A Novel Ketonitrile Synthesis by Palladium-Catalyzed Carbonylative Coupling Reactions of Amides with Arylboronic Acids

Article abstract of DOI:10.1002/ejoc.201901396

A novel, efficient, and simple procedure to synthesize diverse ketonitriles by palladium-catalyzed Suzuki coupling of amides through N–C cleavage has been developed. This procedure features mild conditions, a broad substrate scope, and easily prepared substrates, providing a simple and efficient access to a variety of ketonitriles.

Full text of DOI:10.1002/ejoc.201901396

A Journal of
Accepted Article
Title: A novel ketonitrile synthesis by palladium-catalyzed carbonylative
coupling reactions of amides with arylboronic acids
Authors: Wenpeng Mai, Yang Liu, Hong-Da Sui, Yong-Mei Xiao, Pu
Mao, and Kui Lu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901396
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901396
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10.1002/ejoc.201901396
European Journal of Organic Chemistry
FULL PAPER
A novel ketonitrile synthesis by palladium-catalyzed
carbonylative coupling reactions of amides with arylboronic acids
Wen-Peng Mai,*[a,b] Yang Liu[b], Hong-Dai Sui[b], Yong-Mei Xiao*[b], Pu Mao[b] and Kui Lu*[a,b,c]
Abstract:
A novel, efficient and simple procedure to diverse
Previous works:
ketonitrile by palladium-catalyzed Suzuki coupling of amide via N-C
cleavage has been developed. This procedure features mild
OR
N
fac-[Ir(ppy)3], 2%
O
O
OTMS
conditions,
a broad substrate scope and easily preparative
blue LED, rtref.5a
+
+
substrates, providing a simple and efficient access to a variety of
ketonitriles.
(a)
(b)
(c)
(d)
Ar
Ar
CN
CN
Ar
FeCl2, 5%
。
ref.5b
CH CN, 80
C
3
OR
OR
OH
N
N
fac-[Ir(ppy)3], 2%
blue LED, rt
DMSOref.5c
Ar
Cl
Introduction
O
O
Ni(acac)2, 10%
Mn 3.0 eq
DMF, -55 Cref.5d
O
Aryl ketones are not only key units of many biologically active
molecules but also diverse building blocks in organic synthesis.
CN
Ar
Ar
+
+
。
Ar
The acyl group construction of organic molecules is
a
fundamental transformation in biological and synthetic
chemistry.[1] Ketonitriles have an important place in the big
family of aryl ketones based on their wide utility in many natural
products and pharmaceuticals.[2] Moreover, nitrile itself is
important building block in modern organic synthesis, for
example, it can serve as precursor of amides, amines, ketones
and carboxylic acids, etc.[3] Nitrile functionalities are also
frequently found in pharmaceuticals and agrochemicals.[4]
Therefore, the exploration of practical and simple
methods for the synthesis of cyano-ketones is in high demand.
Recently, several elegant methods have been developed to
construct the ketonitriles via radical pathway. For example, Chen
and Selander developed a photocatalytic and Fe(II)-catalyzed
iminyl-radical-mediated ring-opening process to form the
ketonitriles independently (Scheme 1a).[5a,b] Following the results,
Chen group also reported a photoredox catalyzed three-
component procedure to diversely functionalized ketonitriles in
2018 (Scheme 1b).[5c] Wang and co-workers developed a nickel-
catalyzed a ring opening of cycloketone oxime esters with aroyl
chlorides, providing an access to a variety of cyanoketones
(Scheme 1c).[5d] Zhu group developed a manganese-catalyzed
oxidative ring opening cyanation of cyclobutanol derivatives to
produce ketonitriles in 2016 (Scheme 1d).[5e]
Mn(OAc)3, 20%
PIDA 2.0 eq
CH3CN, rtref.5e
Ar
CN
TsCN
This work:
Boc
N
Pd(OAc)2, 3%
Cy3P, 7%
O
(e)
CN
n
CN
ArB(OH)2
+
n
Ar
n = 2, 3
K2CO3, 2.0 eq
。
N
O
dioxane, 70 C,8h
adjustable carbon chain
mild conditions
non-radical reaction
variable remote group
Scheme 1. Transition-metal-catalysed strategies for the
synthesis of ketonitriles
Transition-metal-catalyzed acylative coupling via Suzuki
reactions provides an efficient method to form acyl-carbon
bonds, in which, a variety of cross-coupling electrophiles such
as acid chlorides,[6] thioesters,[7] anhydrides[8] and esters[9] have
been developed successfully in the past decade. More recently,
activated amides as stable acyl electrophiles undergoing the
cross-coupling
reported
by
Garg,[10]
Zou[11] and Szostak[12] have received much attention. A wide
range of amide substrates such as N-tosyl-amides, N-Boc-
carbamates, N-acyl-saccharins, N-acyl-piperidine-2,6(5)-dione
and N,N-di-Boc amides have been developed as conveniently
available coupling partners in transition-metal-catalyzed cross-
coupling reactions,[13] and some transformations based C-N
bond cleavage of amide have also been reported.[14,15] However,
alkyl amides substrates are very limited, in which primary alkyl
amides have low efficiency in most of the cases due to the
instability of the intermediate after transmetallation.[13e,13g,13i]
Therefore, it is worthwhile to develop new amides as potential
substrate in cross-coupling reactions to synthesize diversely
functionalized ketones. Herein, we disclose palladium-catalysed
[a]
[b]
Prof. W.-P. Mai. School of Materials and Chemical Engineering,
Henan University of Engineering, Zhengzhou, 450006, China. E-
mail: maiwp@yahoo.com
Y. Liu, H.-D. Sui, Prof. Y.-M. Xiao, Prof. P. Mao. School of
Chemistry and Chemical Engineering, Henan University of
Technology, Zhengzhou, 450001, China. E-mail:
mxyy9510@126.com
[c]
Prof. K. Lu. School of Chemical Engineering and Food Science,
Zhengzhou Institute of Technology, Zhengzhou, 450044, China. E-
mail: luckyluke@haue.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201901396
European Journal of Organic Chemistry
FULL PAPER
were screened. Next, we examined the effect of palladium as
catalyst. For substrate 2a, the Pd catalyst system showed
slightly higher reactivity than Ni catalyst (Table 1, entries 7-8).
To our delight, the Pd(OAc)2/PPh3 and Pd(OAc)2/PCy3 were
highly effective, affording the desired product 3a in 76% and 85%
yields respectively when 2b was used as substrate (Table 1,
entries 9-10). Other Pd-complexes, including PdCl2/PPh3 and
Pd(PPh3)2Cl2/PCy3 were also active and provided 3a in similar
yields (Table 1, entries 11-12). Subsequently, solvents such as
dioxane, CH3CN, toluene and DMF were also screened. Of
these, dioxane exhibited the highest activity to give 3a in
excellent yield (Table 1, entry 13). Without base, the reaction still
proceeded well and gave 88% product yield (Table 1, entry 17).
However, no product was observed when the catalytic system
lack palladium or ligand which indicated both of them played
important roles as well as substrate 2b in the reaction (Table 1,
entries 18-19).
N-Boc-cyanoalkyl carbamates coupling with arylboronic acids to
form valuable ketonitriles under mild conditions (Scheme 1e).
Results and Discussion
Table 1. Optimization of the reaction conditions. a
With the optimal conditions established (Table 1, entry 13), we
first evaluated the scope of arylboronic acids 1 with substrate 2b
to synthesize 5-oxo-5-arylpentanenitrile (Table 2). As given in
Table 2, substitution at either the 2- or 3-position with electron-
withdrawing groups (3d, 3f) or electron-donating groups (3b, 3l)
led to moderate to excellent yields of product. Chloride and
fluoride were tolerated under the standard reaction conditions,
for example, products 3a and 3d could be obtained in 92% and
83% yield respectively. For those boronic acids which have
Ligand
(mol %)
Yield
(%)b
Entry
Catalyst (mol %)
2
Solvent
1
2
3
4
5
NiCl2-DME (10 %)
NiBr2 (10 %)
PPh3 (20 %)
PPh3 (20 %)
PCy3 (20 %)
PCy3 (20 %)
PCy3 (20 %)
DTBPY
2a
2a
2a
2b
2b
THF
THF
0
0
Ni(PPh3)2Cl2 (10 %)
Ni(PPh3)2Cl2 (10 %)
Ni(PPh3)2Cl2 (10 %)
THF
0
THF
0
Dioxane
0
6
Ni(PPh3)2Cl2 (10 %)
2b
Dioxane
0
(20 %)
Table 2. Scope of Arylboronic acids coupled with 2ba,b
7
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
PdCl2 (3 %)
PPh3 (7 %)
PCy3 (7 %)
PPh3 (7 %)
PCy3 (7 %)
PPh3 (7 %)
PCy3 (7 %)
PCy3 (7 %)
PCy3 (7 %)
PCy3 (7 %)
PCy3 (7 %)
PCy3 (7 %)
PCy3 (7 %)
-
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
THF
THF
trace
11
76
85
70
83
92
55
30
0
8
9
THF
10
11
12
13
14
15
16
17c
18d
19e
20f
21g
THF
THF
Pd(PPh3)2Cl2 (3 %)
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
-
THF
Dioxane
CH3CN
Toluene
DMF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
88
0
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
Pd(OAc)2 (3 %)
trace
85
90
PCy3 (7 %)
PCy3 (7 %)
a
Reaction conditions: 1a (0.45 mmol), 2a or 2b (0.3 mmol),
catalyst (10 mol% for Ni, 3 mol% for Pd), Ligand (7% or 20%),
b
K2CO3 (2.0 equiv), in solvent (2 mL), N2, under 70℃ for 8h.
f
Isolated yield. c Without K2CO3. d Without Pd. e Without Ligand.
K3PO4 as base. g Cs2CO3 as base.
Initially, we examined the feasibility of 4-chlorophenylboronic
acid (1a) with tert-butyl (3-cyanobutanoyl)(phenyl)carbamate (2a)
using nickel as catalyst (Table 1, entries 1-6). Unfortunately, no
reaction occurred when nickel salts such as NiCl2-DME, NiBr2
and Ni(PPh3)2Cl2 were used as catalyst though different ligands
such as PPh3, PCy3 and DTBPY (4,4'-di-tert-butyl-2,2'-bipyridine)
a Reaction conditions: 1 (0.45 mmol, 1.5 equiv), 2b (0.3 mmol,
1.0 equiv) and Pd(OAc)2 (0.009 mmol, 3 mol%), PCy3 (0.021
mmol, 7 mol%), K2CO3 (0.6 mmol, 2.0 equiv) in dioxane (2.0 mL)
at 70 ℃ under an atmosphere of N2 for 8h. b Isolated yield.
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10.1002/ejoc.201901396
European Journal of Organic Chemistry
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4-substituted electron-deficient groups such as CF3 and CN, low
yields were observed (3j and 3k). However, weak electron-
deficient groups such as acyl and ester at 3- or 4-position could
afford the good product yield (3e and 3f). The reaction
performed well when electron-rich arylboronic acids derivatives
were used, producing the expected products in excellent yields
(3c, 3g and 3m). To our delight, we noted that the presence of
vinyl or amide groups did not limit the formation of the desired
products, affording 3h in 79% and 3l in 43% yield respectively.
However, arylboronic acids containing Br or OH group were not
effective in this reaction (3n and 3o).
Encouraged by the above results, we attempt to carry out
alkylboronic acid 1v with 2c under the standard conditions,
however no product was obtained (Scheme 2a). When cyano-
group was replaced by trifluoromethyl group in 2c, the reaction
still performed very well under the current conditions and
produced 4,4,4-trifluoro-1-arylbutan-1-ones in good yields
(Scheme 2b).
Next, we examined the feasibility of tert-butyl (3-
cyanopropanoyl)(pyridin-2-yl)carbamate (2c) coupled with
arylboronic acids under the standard conditions. The results are
summarized in Table 3. The length of alkyl carbon chain in the
amides did not influence the reactivity and 4-oxo-4-
arylbutanenitrile could also be obtained with good yields. The
reaction similarly tolerates aromatic boronic acids bearing
sensitive functional groups, such as ketone (4e), formyl group
(4s), and halides (4a and 4q), which provide opportunity for
further functionalization. Electron-withdrawing boronic acids (4j,
4r, 4s and 4u) gave products in lower yields than those electron-
donating boronic acids (4c and 4g). Unfortunately, tert-butyl (2-
Scheme 2. The feasibility of alkylboronic acid and tert-butyl
pyridin-2-yl(4,4,4-trifluorobutanoyl)carbamate
transformation.
(2d)
in
this
Based
on
the
previous
works[9a,9f,12]
,
a
primary
plausible mechanism for the palladium-catalyzed Suzuki
coupling of amide via N-C cleavage is described in Scheme 3.
Firstly, the catalyst Pd(Ln) with substrate 2c was translated into
species A. Then Pd inserts into the N-C amide bond due to its
activation and formed acylpalladium intermediate B.
Transmetalation between B and arylbonoric acids affods C, in
which sideproduct N-Boc pyridin-2-amine was isolated and
determined by NMR. Finally, reductive elimination from C
produces ketonitrile with regeneration of active Pd(0) species.
cyanoacetyl)(pyridin-2-yl)carbamate
was
not
prepared
successfully due to its instability (See ESI)16, thus, 3-oxo-3-
arylpropanenitriles could not be obtained under current
conditions.
Table 3. 2-(allyloxy)arylaldehyde scope for the synthesis of chroman-4-one
derivatives.a
Scheme 3. Possible mechanism
a
Conclusions
Reaction conditions: 1 (0.45 mmol, 1.5 equiv), 2c (0.3 mmol,
1.0 equiv) and Pd(OAc)2 (0.009 mmol, 3 mol%), PCy3 (0.021
mmol, 7 mol%), K2CO3 (0.6 mmol, 2.0 equiv) in dioxane (2.0 mL)
at 70 ℃ under an atmosphere of N2 for 8h. b Isolated yield.
In summary, we have developed a catalytic C-C bond
formation through N-C bond cleavage of amide to prepare
ketonitriles which have wide utility in many natural products and
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10.1002/ejoc.201901396
European Journal of Organic Chemistry
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tert-butyl (4,4,4-trifluorobutanoyl)(pyridin-2-yl)carbamate (2d) White
solid. H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 8.0 Hz, 1H), 7.80 (t, J =
pharmaceuticals. The method is operationally convenient and
compatible with various functional groups, providing a novel
approach to synthesize ketonitrile unit. Studies on expanding the
scope of this method to synthesize carbonyl compounds are
ongoing.
1
8.0 Hz, 1H), 7.28-7.32 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.32 (t, J = 8.0
Hz, 2 H), 2.50-2.56 (m, 1H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
173.08, 151.74, 149.29, 138.27, 125.51(q), 123.31, 84.10, 31.03, 29.19,
27.72; 19F NMR (376 MHz, CDCl3) δ -66.46; HRMS (ESI) Calcd. for
C14H18F3N2O3: [M+H]+,319.1270. Found: m/z 319.1269.
5-(4-chlorophenyl)-5-oxopentanenitrile (3a) 1H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 3.15 (t, J = 6.8
Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H), 2.11 (p, J = 6.9 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 196.92, 139.91, 134.73, 129.40, 129.06, 119.36, 36.33,
19.62, 16.61; HRMS (ESI) Calcd. for C11H11ClNO: [M+H]+, 208.0529.
Found: m/z 208.0525.
Experimental Section
All experiments were carried out using common flask in air. Boronic acids
were purchased from commercial suppliers and used as received directly
unless otherwise noted. All solvents and other commercially available
reagents were purchased from J&K or TCI companies and used directly.
Reactions were monitored by thin layer chromatography (TLC) (Qingdao
Haiyang Chemical Co. Ltd. Silica gel 60 F254). Products were detected
using a UV/Vis lamp (254 nm). Column chromatography was performed
5-oxo-5-(o-tolyl)pentanenitrile (3b) 1H NMR (400 MHz, CDCl3) δ 7.70
(d, J = 7.8 Hz, 1H), 7.41 (dt, J = 7.5, 3.8 Hz, 1H), 7.34 – 7.24 (m, 2H),
3.12 (t, J = 6.8 Hz, 2H), 2.56-2.50 (m, 5H), 2.10 (p, J = 6.9 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 201.92, 138.39, 137.07, 132.19, 131.77,
128.62, 125.88, 119.42, 39.05, 21.50, 19.90, 16.62; HRMS (ESI) Calcd.
for C12H14NO: [M+H]+, 188.1075. Found: m/z 188.1072.
1
on Qingdao Haiyang Chemical Co. Ltd. Gel 60 (200–300 mesh). The H
and 13C NMR spectras were obtained on a Bruker 400 MHz NMR Fourier
transform spectrometer. 1H NMR data were reported as: chemical shift (δ
ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR data
were reported in terms of chemical shift (δ ppm), multiplicity, and
coupling constant (Hz). The spectra are referenced against the internal
solvent (CDCl3, δ 1H= 7.26 ppm, 13C= 77.0 ppm). 1H and 13C spectra
were recorded on a Varian Mercury-400 MHz (400 MHz for 1H, 100 MHz
for 13C). ESI-MS spectra were recorded on a Bruker Esquire 3000. High
resolution mass spectra (HR MS) were obtained on a Waters Micromass
Q-Tof MicroTM instrument using the ESI technique.
5-(4-methoxyphenyl)-5-oxopentanenitrile (3c) 1H NMR (400 MHz,
CDCl3) δ 7.98- 7.86 (m, 2H), 7.00-6.87 (m, 2H), 3.87 (s, 3H), 3.12 (t, J =
6.8 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 2.09 (p, J = 6.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 196.66, 163.74, 130.26, 129.54, 119.55, 113.85,
55.52, 35.95, 19.88, 16.67; HRMS (ESI) Calcd. for C12H14NO2: [M+H]+,
204.1025. Found: m/z 204.1022.
5-(2,4-difluorophenyl)-5-oxopentanenitrile (3d) 1HNMR (400 MHz,
CDCl3) δ 7.96 (td, J = 8.6, 6.7 Hz, 1H), 6.99 (td, J = 9.0, 2.3 Hz, 1H), 6.90
(ddd, J = 11.1, 8.6, 2.4 Hz, 1H), 3.15 (td, J = 6.8, 3.4 Hz, 2H), 2.53 (t, J =
7.1 Hz, 2H), 2.11 (p, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
194.82, 194.77, 167.38, 164.70, 164.18, 161.74, 132.70, 132.66, 132.59,
132.55, 121.50, 119.32, 112.52, 112.49, 112.31, 112.28, 105.16, 104.89,
104.64, 41.31, 41.23, 19.65, 19.62, 16.56. 19F NMR (376 MHz, CDCl3) δ
-100.99 (d, J = 12.5 Hz), -103.86 (d, J = 12.4 Hz); HRMS (ESI) Calcd. for
C11H10F2NO: [M+H]+, 210.0730. Found: m/z 210.0728.
Typical catalytic procedure: Amide 2a-2c (0.3 mmol), ArB(OH)2 (0.45
mmol), Pd(OAc)2 (0.009 mmol, 2.0 mg), PCy3 (0.021 mmol, 5.8 mg) and
K2CO3 (2.0 equiv) were added to a 10 mL two-necked flask equipped
with a reflux condenser. The vessel was evacuated and backfilled with N2
(3 times) and dioxane (2 mL) was added via a syringe. The flask was
heated in an oil bath at 70 °C for 8 h followed by cooling to room
temperature. The volatile components were removed in vacuo and the
residue was subjected to column chromatography on silica gel using
(PE/EA = 100/10/mL) to afford the desired ketonitrile.
tert-butyl (4-cyanobutanoyl)(phenyl)carbamate (2a) White solid. 1H
NMR (400 MHz, CDCl3) δ 7.40-7.44 (t, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0
Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 3.16 (t, J = 8.0 Hz, 2H), 2.51 (t, J = 8.0
Hz, 2H), 2.04-2.07 (m, 2H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
174.22, 152.50, 138.59, 129.05, 128.10, 119.45, 83.52, 36.24, 27.80,
20.75, 16.49; HRMS (ESI) Calcd. for C16H21N2O3: [M+H]+, 289.1552.
Found: m/z 289.1547.
5-(4-acetylphenyl)-5-oxopentanenitrile
(3e) 1H NMR (400 MHz,
CDCl3) δ 8.07 (s, 4H), 3.24 (t, J = 6.8 Hz, 2H), 2.68 (s, 3H), 2.57 (dd, J =
8.5, 5.4 Hz, 2H), 2.16 (p, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
197.61, 140.46, 139.47, 128.63, 128.21, 119.25, 36.74, 26.92, 19.57,
16.62; HRMS (ESI) Calcd. for C13H14NO2: [M+H]+, 216.1025. Found: m/z
216.1021.
1
ethyl 3-(4-cyanobutanoyl)benzoate (3f) H NMR (400 MHz, CDCl3) δ
tert-butyl (4-cyanobutanoyl)(pyridin-2-yl)carbamate (2b) White solid.
1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.28 (t,
J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 3.16 (t, J = 8.0 Hz, 2H), 2.47 (t,
J = 8.0 Hz, 2H), 2.01-2.05 (m, 2H), 1.35 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 174.33, 151.83, 151.72, 149.23, 138.29, 123.27, 119.44, 83.92,
36.11, 27.75, 20.58, 16.48; HRMS (ESI) Calcd. for C15H20N3O3: [M+H]+,
290.1505. Found: m/z 290.1503.
8.59 (t, J = 1.5 Hz, 1H), 8.26 (dt, J = 7.7, 1.4 Hz, 1H), 8.18-8.13 (m, 1H),
7.58 (t, J = 7.8 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.23 (t, J = 6.8 Hz, 2H),
2.55 (t,J = 7.0Hz, 2H), 2.14 (p,J = 6.9 Hz, 2H),1.43 (t,J = 7.1Hz, 3H).
13CNMR (100MHz,CDCl3) δ 197.37, 165.62, 136.59, 134.16, 131.92,
131.28, 128.99, 128.95, 119.34, 61.46, 36.53, 19.62, 16.57, 14.31;
HRMS (ESI) Calcd. for C14H16NO3: [M+H]+, 246.1130. Found: m/z
246.1128.
5-(4-(tert-butyl)phenyl)-5-oxopentanenitrile (3g) 1H NMR (400 MHz,
CDCl3) δ 7.92 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 3.17 (t, J = 6.8
Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H), 2.12 (p, J = 6.9 Hz, 2H), 1.36 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 197.84, 157.27, 133.91, 127.98, 125.69,
119.49, 36.24, 35.16, 31.07, 19.82, 16.66; HRMS (ESI) Calcd. for
C15H20NO: [M+H]+, 230.1545. Found: m/z 230.1549.
tert-butyl (3-cyanopropanoyl)(pyridin-2-yl)carbamate (2c) White solid.
1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 8.0 Hz,
1H), 7.34 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 3.44 (t, J = 8.0 Hz,
2H), 2.71 (t, J = 8.0 Hz, 2H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.35, 151.67, 151.42, 149.32, 138.35, 123.45, 123.29, 118.96, 84.34,
33.97, 27.75, 12.72; HRMS (ESI) Calcd. for C14H17N3O3: [M+H]+,
275.1270. Found: m/z 275.1266.
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10.1002/ejoc.201901396
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5-oxo-5-(4-vinylphenyl)pentanenitrile (3h) 1H NMR (400 MHz, CDCl3)
δ 7.99-7.88 (m, 2H), 7.50 (d, J = 8.3 Hz, 2H), 6.77 (dd, J = 17.6, 10.9 Hz,
1H), 5.90 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 10.9 Hz, 1H), 3.17 (t, J = 6.8
Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H), 2.12 (p, J = 6.9 Hz, 2H). 13C NMR (100
MHz, CDCl3) δ 197.55, 142.44, 135.82, 135.54, 128.39, 126.45, 119.46,
117.03, 36.32, 19.76, 16.66; HRMS (ESI) Calcd. for C13H14NO: [M+H]+,
200.1075. Found: m/z 200.1074.
3.40-3.27 (m, 2H), 2.81-2.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
193.85, 164.06, 130.36, 128.70, 119.51, 114.02, 55.59, 33.86, 11.86;
HRMS (ESI) Calcd. for C11H12NO2: [M+H]+, 190.0868. Found: m/z
190.0866.
4-(4-acetylphenyl)-4-oxobutanenitrile (4e) 1H NMR (400 MHz, CDCl3)
δ 8.02 (s, 4H), 3.42 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H), 2.63 (d, J
= 1.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.37, 195.07, 140.67,
138.59, 128.68, 128.28, 119.15, 34.63, 26.95, 11.75; HRMS (ESI) Calcd.
for C12H12NO2: [M+H]+, 202.0868. Found: m/z 202.0868.
5-([1,1'-biphenyl]-4-yl)-5-oxopentanenitrile (3i) 1H NMR (400 MHz,
CDCl3) δ 8.20 (t, J = 1.6 Hz, 1H), 7.94 (dd, J = 7.8, 1.2 Hz, 1H), 7.85-7.79
(m, 1H), 7.67-7.61 (m, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.50 (dd, J = 10.2,
4.7 Hz, 2H), 7.45-7.38 (m, 1H), 3.22 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 7.0
Hz, 2H), 2.14 (p, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 198.14,
141.84, 140.00, 136.99, 132.07, 129.25, 129.02, 127.96, 127.20, 126.84,
126.61, 119.54, 36.56, 19.79, 16.65; HRMS (ESI) Calcd. for C17H16NO:
[M+H]+, 250.1232. Found: m/z 250.1232.
4-(4-(tert-butyl)phenyl)-4-oxobutanenitrile (4g) 1H NMR (400 MHz,
CDCl3) δ 7.95-7.89 (m, 2H), 7.53 (d, J = 8.6 Hz, 2H), 3.42-3.35 (m, 2H),
2.83-2.76 (m, 2H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 194.99,
157.83, 133.05, 128.02, 125.85, 119.39, 35.25, 34.17, 31.05, 11.84;
HRMS (ESI) Calcd. for C14H18NO: [M+H]+, 216.1388. Found: m/z
216.1385.
5-oxo-5-(4-(trifluoromethyl)phenyl)pentanenitrile (3j) 1H NMR (400
MHz, CDCl3) δ 8.09 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 3.23 (t,
J = 6.8 Hz, 2H), 2.57 (t, J = 6.9 Hz, 2H), 2.16 (p, J = 6.9 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 197.16, 139.05, 134.94, 134.61, 128.33,
125.85, 125.81, 124.87, 122.16, 119.16, 36.66, 19.53, 16.57; 19F NMR
(376 MHz, CDCl3) δ -63.17 (s); HRMS (ESI) Calcd. for C12H11F3NO:
[M+H]+, 242.0793. Found: m/z 242.0789.
4-oxo-4-(4-(trifluoromethyl)phenyl)butanenitrile (4j) 1H NMR (400
MHz, CDCl3) δ 8.09 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 3.44 (t,
J = 7.1 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
194.54, 138.16, 137.91, 135.62, 135.30, 134.97, 134.64, 128.43, 126.05,
126.01, 125.97, 125.94, 124.78, 122.07, 118.95, 34.60, 11.75; 19F NMR
(376 MHz, CDCl3) δ -63.21; HRMS (ESI) Calcd. for C11H9F3NO: [M+H]+,
228.0636. Found: m/z 228.0639.
4-(4-cyanobutanoyl)benzonitrile (3k) 1H NMR (400 MHz, CDCl3) δ 7.92
(d, J = 8.7 Hz, 2H), 6.95-6.88 (m, 2H), 3.15 (t, J = 6.8 Hz, 2H), 2.56 (t, J =
6.9 Hz, 2H), 2.13 (p, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
197.15, 160.97, 130.67, 129.30, 119.51, 115.55, 35.93, 19.83, 16.71;
HRMS (ESI) Calcd. for C12H11N2O: [M+H]+, 199.0871. Found: m/z
199.0870.
4-(3,4-dichlorophenyl)-4-oxobutanenitrile (4q) 1H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.61 (d, J =
8.4 Hz, 1H), 3.37 (t, J = 7.1 Hz, 2H), 2.81 (t, J = 7.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 193.28, 138.69, 135.04, 133.73, 131.08, 130.05,
127.01, 118.85, 34.37, 11.76; HRMS (ESI) Calcd. for C10H8Cl2NO:
[M+H]+, 227.9983. Found: m/z 227.9981.
3-(4-cyanobutanoyl)-N-methylbenzamide (3l) 1H NMR (400 MHz,
CDCl3) δ 8.44 (s, 1H), 8.07 (s, 1H), 7.83 (dd, J = 8.0, 1.1 Hz, 1H), 7.64 (d,
J = 7.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 3.10 (t, J = 6.8 Hz, 2H), 2.49 (t, J
= 7.0 Hz, 2H), 2.19 (s, 3H), 2.06 (p, J = 7.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 198.01, 169.38, 138.81, 136.96, 129.36, 124.88, 123.55,
119.59, 119.18, 36.49, 24.43, 19.69, 16.57; HRMS (ESI) Calcd. for
C13H15N2O2: [M+H]+, 231.1134. Found: m/z 231.1130.
1
4-(4-fluorophenyl)-4-oxobutanenitrile (4f) H NMR (400 MHz, CDCl3) δ
8.10-7.95 (m, 2H), 7.27-7.13 (m, 2H), 3.41 (t, J = 7.1 Hz, 2H), 2.82 (t, J =
7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 193.85, 167.43, 164.88,
132.09, 132.06, 130.81, 130.72, 119.22, 116.19, 115.98, 34.19, 11.82;
19F NMR (376 MHz, CDCl3) δ -103.54 (s); HRMS (ESI) Calcd. for
C10H9FNO: [M+H]+, 178.0668. Found: m/z 178.0665.
5-(4-(diphenylamino)phenyl)-5-oxopentanenitrile (3m) 1H NMR (400
MHz, CDCl3) δ 7.87-7.80 (m, 2H), 7.38-7.31 (m, 4H), 7.22-7.12 (m, 6H),
7.01 (d, J = 8.9 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H),
2.12 (p, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 196.33, 152.48,
146.35, 129.69, 129.61, 128.83, 126.09, 124.85, 119.58, 119.52, 35.80,
19.99, 16.73; HRMS (ESI) Calcd. for C23H21N2O: [M+H]+, 341.1654.
Found: m/z 341.1655.
1
4-(4-formylphenyl)-4-oxobutanenitrile (4s) H NMR (400 MHz, CDCl3)
δ 10.12 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 3.45 (t,
J = 7.0 Hz, 2H), 2.81 (t, J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
194.99, 191.48, 139.63, 139.52, 130.00, 128.63, 119.04, 34.76, 11.78;
HRMS (ESI) Calcd. for C11H10NO2: [M+H]+, 188.0712. Found: m/z
188.0710.
4-oxo-4-phenylbutanenitrile (4t) 1H NMR (400 MHz, CDCl3) δ 8.03-7.92
(m, 2H), 7.63 (dd, J = 10.5, 4.3 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 3.40 (t, J
= 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
195.40, 135.60, 133.94, 128.90, 128.05, 119.31, 34.27, 11.82; HRMS
(ESI) Calcd. for C10H10NO: [M+H]+, 160.0762. Found: m/z 160.0760.
1
4-(4-chlorophenyl)-4-oxobutanenitrile (4a) H NMR (400 MHz, CDCl3)
δ 7.89 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 3.36 (t, J = 7.1 Hz,
2H), 2.77 (t, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 194.33,
140.38, 133.91, 129.46, 129.22, 119.22, 34.25, 11.78; HRMS (ESI)
Calcd. for C10H9ClNO: [M+H]+, 194.0373. Found: m/z 194.0370.
5-(4-nitrophenyl)-5-oxopentanenitrile (4u) 1H NMR (400 MHz, CDCl3)
δ 8.43-8.30 (m, 2H), 8.16 (d, J = 8.9 Hz, 2H), 3.47 (t, J = 7.1 Hz, 2H),
2.85 (t, J = 7.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 193.91, 153.64,
139.82, 129.15, 124.16, 99.99, 34.88, 11.76; HRMS (ESI) Calcd. for
C10H9N2O3: [M+H]+, 205.0613. Found: m/z 205.0611.
4-oxo-4-(o-tolyl)butanenitrile (4b) 1H NMR (400 MHz, CDCl3) δ 7.72 (d,
J = 7.9 Hz, 1H), 7.46 (td, J = 7.5, 1.2 Hz, 1H), 7.33 (dd, J = 9.0, 7.9 Hz,
2H), 3.35 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.57 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 198.40, 139.29, 135.67, 132.47, 132.38,
128.85, 125.99, 119.30, 36.46, 21.78, 12.05; HRMS (ESI) Calcd. for
C11H12NO: [M+H]+, 174.0919. Found: m/z 174.0915.
4,4,4-trifluoro-1-phenylbutan-1-one (6a) 1H NMR (400 MHz, CDCl3) δ
8.0 (d, J = 8.0 Hz, 2 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 2 H),
3.30 (t, J = 8.0 Hz, 2 H), 2.57-2.69 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
196.35, 136.10, 132.64, 128.80, 128.03, 125.81(t), 31.25, 28.51(q); 19F
4-(4-methoxyphenyl)-4-oxobutanenitrile (4c) 1H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H),
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10.1002/ejoc.201901396
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NMR (376 MHz, CDCl3) δ -66.42 (s); HRMS (ESI) Calcd. For C10H10F3O:
[M+H]+, 203.0678. Found: m/z 206.0671.
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Keywords: palladium • ketonitrile • amide • N-C cleavage •
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Entry for the Table of Contents (Please choose one layout)
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Ketonitrile synthesis*
Wen-Peng Mai,*[a,b] Yang Liu[b], Hong-
Dai Sui[b], Yong-Mei Xiao*[b], Pu Mao[b]
and Kui Lu*[a,b,c]
Page No. – Page No.
A novel ketonitrile synthesis by
palladium-catalyzed carbonylative
coupling reactions of amides with
arylboronic acids
A novel, efficient and simple procedure to diverse ketonitrile by palladium-catalyzed
Suzuki coupling of amide via N-C cleavage has been developed. This procedure
features mild conditions, a broad substrate scope and easily preparative substrates,
providing a simple and efficient access to a variety of ketonitriles.
*one or two words that highlight the emphasis of the paper or the field of the study
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