitrile (3g): Following the Method A with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
1
(
58%, 36.5 mg); R 0.13 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.50 –
f
3
7
.42 (m, 1H), 7.39 (t, J = 1.7 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.23 – 7.16 (m, 3H), 6.75 (t, J = 7.3
Hz, 1H), 6.60 (dd, J = 8.5, 0.9 Hz, 2H), 3.67 (s, 1H), 3.62 – 3.49 (m, 1H), 3.45 – 3.40 (m, 1H),
3
1
3
.31 – 3.24 (m, 1H), 2.79 – 2.66 (m, 2H); 13C{ H} NMR (101 MHz, CDCl ) δ = 146.9, 141.6,
1
3
31.2, 130.7, 130.4, 129.4, 126.0, 123.2, 118.3, 117.8, 113.0, 47.9, 41.1, 21.9 ppm; IR (neat): υmax
-1
397, 2923, 2246, 1602, 1567, 1259, 1074, 788, 694 cm ; HRMS (ESI) calcd for C H BrN
16 16
2
+
[
M+H] 315.0491, found 315.0494.
3-(2,3-Dichlorophenyl)-4-(phenylamino)butanenitrile (3h): Following the Method A with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
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(55%, 33.4 mg); R 0.21 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.50 –
f
3
7
.42 (m, 1H), 7.26 (dd, J = 7.1, 4.0 Hz, 2H), 7.23 – 7.15 (m, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.63
(
(
dd, J = 8.6, 0.9 Hz, 2H), 4.03 – 3.89 (m, 1H), 3.75 (s, 1H), 3.56 (d, J = 6.6 Hz, 2H), 2.90 – 2.74
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
6
0
1
2
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8
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0
1
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9
0
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8
9
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6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
3
1
m, 2H); C{ H} NMR (101 MHz, CDCl ) δ = 146.9, 138.9, 134.0, 132.5, 129.9, 129.4, 127.8,
3
1
25.7, 118.3, 117.6, 112.9, 46.5, 38.1, 20.7 ppm; IR (neat): υmax 3399, 2925, 2248, 1600, 1507,
-1
+
1260, 792, 693 cm ; HRMS (ESI) calcd for C H Cl N [M+H] 305.0607, found 305.0608.
1
6
15
2
2
3
-Benzyl-4-(phenylamino)butanenitrile (3i): Following the Method A with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid (93%, 46.5 mg);
1
R 0.35 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.33 (t, J = 7.3 Hz, 2H),
f
3
7
.29 – 7.12 (m, 5H), 6.72 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 7.8 Hz, 2H), 3.79 (s, 1H), 3.32 – 3.17 (m,
2H), 2.87 (dd, J = 13.7, 5.9 Hz, 1H), 2.72 (dd, J = 13.8, 8.1 Hz, 1H), 2.51 – 2.40 (m, 1H), 2.39 –
1
2
1
1
5
.27 (m, 2H); 13C{ H} NMR (101 MHz, CDCl ): δ = 147.4, 138.1, 129.3, 128.9, 128.7, 126.8,
3
18.2, 117.9, 112.8, 46.7, 37.7, 37.2, 19.4 ppm; IR (neat): υmax 3404, 2974, 2246, 1602, 1497,
-
1
+
048, 747, 694 cm ; HRMS (ESI) calcd for C H N [M+H] 251.1543, found 251.1537.
17 19
2
-Cyano-4-((phenylamino)methyl)pentyl benzoate (3j): Following the Method A with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
1
(
60%, 38.7 mg); R 0.19 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 8.04 (d,
f
3
J = 7.4 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.8 Hz, 2H), 6.74 (t,
J = 7.3 Hz, 1H), 6.61 (d, J = 7.9 Hz, 2H), 4.37 (t, J = 6.4 Hz, 2H), 3.80 (s, 1H), 3.30 (dd, J = 13.6,
5
.0 Hz, 1H), 3.17 (dd, J = 13.4, 8.6 Hz, 1H), 2.65 – 2.42 (m, 2H), 2.22 – 2.08 (m, 1H), 1.99 – 1.78
1
3
1
(m, 2H), 1.77 – 1.62 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 166.5, 147.4, 133.0, 130.0,
3
1
29.5, 129.4, 128.4, 118.1, 118.0, 112.8, 64.3, 46.9, 35.0, 28.0, 26.0, 19.9 ppm; IR (neat): υmax
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6
-
1
3400, 2925, 2245, 1716, 1602, 1509, 1274, 1114, 713, 694 cm ; HRMS (ESI) calcd for
+
C H N O [M+H] 323.1754, found 323.1757.
2
0
23
2
2
3
-(Benzyloxy)-4-(phenylamino)butanenitrile (3k): Following the Method A with the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
1
(
52%, 27.7 mg); R 0.15 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.53 –
f
3
7.28 (m, 5H), 7.19 (t, J = 7.8 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 4.67 (dd,
1
3
1
J = 39.3, 11.6 Hz, 2H), 4.03 – 3.83 (m, 2H), 3.48 – 3.21 (m, 2H), 2.68 (d, J = 5.8 Hz, 2H); C{ H}
NMR (101 MHz, CDCl ): δ = 147.3, 137.0, 129.3, 128.6, 128.2, 127.9, 118.2, 117.2, 113.1, 73.0,
3
-1
7
2.3, 46.3, 21.2 ppm; IR (neat): υmax 3398, 2925, 2249, 1603, 1508, 1260, 1097, 750, 695 cm ;
+
HRMS (ESI) calcd for C H N O [M+H] 267.1492, found 267.1500.
1
7
19
2
3-Methyl-3-phenyl-4-(phenylamino)butanenitrile (3l): Following the Method A with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
1
(
87%, 43.5 mg); R 0.3 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.47 –
f
3
7
1
.29 (m, 5H), 7.20 – 7.10 (m, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.60 – 6.54 (m, 2H), 3.46 (dd, J = 36.6,
2.5 Hz, 2H), 3.29 (s, 1H), 2.85 (s, 2H), 1.63 (s, 3H); 13C{ H} NMR (101 MHz, CDCl ): δ =
1
3
147.8, 142.0, 129.3, 129.1, 127.5, 125.8, 118.1, 117.9, 113.2, 53.5, 41.5, 28.4, 24.3 ppm; IR (neat):
-
1
υmax 3394, 2964, 2244, 1602, 1501, 1258, 1029, 799, 752, 696 cm ; HRMS (ESI) calcd for
+
C H N [M+H] 251.1543, found 251.1546.
1
7
19
2
tert-Butyl
4-(cyanomethyl)-4-((phenylamino)methyl)piperidine-1-carboxylate
(3m):
Following the Method A with the corresponding cyclobutanone oxime ester (0.2 mmol) and
1
aniline (0.4 mmol). Faint yellow liquid (79%, 52.0 mg); R 0.2 (EtOAc/petroleum ether = 1:3); H
f
NMR (400 MHz, CDCl ): δ = 7.23 – 7.14 (m, 2H), 6.75 (t, J = 7.3 Hz, 1H), 6.71 – 6.65 (m, 2H),
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3.64 (d, J = 13.2 Hz, 3H), 3.26 (dt, J = 19.1, 6.2 Hz, 4H), 2.53 (s, 2H), 1.66 – 1.59 (m, 4H), 1.46
1
(
s, 9H); 13C{ H} NMR (101 MHz, CDCl ): δ = 154.6, 148.0, 129.4, 118.3, 117.5, 113.2, 79.9,
3
5
7
2
0.5, 36.3, 32.2, 28.3, 23.7 ppm; IR (neat): υmax 3378, 2929, 2244, 1686, 1602, 1424, 1261, 1157,
1
1
1
1
1
1
1
1
1
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
50, 694 cm ; HRMS (ESI) calcd for C H N O [M+H] 330.2176, found 330.2180.
19 28
3
2
-(3-Phenyl-1-((phenylamino)methyl)cyclobutyl)acetonitrile (3n): Following the Method A
with the corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint
yellow liquid (86%, 47.5 mg); R 0.3 (EtOAc/petroleum ether = 1:5); the title compound as a 1:1
f
1
mixture of inseparable diastereomers; H NMR (400 MHz, CDCl ): δ = 7.32 (q, J = 7.1 Hz, 2H),
3
7
.27 – 7.13 (m, 5H), 6.79 – 6.68 (m, 2H), 6.64 (d, J = 8.0 Hz, 1H), 3.60 (tq, J = 18.3, 9.2 Hz, 2H),
3
.46 (s, 1H), 3.27 (s, 1H), 2.76 (s, 1H), 2.59 (s, 1H), 2.50 – 2.35 (m, 2H), 2.29 – 2.18 (m, 2H);
1
3
1
C{ H} NMR (101 MHz, CDCl ): δ = 148.1, 148.0, 144.2, 144.1, 129.4, 129.3, 128.5, 128.4,
3
1
3
26.4, 126.3, 126.2, 126.2, 118.4, 118.2, 118.1, 118.0, 113.1, 113.1, 52.2, 50.0, 37.4, 36.7, 36.5,
6.5, 33.2, 32.9, 27.3, 25.4 ppm; IR (neat): υmax 3393, 2928, 2244, 1602, 1509, 1257, 752, 696
-1
+
cm ; HRMS (ESI) calcd for C H N [M+H] 277.1699, found 277.1703.
19 21
2
4
-(Phenylamino)butanenitrile (3o): Following the Method A with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid (80%, 25.6 mg);
1
R 0.3 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.20 (t, J = 7.8 Hz, 2H),
f
3
6
7
1
.74 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.2 Hz, 2H), 3.64 (s, 1H), 3.32 (t, J = 6.6 Hz, 2H), 2.48 (t, J =
.1 Hz, 2H), 2.00 – 1.94 (m, 2H); 13C{ H} NMR (101 MHz, CDCl ): δ = 147.4, 129.3, 119.3,
1
3
17.9, 112.8, 42.2, 25.2, 14.7 ppm. Spectral data match those previously reported.17b
(E)-3,5-Diphenylpent-4-enenitrile (3p’): Following the Method A with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid (88%, 41.0 mg);
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1
R 0.28 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.43 – 7.36 (m, 4H),
f
3
7
.35 – 7.26 (m, 6H), 6.55 (d, J = 15.9 Hz, 1H), 6.40 (dd, J = 15.9, 7.3 Hz, 1H), 3.89 (q, J = 7.2 Hz,
1
1
H), 2.92 – 2.77 (m, 2H); 13C{ H} NMR (101 MHz, CDCl ): δ = 140.5, 136.3, 131.9, 129.2,
3
0
1
2
3
4
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0
1
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4
5
6
7
8
9
0
1
29.0, 128.5, 127.8, 127.6, 127.2, 126.4, 118.1, 44.9, 24.4 ppm; IR (neat): υmax 3027, 2961, 2245,
-1
+
1
599, 1493, 1452, 1260, 1028, 965, 745, 696 cm ; HRMS (ESI) calcd for C H N [M+H]
17 16
234.1277, found 234.1282.
2
-(3-(Phenylamino)cyclopentyl)acetonitrile (3q): Following the Method
B
with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aniline (0.4 mmol). Faint yellow liquid
(
28%, 11.2 mg); R 0.25 (EtOAc/petroleum ether = 1:5); the title compound as a 1:1 mixture of
f
1
inseparable diastereomers; H NMR (400 MHz, CDCl ): δ = 7.22 – 7.13 (m, 2H), 6.73 – 6.69 (m,
3
1H), 6.65 – 6.55 (m, 2H), 4.01 – 3.80 (m, 1H), 3.67 (s, 1H), 3.15 (d, J = 6.8 Hz, 0.7H), 2.89 – 2.66
(
m, 0.3H), 2.48 – 2.38 (m, 2H), 2.34 – 2.25 (m, 1H), 2.11 – 1.90 (m, 2H), 1.79 – 1.41 (m, 3H);
13
1
C{ H} NMR (101 MHz, CDCl ): δ = 147.9, 147.5, 147.3, 129.2, 129.2, 122.9, 118.8, 118.8,
3
1
3
17.5, 117.4, 113.2, 113.1, 112.7, 54.2, 53.8, 48.5, 39.8, 39.2, 39.1, 35.6, 34.9, 34.5, 33.5, 32.9,
0.5, 30.4, 29.9, 29.5, 27.5, 23.0, 22.6 ppm; IR (neat): υmax 3394, 2973, 2242, 1602, 1501, 1048,
-1
+
749, 693 cm ; HRMS (ESI) calcd for C H N [M+NH ] 218.1652, found 218.1647.
1
3
20
3
4
Characterization of Products 5
-(o-Tolylamino)butanenitrile (5a): Following the Method A with the corresponding
4
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (88%,
1
3
0.6 mg); R 0.2 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.14 (t, J = 7.7
f
3
Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 3.56 (s, 1H),
1
3
1
3
.38 (t, J = 6.6 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H), 2.15 (s, 3H), 2.05 – 1.98 (m, 2H); C{ H} NMR
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(101 MHz, CDCl ): δ = 145.3, 130.3, 127.1, 122.2, 119.4, 117.4, 109.5, 42.2, 25.1, 17.4, 14.8 ppm;
3
-1
IR (neat): υmax 3433, 2962, 2245, 1604, 1511, 1260, 1021, 799, 702 cm ; HRMS (ESI) calcd for
+
C H KN [M+K] 213.0789, found 213.0785.
1
1
14
2
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
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0
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8
9
0
1
2
3
4
5
6
7
8
9
0
4
-((2-Methoxyphenyl)amino)butanenitrile (5b): Following the Method
A
with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint
1
yellow liquid (89%, 33.8 mg); R 0.17 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz,
f
CDCl ): δ = 6.88 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.70 (t, J = 7.7 Hz, 1H), 6.62 (d, J =
3
7
1
1
.8 Hz, 1H), 4.26 (s, 1H), 3.85 (s, 3H), 3.33 (t, J = 6.6 Hz, 2H), 2.49 (t, J = 7.1 Hz, 2H), 2.03 –
.96 (m, 2H); 13C{ H} NMR (101 MHz, CDCl ): δ = 146.8, 137.4, 121.2, 119.3, 117.0, 109.7,
1
3
09.6, 55.4, 42.0, 25.3, 14.8 ppm. Spectral data match those previously reported.17c
4-(m-Tolylamino)butanenitrile (5c): Following the Method A with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (60%,
1
2
0.9 mg); R 0.19 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.08 (dd, J =
f
3
8
.3, 7.5 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 6.44 (d, J = 7.4 Hz, 2H), 3.65 (s, 1H), 3.31 (t, J = 6.6
1
3
1
Hz, 2H), 2.47 (t, J = 7.1 Hz, 2H), 2.29 (s, 3H), 2.00 – 1.93 (m, 2H); C{ H} NMR (101 MHz,
CDCl ): δ = 147.5, 139.2, 129.2, 119.3, 118.8, 113.6, 109.9, 42.2, 25.2, 21.5, 14.7 ppm; IR (neat):
3
-1
+
υmax 2962, 2245, 1416, 1260, 1092, 1020, 799, 691 cm ; HRMS (ESI) calcd for C H N [M+H]
11
15
2
1
75.1230, found 175.1235.
4
-((3-Methoxyphenyl)amino)butanenitrile (5d): Following the Method
A
with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint
1
yellow liquid (31%, 11.8 mg); R 0.16 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz,
f
CDCl ): δ = 7.09 (t, J = 8.1 Hz, 1H), 6.46 – 6.19 (m, 2H), 6.17 (t, J = 2.3 Hz, 1H), 3.76 (d, J =
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10.3 Hz, 4H), 3.30 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 7.1 Hz, 2H), 1.99 – 1.92 (m, 2H); 13C{ H}
1
NMR (101 MHz, CDCl ): δ = 160.8, 148.8, 130.1, 119.3, 105.9, 102.8, 98.8, 55.0, 42.2, 25.1, 14.7
3
-1
ppm; IR (neat): υmax 2962, 2245, 1597, 1261, 1094, 1023, 799, 687 cm ; HRMS (ESI) calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
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0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
C H N O [M+H] 191.1179, found 191.1186.
11 15
2
4
-(p-Tolylamino)butanenitrile (5e): Following the Method A with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (82%,
1
2
8
2
1
8.6 mg); R 0.19 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 6.98 (d, J =
f
3
.1 Hz, 2H), 6.52 (d, J = 8.3 Hz, 2H), 3.54 (s, 1H), 3.26 (t, J = 6.6 Hz, 2H), 2.43 (t, J = 7.1 Hz,
1
3
1
H), 2.22 (s, 3H), 1.96 – 1.89 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 145.1, 129.8, 127.1,
3
19.3, 112.9, 42.5, 25.2, 20.3, 14.7 ppm; IR (neat): υmax 2961, 2245, 1518, 1260, 1093, 1019, 800,
-1
+
704 cm ; HRMS (ESI) calcd for C H N [M+H] 175.1230, found 175.1236.
1
1
15
2
4
-((4-Methoxyphenyl)amino)butanenitrile (5f): Following the Method
A
with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint
1
yellow liquid (65%, 24.7 mg); R 0.3 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ):
f
3
δ = 6.80 – 6.78 (m, 2H), 6.64 – 6.44 (m, 2H), 3.75 (s, 3H), 3.41 (s, 1H), 3.26 (dd, J = 8.8, 4.3 Hz,
1
3
1
2H), 2.47 (dd, J = 9.5, 4.5 Hz, 2H), 2.11 – 1.80 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ =
3
1
52.4, 141.6, 119.4, 114.9, 114.2, 55.7, 43.2, 25.3, 14.8 ppm; IR (neat): υmax 3393, 2961, 2245,
-1
+
1
512, 1260, 1094, 1025, 799, 704 cm ; HRMS (ESI) calcd for C H N O [M+H] 191.1179,
11 15 2
found 191.1188.
4
-((2,4-Dimethoxyphenyl)amino)butanenitrile (5g): Following the Method A with the
corresponding cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint
1
yellow liquid (48%, 21.1 mg); R 0.12 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz,
f
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CDCl ): δ = 6.54 – 6.40 (m, 3H), 3.83 (s, 3H), 3.76 (s, 3H), 3.27 (t, J = 6.6 Hz, 2H), 2.85 (s, 1H),
3
1
3
1
2
1
1
2
.49 (t, J = 7.1 Hz, 2H), 2.01 – 1.94 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 152.2, 148.0,
3
31.6, 119.4, 110.3, 103.7, 99.2, 55.7, 55.4, 42.8, 25.4, 14.8 ppm; IR (neat): υmax 2962, 2245, 1517,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
4
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4
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4
4
4
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5
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5
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0
1
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8
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0
1
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7
8
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0
1
2
3
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7
8
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0
1
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
260, 1093, 1020, 799 cm ; HRMS (ESI) calcd for C H N O [M+H] 221.1285, found
12 17
2
2
21.1288.
4-((2-Fluorophenyl)amino)butanenitrile (5h): Following the Method B with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (65%,
1
2
3.2 mg); R 0.19 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.05 – 6.93
f
3
(m, 2H), 6.73 – 6.63 (m, 2H), 3.94 (s, 1H), 3.35 (t, J = 6.6 Hz, 2H), 2.49 (t, J = 7.1 Hz, 2H), 2.03 –
1
3
1
1
.96 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 151.5 (d, J = 237.0 Hz), 136.4 (d, J = 11.4
3
Hz), 124.6 (d, J = 3.4 Hz), 119.1, 117.2 (d, J = 6.9 Hz), 114.6 (d, J = 18.3 Hz), 111.9 (d, J = 3.0
Hz), 41.9, 25.2, 14.7 ppm; IR (neat): υmax 3395 2962, 2246, 1620, 1512, 1260, 1091, 1020, 798
,
-1
+
cm ; HRMS (ESI) calcd for C H FN [M+NH ] 196.1245, found 196.1238.
1
0
15
3
4
4
-((2-Bromophenyl)amino)butanenitrile (5i): Following the Method B with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (52%,
1
24.8 mg); R 0.25 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.43 (dd, J =
f
3
7
.9, 1.4 Hz, 1H), 7.23 – 7.14 (m, 1H), 6.69 – 6.55 (m, 2H), 4.34 (s, 1H), 3.38 (t, J = 6.6 Hz, 2H),
13
1
2
.49 (t, J = 7.1 Hz, 2H), 2.05 – 1.98 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 144.2, 132.6,
3
1
28.5, 119.1, 118.3, 111.1, 109.9, 42.1, 25.0, 14.7 ppm; IR (neat): υmax 3398, 2961, 2246, 1737,
-1
+
1
595, 1260, 1094, 1018, 799 cm ; HRMS (ESI) calcd for C H BrN [M+H] 239.0178, found
10 12 2
239.0186.
4
-([1,1'-Biphenyl]-2-ylamino)butanenitrile (5j): Following the Method
B
with the
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6
corresponding cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint
1
yellow liquid (80%, 37.8 mg); R 0.15 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz,
f
CDCl ): δ = 7.51 – 7.43 (m, 2H), 7.43 – 7.34 (m, 3H), 7.30 – 7.21 (m, 1H), 7.11 (dd, J = 7.4, 1.6
3
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
6
7
8
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0
1
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8
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5
6
7
8
9
0
Hz, 1H), 6.81 (td, J = 7.4, 0.9 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.93 (s, 1H), 3.29 (t, J = 6.6 Hz,
1
3
1
2
H), 2.40 (t, J = 7.1 Hz, 2H), 1.95 – 1.88 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 144.2,
3
139.1, 130.4, 129.2, 128.9, 128.7, 128.0, 127.3, 119.2, 117.5, 110.3, 42.3, 25.1, 14.7 ppm; IR
-1
(
neat): υmax 3419, 2962, 2246, 1580, 1262, 1086, 800, 703 cm ; HRMS (ESI) calcd for C H N
16 20 3
+
[
M+NH ] 254.1652, found 254.1651.
4
4
-((3-Chlorophenyl)amino)butanenitrile (5k): Following the Method B with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (75%,
1
29.1 mg); R 0.25 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.09 (t, J =
f
3
8
3
.0 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.58 (s, 1H), 6.48 (dd, J = 8.2, 1.9 Hz, 1H), 3.81 (s, 1H),
13
1
.30 (d, J = 4.1 Hz, 2H), 2.47 (t, J = 7.0 Hz, 2H), 2.00 – 1.93 (m, 2H); C{ H} NMR (101 MHz,
CDCl ): δ = 148.6, 135.1, 130.3, 119.1, 117.7, 112.4, 111.1, 42.1, 24.9, 14.7 ppm; IR (neat): υ
3
max
-1
+
2
962, 2244, 1601, 1511, 1260, 1093, 1023, 799 cm ; HRMS (ESI) calcd for C H ClN [M+H]
1
0
12
2
195.0684, found 195.0691.
4
-((4-Fluorophenyl)amino)butanenitrile (5l): Following the Method B with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (78%,
1
2
7.8 mg); R 0.15 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.01 – 6.78
f
3
(m, 2H), 6.66 – 6.41 (m, 2H), 3.61 (s, 1H), 3.28 (t, J = 6.5 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H), 2.00 –
1
3
1
1.93 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 156.0 (d, J = 234.2 Hz), 143.8, 119.3, 115.7
3
(d, J = 22.2 Hz), 113.7 (d, J = 7.3 Hz), 42.9, 25.1, 14.7 ppm; IR (neat): υmax 2962, 2246, 1510,
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Page 29 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
-
1
+
1260, 1091, 1019, 799, 701 cm ; HRMS (ESI) calcd for C H FN [M+H] 179.0979, found
1
0
12
2
1
79.0987.
-((4-Chlorophenyl)amino)butanenitrile (5m): Following the Method B with the corresponding
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (82%,
1
3
1.8 mg); R 0.25 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.19 – 6.95
f
3
(m, 2H), 6.57 – 6.45 (m, 2H), 3.74 (s, 1H), 3.28 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 7.0 Hz, 2H), 1.98 –
1
3
1
1
1
.91 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 146.0, 129.1, 122.4, 119.2, 113.8, 42.3, 25.0,
3
-1
4.7 ppm; IR (neat): υmax 2962, 2246, 1260, 1090, 1019, 799, 700 cm ; HRMS (ESI) calcd for
+
C H ClN [M+H] 195.0684, found 195.0690.
10 12
2
4
-((4-Bromophenyl)amino)butanenitrile (5n): Following the Method B with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (60%,
1
2
2
1
1
8.6 mg); R 0.15 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.29 – 7.23 (m,
f
3
H), 6.55 – 6.36 (m, 2H), 3.74 (s, 1H), 3.29 (t, J = 6.6 Hz, 2H), 2.47 (t, J = 7.0 Hz, 2H), 1.99 –
1
3
1
.92 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 146.4, 132.0, 119.1, 114.3, 109.5, 42.3, 25.0,
3
-1
4.8 ppm; IR (neat): υmax 2962, 2246, 1260, 1092, 1019, 799, 696 cm ; HRMS (ESI) calcd for
+
C H BrN [M+H] 239.0178, found 239.0180.
1
0
12
2
4
-((4-Iodophenyl)amino)butanenitrile (5o): Following the Method B with the corresponding
cyclobutanone oxime ester (0.2 mmol) and aromatic aniline (0.4 mmol). Faint yellow liquid (61%,
1
3
2
4.9 mg); R 0.2 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.55 – 7.34 (m,
f
3
H), 6.40 (d, J = 8.8 Hz, 2H), 3.76 (s, 1H), 3.29 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 7.0 Hz, 2H), 1.98
1
3
1
– 1.92 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 147.0, 137.9, 119.1, 115.0, 78.5, 42.1, 24.9,
3
-1
1
4.7 ppm; IR (neat): υmax 2962, 2245, 1260, 1019, 799, 701 cm ; HRMS (ESI) calcd for
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