Facile Synthesis of γ-Ketonitriles in Water via C(sp2)–H Activation of Aromatic Aldehydes over Cu?g-C3N4 under Visible-Light

Article abstract of DOI:10.1002/ejoc.202000945

A facile C(sp²)–H activation of aldehyde under visible-light conditions using Cu?g-C₃N₄ as photocatalyst and water as solvent is reported. The envisaged method involves photocatalytic intermolecular Stetter reaction using

Full text of DOI:10.1002/ejoc.202000945

Full Paper
doi.org/10.1002/ejoc.202000945
EurJOC
European Journal of Organic Chemistry
Photocatalysis
Facile Synthesis of γ-Ketonitriles in Water via C(sp2)–H Activation
of Aromatic Aldehydes over Cu@g-C3N4 under Visible-Light
Vijai K. Rai,*[a] Fooleswar Verma,[a] Smita R. Bhardiya,[a] Harendra Sheshma,[b] Ankita Rai,[b]
and Manorama Singh[a]
Abstract: A facile C(sp2)–H activation of aldehyde under visi- at r.t. Operational simplicity, ambient reaction conditions, visi-
ble-light conditions using Cu@g-C3N4 as photocatalyst and
water as solvent is reported. The envisaged method involves
photocatalytic intermolecular Stetter reaction using differently
substituted aldehydes and acrylonitrile to produce various
γ-keto nitriles in good to excellent yield (80–95 %) and 4–10 h
ble-light condition, and application of the Cu@g-C3N4 as photo-
catalyst make the envisaged protocol an efficient and highly
green alternative to the existing methods for synthesis of
γ-keto nitriles.
Introduction
ganic synthesis, such as nitriles can serve as precursor for alde-
hyde, amide, N-containing heterocycles and carboxylic acids
etc.[6] The γ-ketonitrile scaffolds, containing both these func-
tionalities, are important synthetic target as well as building
block for many biologically significant compounds and pharma-
ceuticals.[7] Looking to their synthetic and biological impor-
tance, several methodologies have been developed to synthe-
size the γ-keto nitriles.[8–19] General approach to prepare the
γ-ketonitriles involves oxidative coupling (Scheme 1a) via ring-
opening cyanation of cyclopropanol,[8] decarboxylative oxo-
cyanomethylation of alkynyl carboxylic acid,[9] oxo-cyanometh-
ylation,[10] decarboxylative alkylation[11] and cross-dehydrogen-
ative coupling[12] of styrenes. Furthermore, synthesis of γ-keto
nitriles has also been reported by nucleophilic substitution of
suitable aryl ketones with KCN[13] and that of diketone with
Catalytic C–H bond activation provides high atom and step eco-
nomic C–C bond formation for cross-coupling reactions, has
now moved into mainstream tailor-made synthesis of complex
molecules including drugs, (poly)functional ligands and even
molecular materials of industrial applications.[1] Although,
cleavage of C–H bond by metal catalyst is easy, functionaliza-
tion of the formed C–M bond usually requires high energy and
stoichiometric amounts of strong oxidant to generate the active
metal-catalysts, which avoid these processes to be truly eco-
friendly.[2] To circumvent, visible-light photoredox catalytic C–H
activation could be efficient and eco-friendly synthetic tool due
to its green credentials.[2] Starting from the pioneer work of
MacMillan in 2011, the photoredox catalytic C(sp2)–H activation
is now well established synthetic tool,[3a] which includes direct
arylation, alkylation, acylation and even cyanation via photo-
chemical induced generation of a radical followed by its regio-
selective addition to arenes, heteroarenes, or alkenes, leading
to the building of a new C(sp2)–C bond.[2b,3] Furthermore, gra-
phitic carbon nitride (g-C3N4) has now become a new research
hotspot and drawn broad interdisciplinary attention as visible-
light-responsive photocatalyst in the arena of modern synthe-
sis.[4] Though, its rapid charge recombination creates some bar-
riers to be utilized as photocatalyst, doping of metal/non-metal
in its cavity improves its catalytic activity.[5]
Aryl ketones and nitriles are not only the key units of many
biologically active molecules but also diverse substrates in or-
[a] Dr. V. K. Rai, F. Verma, S. R. Bhardiya, Dr. M. Singh
Department of Chemistry, Guru Ghasidas Vishwavidyalaya,
Bilaspur–495 009, C. G., India
E-mail: vijaikrai@hotmail.com
http://www.ggu.ac.in
[b] H. Sheshma, Dr. A. Rai
School of Physical Sciences, Jawaharlal Nehru University,
New Delhi, 110 067, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000945.
Scheme 1. Synthesis of γ-ketonitriles.
Eur. J. Org. Chem. 2020, 5841–5846
5841
© 2020 Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202000945
EurJOC
European Journal of Organic Chemistry
MeCN followed by C–C bond cleavage.[14] In spite of these tion showing preeminent results with 94 % yield in 4 h (Table 1,
methods, direct synthesis of γ-keto nitrile is still a challenging entry 5).
goal and paid less attention. However, direct synthesis of γ-keto
Table 1. Optimization of reaction conditions for synthesis of 3a.[a]
.
nitrile using aromatic aldehyde and α,ꢀ-unsaturated nitrile was
first reported by Stetter in 1967.[15]
Following this pioneer work, NHC-catalyzed direct synthesis
of γ-keto sulfones/phosphonates using α,ꢀ-unsaturated sulf-
ones[16]/phosphonates[17] was reported. Despite high efficiency,
these protocols are associated with one or more limitations
such as the use of expensive and relatively hazardous 4d and/
or 5d noble-metal catalysts, tedious syntheses of the catalysts,
high cost, prolonged reaction time, the need for oxidant/pure
O2, and so on. Furthermore, photocatalytic acylative synthesis
of γ-keto nitriles has also been reported, however, substrate
scope is limited either to aliphatic aldehyde[18] or to 2-S-pyridyl
thioesters[19] (Scheme 1b). However, application of photocata-
lytic C–H activation in Stetter reaction for synthesis of γ-keto
nitriles in water at room temperature has been unexplored so
far. Therefore, considering the above limitations and challenges
and due to our interest to develop sustainable methods in or-
ganic synthesis,[20] we envisioned to develop simple, general,
and practical photocatalytic C(sp2)-H activation of aromatic al-
dehydes to get reacted with electrophilic acrylonitrile via reduc-
tive coupling under visible light condition.
Recently, we have prepared the Cu@g-C3N4 catalyst[20b] by its
reported method in literature[22] and utilized it as the efficient
photocatalyst for methylenation of aromatic ketones under visi-
ble-light condition.[20b] In continuation, we next envisioned to
explore this photocatalyst for the present intermolecular Stetter
reaction.
Herein, we report Cu@g-C3N4 as a highly active and reusable
catalyst for photocatalytic Stetter reaction to synthesize the tar-
get γ-ketonitrile skeletons employing green chemistry protocol,
which is hitherto unreported and not accessible in literature to
the best of knowledge (Scheme 1c).
Entry
Catalyst [mg]
Solvent
Time [h]
Yield [%][b,c]
1
2
3
4
5
6
7
8
@g-C3N4 (20)
H2O
H2O
H2O
H2O
H2O
MeOH
EtOH
DMF
8
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
21
48
78
66
94
66
63
32
34
74
78
77
86
94
–
Ni@g-C3N4 (20)
Co@g-C3N4 (20)
Fe@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (20)
Cu@g-C3N4 (15)
Cu@g-C3N4 (25)
Cu@g-C3N4 (20)
–
9
MeCN
10
11
12
13
14
15[d]
16[e]
H2O/MeOH (2:3)
H2O/MeOH (3:2)
H2O/MeOH (1:1)
H2O
H2O
H2O
H2O
–
[a] Reaction conditions: 4-chlorobenzaldehyde 1a (1 mmol), acrylonitrile 2
(1.5 mmol), 7-volt LED light, r.t. [b] Yield of isolated and purified product.
[c] All compounds gave C, H and N analyses, and satisfactory spectral
(1H NMR, 13C NMR and EIMS) data. [d] Without LED. [e] Without catalyst.
Next, we optimized the effect of catalyst loading on the reac-
tion and performed several preliminary experiments to opti-
mize the catalytic loading by varying 1 mg from 10 mg to
20 mg of the catalyst. The best result was found by using 20 mg
catalyst loading (Table 1, entry 5) and there was no effect of
further increasing the catalytic loading (Table 1, entries 5 and
14) on the yield of product 3a. However, by using less than
20 mg of catalyst, the yield of product 3a was decreased
(Table 1, entries 5 and 13) and hence, 20 mg of Cu@g-C3N4 was
taken as optimum catalyst loading (Table 1, entry 5). Next, to
ensure the individual role of photocatalyst and visible light, two
separate reactions were performed employing the optimized
reaction conditions; one in absence of catalyst (Table 1, entry
16) and other in absence of visible light (Table 1, entry 15).
However, we did not isolate the desired product 3a in either
case (Table 1, entries 15, 16) confirming synergistic catalysis i.e.
the reaction is catalyzed by photocatalyst, Cu@g-C3N4 and visi-
ble light condition as well. Thus, the optimized condition for
the present reaction was concluded as: Cu@g-C3N4 (20 mg),
with H2O (5 mL) in presence of LED light at room temperature,
and this outcome was applied as preeminent condition for con-
struction of product 3.
Results and Discussion
At the outset, 4-chlorobenzaldehyde 1a and acrylonitrile 2 were
taken as model substrates in the optimization reaction for syn-
thesis of corresponding γ-keto nitrile 3a under visible light con-
dition. The sealed reaction mixture was stirred under the visible
light at room temperature, and the results are summarized in
Table 1. Surprisingly, we were happy to isolate the desired prod-
uct 3a albeit in very low yield by stirring the mixture of
4-chlorobenzaldehyde 1a (1.0 mmol) and acrylonitrile
2
(1.5 mmol) for 8 h in presence of 20 mg of g-C3N4 (Table 1,
entry 1). Then, we used different metal-doped@g-C3N4 as
photocatalysts viz., Ni@g-C3N4, Cu@g-C3N4, Fe@g-C3N4 and
Co@g-C3N4 (15 wt.-%), and our approach worked well as the
After optimizing the reaction conditions for 3a (Table 1, en-
product 3a was isolated only in 4 h using Ni@g-C3N4 (20 mg) try 5) in hand, substrate scope of aldehyde 1 was also investi-
with improved yield of 3a (Table 1, entry 2). However, among gated to check the general validity of the envisaged reaction
different catalysts screened, Cu@g-C3N4 (20 mg) was found the for the synthesis of γ-ketonitriles (Scheme 2). A variety of differ-
most efficient catalyst for the present conversion in terms of ently substituted aromatic aldehydes 1a–n as well as aliphatic
yield and conversion rate (Table 1, entries 2–5). Next, solvent aldehyde 1o were utilized to afford the γ-ketonitriles 3a–o in
screening was also performed (Table 1, entries 5–12) and H2O good to excellent yield (Scheme 2). However, there was no
(5.0 mL) was found the best solvent for the present transforma- specific effect of substituents on phenyl ring was noted and
Eur. J. Org. Chem. 2020, 5841–5846
www.eurjoc.org
5842
© 2020 Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202000945
EurJOC
European Journal of Organic Chemistry
aromatic aldehyde 1 tolerated both electron-withdrawing (F, Cl,
Br and CN) as well as electron releasing (Me, OMe, tBu and
CH2Cl) groups to afford the corresponding alkyl nitrile 3 within
4–10 h under mild reaction conditions (Scheme 2). However,
aliphatic cyclic aldehyde 1n was also utilized under the present
optimized reaction condition and the corresponding product
3n was isolated in 80 % yield. Herein, the catalyst is well-dis-
persed in water with comparison to other solvents, and also
vacant d-orbitals of metal helps in polarization of C=O bond in
presence of water, which is presumably the reason for achieved
highest yield. Structure of all the synthesized compounds was
1
confirmed by their H and 13C NMR spectra (ESI).
Scheme 3. Control experiment for the synthesis of 3a.
Cu-catalyzed activation of aromatic aldehyde C–H bond via loss
of one proton with one electron generating acyl radical is re-
ported.[21a] Thus, on basis of these literature reports on C–H
activation[2b] through photocatalytic acyl radical[18,19,21] and the
control experiments (Scheme 3), a plausible mechanism for the
formation of γ-ketonitrile is given (Scheme 4). Presumably, for-
mation of the product 3 involves homolytic cleavage of C–H
bond of aldehyde in the presence of photocatalyst under visible
light condition. Herein, Cu@g-C3N4 (PC) is transformed into its
excited state (PC*) by irradiation with visible light, which ab-
stract carbonyl hydrogen from aldehyde 1, producing the acyl
radical 1′ and (PCH*). The acyl radical 1′ then adds to the alkene
2 to produce adduct radical 2′ and finally the product 3 was
formed via the back-hydrogen-transfer to the adduct radical 2′,
thus closing the catalytic cycle (Scheme 4).
Scheme 2. Substrate scope for synthesis of γ-ketonitriles 3.
Furthermore, four sets of controlled experiments were also
performed to observe the catalytic effect of visible light in the
present investigation by taking 1a (1.0 mmol), 2 (1.5 mmol),
Cu@g-C3N4 (20 mg) and water (5 mL) at room temperature
(Scheme 3a-d). Two separate experiments were run in absence
of visible light under room temperature, (i) in dark condition
(Scheme 3a) and (ii) at 80 °C (Scheme 2b); however, the desired
product 3a was not isolated in either condition (Scheme 3a, b).
Another experiment was performed in the presence of
TEMPO (a stable free radical) radical scavenger in presence of
visible light and again, we did not isolate even trace of 3a
(Scheme 3c). Finally, the controlled experiment concluded
that presence of visible light along with the photocatalyst
Scheme 4. Plausible mechanism for the formation of 3.
Next, seven sequential experiments were run to check the
Cu@g-C3N4 is the necessary condition in the envisaged protocol reusability of catalyst using 4-chlorobenzaldehyde 1a and
for the formation of the synthesis of γ-ketonitrile 3 (Scheme 3d). acrylonitrile 2 in H2O (5 mL), with Cu@g-C3N4 (20 mg) under
In control experiment (Scheme 3c), addition of a radical inhibi- visible light condition at room temperature. After completion
tor, TEMPO in the reaction system completely shut down the of each reaction, Cu@g-C3N4 was recovered using centrifuge,
generation of the coupling product, indicating that a radical washed with water and EtOH, and reused for the next reaction
process is most likely involved in the mechanism. Furthermore, of fresh batch of 4-chlorobenzaldehyde 1a and acrylonitrile 2
Eur. J. Org. Chem. 2020, 5841–5846
www.eurjoc.org
5843
© 2020 Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202000945
EurJOC
European Journal of Organic Chemistry
Merck 60F254 silica gel plates (0.25 mm thickness). Buchi flash chro-
matography was used to obtain the analytically pure product. 1H
NMR spectra were recorded on Bruker AV 400 and 600. The
1H NMR chemical shifts are reported relative to the centre of solvent
resonance (CDCl3: 7.26 (1H). Chemical shifts are expressed in parts
per million (δ) and the signals were reported as s (singlet), d (dou-
blet), dd (double doublet), t (triplet), dt (doublet triplet), tt (triplet
triplet), q (quartet), m (multiplet) and coupling constants J were
given in Hz. 13C NMR spectra were recorded at 100 and 151 MHz
in CDCl3 solution. Chemical shifts are expressed in parts per million
(Figure 1). The effect of doping amount of metal in the catalyst
on its catalytic performance was also undertaken. The catalytic
performance of prepared catalyst was checked by varying
the doping amount of metal ranging from 10–20 wt %. The
15 w/w % amount of metal was optimized for doping with
g-C3N4 after a number of different preliminary experiments. On
increasing doping amount from 10 to 15 wt %, yield of the
product was increased. However, there was no increase in the
yield found by increasing the amount after 15 wt %, therefore,
15 wt % was optimized for doping of metal to prepare the (δ) and are referenced to CDCl3 (δ = 77.16) as internal standard.
catalyst and was used throughout the reaction. The Cu@g-C3N4
catalyst could be recycled and reused seven times with good
yield without any significant loss of its activity (Figure 1). Fur-
thermore, the XRD pattern (ESI, Figure S3) reveals the same
structure of catalyst before (ESI, Figure S3a red line) and after
use (ESI, Figure S3b) in seven consecutive reactions.
Preparation of Cu@g-C3N4: We have recently reported[20b] prepa-
ration of Cu@g-C3N4 along with its detail characterization viz., scan-
ning electron microscopy (SEM), transmission electron microscopy
(TEM), X-ray diffraction (XRD), FTIR and X-ray photo electron phos-
phorescence (XPS) data and the same catalyst has been utilized in
the present methodology.[20b] However, preparation of Cu@g-C3N4
is given herein. It was prepared by calcination of urea at 500 °C (air
free condition) in muffle furnace for 2 h and yellowish graphitic
carbon nitride (g-C3N4) was obtained. Further, it was encapsulated
with Cu.[20b,22] In brief, solutions of 425 mg of g-C3N4 (solution A)
and 238 mg of Cu(OAc)2·H2O (15 wt % g-C3N4, Cu 75 mg) (solution
B) were prepared in 50 % aqueous CH3OH individually. Now, the
mixture solution of Sol A and Sol B was stirred for 6 h. Prepared
photocatalyst Cu@g-C3N4 was centrifuged, washed with water and
CH3OH and dried at 50 °C in vacuo.[20b,22]
Experimental procedure for γ-ketonitriles (3): A mixture of alde-
hyde 1 and acrylonitrile 2 was charged in flame-dried sealed flask
with Cu@g-C3N4 (20 mg) in water (5 mL) and stirred under the
visible light condition at room temperature for 4–10 h. After com-
pletion of the reaction (as monitored by TLC), water was added to
the reaction mixture and the catalyst was filtered and added EtOAc.
Then, the organic layer was washed with brine (2 × 10 mL) and
water (1 × 10 mL), dried under vacuum evaporator to obtain the
crude isolates, which were further purified by flash chromatogra-
phy, EtOAc/n-hexane to obtain the analytically pure sample of 3.
Characterization data of all the synthesized compounds are given
Figure 1. Recyclability of Cu@g-C3N4 for synthesis of 3a.
1
as following, while their H and 13C NMR spectra in ESI.
4-(4-Chlorophenyl)-4-oxobutanenitrile (3a): Colourless solid,
94 % yield (182 mg), (ethyl acetate/n-hexane = 1:6); 1H NMR
(400 MHz, CDCl3) δ 7.89 (d, J = 8.00 Hz, 2H), 7.47 (d, J = 8.00 Hz,
2H), 3.35 (t, J = 7.10 Hz, 2H), 2.77 (t, J = 7.18 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 194.04, 140.45, 133.93, 129.42, 129.27, 119.17,
34.23, 11.77; Anal. Calcd for C10H7ClNO: C 62.03, H 4.16, N 7.23 %;
found C 62.17, H 4.39, N 7.12 %.
Conclusions
In summary, we disclose an original visible light induced mild
and efficient method for C(sp2)–H activation towards green syn-
thesis of various γ-ketonitriles by photocatalytic intermolecular
Stetter reaction in water. Operational simplicity, wide substrate
scope, excellent yield (80–95 %), ambient reaction conditions
and visible-light photocatalysis are the salient features of the
envisaged protocols. We believe the key to achieve our
goal lies in an appropriate choice of photocatalytic system,
Cu@g-C3N4, making it more advantageous than earlier reported
methods for synthesis of such kind of fine chemicals and would
be the best alternative to be further exploited for academia and
industries.
4-Oxo-4-phenylbutanenitrile (3b): Colourless solid, 90 % yield
1
(143 mg), (ethyl acetate/n-hexane = 1:6); H NMR (400 MHz, CDCl3)
δ 7.95 (d, J = 8.00 Hz, 2H), 7.62 (t, J = 7.44 Hz, 1H), 7.50 (t, J =
7.88 Hz, 2H), 3.39 (t, J = 7.12 Hz, 2H), 2.78 (t, J = 7.28 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 195.74, 135.80, 133.28, 128.75, 127.99,
119.08, 34.26, 11.83; Anal. Calcd for C10H9NO: C 75.45, H 5.70,
N 8.80 %; found C 75.60, H 5.73, N 8.68.
4-(4-Fluorophenyl)-4-oxobutanenitrile (3c): Colourless solid, 89 %
yield (158 mg), (ethyl acetate/n-hexane = 1:6); 1H NMR (400 MHz,
CDCl3) δ 7.99–7.95 (m, 2H), 7.15 (t, J = 8.58 Hz, 2H), 3.34 (t, J =
7.08 Hz, 2H), 2.75 (t, J = 7.16 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ = 193.88, 167.43, 164.77, 132.13, 132.10, 130.78, 130.69, 119.17,
116.12, 115.90, 34.19, 11.85; Anal. Calcd for C10H7FNO: C 67.79,
H 4.55, N 7.91 %; found C 67.44, H 4.81, N 8.10 %.
Experimental Section
General: All chemicals were purchased from Aldrich, S. D. Fine and
HiMedia (India) and used as received, except all solvents which were
used after distillation. All reactions were carried out with oven-dried
glassware under air. Distilled n-hexane and ethyl acetate were used
for column chromatography. Analytical TLC was performed on
4-(4-Bromophenyl)-4-oxobutanenitrile (3d): Colourless solid,
95 % yield (226 mg), (ethyl acetate/n-hexane = 1:6); 1H NMR
Eur. J. Org. Chem. 2020, 5841–5846
www.eurjoc.org
5844
© 2020 Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202000945
EurJOC
European Journal of Organic Chemistry
(400 MHz, CDCl3) δ 7.81 (d, J = 7.88 Hz, 2H), 7.64 (d, J = 8.56 Hz,
2H), 3.34 (t, J = 7.08 Hz, 2H), 2.77 (t, J = 7.12 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 194.34, 134.37, 132.26, 129.50, 129.26, 119.01,
4-(Naphthalen-2-yl)-4-oxobutanenitrile (3m): Colourless solid,
81 % yield (169 mg), (ethyl acetate/n-hexane = 1:6); 1H NMR
(400 MHz, CDCl3) δ 8.42 (s, 1H), 7.99–7.87 (m, 4H), 7.65–7.56 (m,
34.24, 11.77; Anal. Calcd for C10H7BrNO: C 50.45, H 3.39, N 5.88 %; 2H), 3.50 (t, J = 7.12 Hz, 2H), 2.82 (t, J = 7.28 Hz, 2H); 13C NMR
found C 50.78, H 3.74, N 5.80 %.
(100 MHz, CDCl3) δ 195.30, 135.87, 132.91, 132.38, 129.91, 129.59,
128.92, 128.79, 127.83, 127.07, 123.38, 119.23, 34.21, 11.85; Anal.
Calcd for C14H11NO: C 80.36, H 5.30, N 6.69 %; Found: C 80.45,
H 5.56, N 6.84 %.
4-(3-Cyanopropanoyl)benzonitrile (3e): Colourless solid, 88 %
yield (162 mg), (ethyl acetate/n-hexane = 1:2); 1H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 8.40 Hz, 2H), 7.86 (d, J = 8.40 Hz, 2H), 3.40 (t,
J = 7.04 Hz, 2H), 2.80 (t, J = 7.04 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ = 194.08, 138.46, 132.76, 128.41, 118.65, 117.60, 117.27, 34.73,
11.65; Anal. Calcd for C11H7N2O: C 71.73, H 4.38, N 15.21 %; found
C 71.45, H 4.70, N 15.56 %.
4-(Benzo[b]thiophen-2-yl)-4-oxobutanenitrile (3n): Yellow solid,
80 % yield (172 mg), (ethyl acetate/n-hexane = 1:5); 1H NMR
(600 MHz, CDCl3) δ 7.99 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.88 (d, J =
8.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.45–7.41 (m, 1H), 3.42 (t, J =
6.8 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ =
189.82, 142.77, 141.90, 138.91, 129.82, 128.04, 126.25, 125.41,
123.12, 119.05, 34.77, 11.97. Anal. Calcd for C12H9NOS: C 66.95,
H 4.21, N 6.51 %; Found: C 67.15, H 4.34, N 6.44 %.
4-Oxo-4-(pTol)butanenitrile (3f): Colourless solid, 87 % yield
(151 mg), (ethyl acetate/n-hexane = 1:6); H NMR (400 MHz, CDCl3)
1
δ 7.86 (d, J = 7.52 Hz, 2H), 7.33 (d, J = 7.72 Hz, 2H), 3.35 (t, J =
7.12 Hz, 2H), 2.76 (t, J = 7.12 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 194.88, 144.93, 133.30, 129.55, 128.14, 119.21, 34.14,
21.82, 11.72. Anal. Calcd for C11H11NO: C 76.28, H 6.40, N 8.09 %;
found C 75.99, H 6.70, N 8.01 %.
4-Cyclohexyl-4-oxobutanenitrile (3o): Yellow oil, 80 % yield
1
(132 mg), (ethyl acetate/n-hexane = 1:5); H NMR (600 MHz, CDCl3)
δ 2.83 (t, J = 7.2 Hz, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.37 (tt, J = 11.3,
3.4 Hz, 1H), 1.86 (d, J = 12.8 Hz, 2H), 1.81–1.79 (m, 2H), 1.71–1.65
(m, 1H), 1.37–1.19 (m, 6H); 13C NMR (151 MHz, CDCl3) δ = 209.26,
119.27, 50.61, 35.83, 28.50, 25.87, 25.63, 11.59; Anal. Calcd for
4-(4-Methoxyphenyl)-4-oxobutanenitrile (3g): Colourless solid,
86 % yield (163 mg), (ethyl acetate/n-hexane = 1:6); 1H NMR
(400 MHz, CDCl3) δ 7.92 (d, J = 8.84 Hz, 2H), 6.89 (d, J = 8.92 Hz,
2H), 3.86 (s, 3H), 3.28 (t, J = 7.08 Hz, 2H), 2.71 (t, J = 7.28 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ = 193.86, 164.00, 130.33, 128.73,
119.46, 114.05, 55.56, 33.83, 11.83; Anal. Calcd for C11H11NO2:
C 69.89, H 5.86, N 7.40 %; Found C 70.24, H 5.62, N 7.35 %.
C
10H15NO: C 72.69, H 9.15, N 8.48 %; Found: C 72.55, H 8.99,
N 8.56 %.
Acknowledgments
We sincerely thank the SERB (No.–SR/FT/CS-99/2010), DST, New
Delhi, Government of India, for financial support and AIRF, JNU
New Delhi, for providing microanalysis and spectra.
4-(4-(tert-Butyl)phenyl)-4-oxobutanenitrile (3h): Colourless solid,
84 % yield (181 mg), (ethyl acetate/n-hexane = 1:6); 1H NMR
(400 MHz, CDCl3) δ 7.91 (d, J = 7.48 Hz, 2H), 7.51 (d, J = 7.48 Hz,
2H), 3.36 (t, J = 7.16 Hz, 2H), 2.77 (t, J = 7.14 Hz, 2H), 1.34 (s, 9H).
13C NMR (100 MHz, CDCl3) δ = 194.81, 157.93, 133.27, 128.00,
125.81, 119.12, 35.22, 34.16, 31.03, 11.82; Anal. Calcd for C14H17NO:
C 78.10, H 7.96, N 6.51; Found: C 78.25, H 8.10, N 6.16.
Keywords: Stetter reaction · C–H activation · Carbon
nitride · γ-Ketonitriles · Aromatic aldehyde
4-(4-(Chloromethyl)phenyl)-4-oxobutanenitrile (3i): Colourless
solid, 87 % yield (180 mg), (ethyl acetate/n-hexane = 1:6); H NMR
1
[1] a) R. H. Crabtree, A. Lei, Chem. Rev. 2017, 117, 8481–8482; b) Y. Segawa,
T. Maekawa, K. Itami, Angew. Chem. Int. Ed. 2015, 54, 66–81; Angew.
Chem. 2015, 127, 68.
[2] a) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem.
Int. Ed. 2012, 51, 10236–10254; Angew. Chem. 2012, 124, 10382; b) H. Yi,
G. Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh, A. Lei, Chem. Rev.
2017, 117, 9016–9085.
(400 MHz, CDCl3) δ 7.93 (d, J = 8.36 Hz, 2H), 7.56 (d, J = 8.44 Hz,
1H), 4.62 (s, 2H), 3.37 (t, J = 7.04 Hz, 2H), 2.77 (t, J = 7.04 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ = 194.62, 143.56, 135.10, 128.94,
128.50, 119.00, 45.26, 34.25, 11.79; Anal. Calcd for C11H11ClNO:
C 63.62, H 4.85, N 6.75 %; Found: C 63.61, H 5.03, N 6.80 %.
4-(3-Chlorophenyl)-4-oxobutanenitrile (3j): Colourless solid, 83 %
yield (160 mg), (ethyl acetate/n-hexane = 1:6); 1H NMR (400 MHz,
CDCl3) δ 7.92 (s, 1H), 7.84 (d, J = 7.76 Hz, 1H), 7.59 (d, J = 8.00 Hz,
1H), 7.44 (t, J = 7.08 Hz, 1H), 3.35 (t, J = 7.16 Hz, 2H), 2.77 (t, J =
7.06 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 194.33, 137.24, 135.43,
133.87, 130.30, 128.22, 126.16, 118.89, 34.52, 11.81; Anal. Calcd for
C10H7ClNO: C 62.03, H 4.16, N 7.23; Found: C 62.23, H 4.21, N 7.08 %.
[3] a) D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480, 224–228; b) M. H.
Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81, 6898–6926;
c) B. L. Tóth, O. Tischler, Z. Novák, Tetrahedron Lett. 2016, 57, 4505–4513;
d) O. Boubertakh, J.-P. Goddard, Eur. J. Org. Chem. 2017, 2017, 2072–
2084; e) R. Chaudhary, P. Natarajan, ChemistrySelect 2017, 2, 6458–6479;
f) M. P. Plesniak, H.-M. Huang, D. J. Procter, Nat. Rev. Chem. 2017, 1, 77.
[4] a) M. Baar, S. Blechert, Chem. Eur. J. 2015, 21, 526–530; b) W.-J. Ong,
L.-L. Tan, Y. H. Ng, S.-T. Yong, S.-P. Chai, Chem. Rev. 2016, 116, 7159–7329;
c) C. Yang, B. Wang, L. Zhang, L. Yin, X. Wang, Angew. Chem. Int. Ed. 2017,
56, 6627–6631; Angew. Chem. 2017, 129, 6727; d) X. Wang, X. Chen, A.
Thomas, X. Fu, Adv. Mater. 2009, 21, 1609–1612.
[5] a) X. Wang, K. Maede, A. Thomas, K. Takanabe, G. Xin, J. M. Carsson, K.
Domen, M. Antonietti, Nat. Mater. 2009, 8, 76–80; b) Y. Zhang, T. More,
J. Ye, M. Antonietti, J. Am. Chem. Soc. 2010, 132, 6294–6295; c) Y. Wang,
X. Wang, M. Antonietti, Angew. Chem. Int. Ed. 2011, 50, 68–89; Angew.
Chem. 2011, 123, 12746; d) F. Dong, L. Wu, Y. Sun, M. Fu, Z. Wu, S. C.
Lee, J. Mater. Chem. 2011, 21, 15171–15174; e) G. Zhang, J. Zhang, M.
Zhang, X. Wang, J. Mater. Chem. 2012, 22, 8083–8091; f) S. Duan, G. Han,
Y. Su, X. Zhang, Y. Liu, X. Wu, B. Li, Langmuir 2016, 32, 6272–6281.
[6] a) C. W. Liskey, X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 11389;
b) T. Jinzaki, M. Arakawa, H. Kinoshita, J. J. Ichikawa, K. Miura, Org. Lett.
2013, 15, 3750; c) Y. Zheng, Y. He, G. Rong, X. Zhang, Y. Weng, K. Dong,
X. Xu, J. Mao, Org. Lett. 2015, 17, 5444.
4-Oxo-4-(m-tolyl)butanenitrile (3k): Yellow solid, 82 % yield
1
(142 mg), (ethyl acetate/n-hexane = 1:6); H NMR (400 MHz, CDCl3)
δ 7.75–7.72 (m, 2H), 7.42–7.35 (m, 2H), 3.35 (t, J = 7.24 Hz, 2H), 2.75
(t, J = 7.24 Hz, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.53,
138.75, 135.70, 134.63, 128.73, 128.53, 125.23, 119.22, 34.32, 21.31,
11.80; Anal. Calcd for C11H11NO: C 76.28, H 6.40, N 8.09 %; Found
C 76.15, H 6.72, N 8.30 %.
4-(2-Chlorophenyl)-4-oxobutanenitrile (3l): Yellow oil, 81 % yield
1
(156 mg), (ethyl acetate/n-hexane = 1:6); H NMR (400 MHz, CDCl3)
δ 7.58 (d, J = 7.60 Hz, 1H), 7.45 (d, J = 3.84 Hz 2H), 7.39–7.34 (m,
1H), 3.38 (t, J = 7.12 Hz, 2H), 2.77 (t, J = 7.12 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 198.03, 137.36, 132.74, 131.41, 130.89, 129.54,
127.23, 118.84, 38.27, 12.10; Anal. Calcd for C10H9ClNO: C 62.03,
H 4.16, N 7.23 %; Found: C 62.07, H 4.230, N 7.04 %.
Eur. J. Org. Chem. 2020, 5841–5846
www.eurjoc.org
5845
© 2020 Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202000945
EurJOC
European Journal of Organic Chemistry
[7] a) A. S. Girgis, N. Mishriky, A. M. Farag, W. I. El-Eraky, H. Farag, Eur. J. Med.
Chem. 2008, 43, 1818; b) B. A. Provencher, K. J. Bartelson, Y. Liu, M. F.
Bruce, L. Deng, Angew. Chem. Int. Ed. 2011, 50, 10565; Angew. Chem.
2011, 123, 10753; c) E. F. Sarah, R. W. Richard, A. W. Laura, L. A. Wright,
B. A. Weaver, R. C. Hartage, I. Ghiviriga, G. Gumina, B. D. Feske, Synthesis
2013, 45, 2171; d) D. Wu, F. Donal, Org. Lett. 2013, 15, 3392; e) G. Frey,
H.-T. Luu, P. Bichovski, M. Feurer, J. Streuff, Angew. Chem. Int. Ed. 2013,
52, 7131; Angew. Chem. 2013, 125, 7271; f) K. U. Krishnaraj, K. S. Devaky,
Tetrahedron 2014, 70, 6450; g) J. Cai, L. G. Liu, K. H. Hong, P. Wang, L. S.
Li, M. Cao, C. L. Sun, X. Q. Wu, X. Zong, J. Q. Chen, Bioorg. Med. Chem.
2015, 23, 657.
[8] Y.-S. Feng, Y.-J. Shu, P. Cao, T. Xu, H.-J. Xu, Org. Biomol. Chem. 2017, 15,
3590.
[9] Y. Li, J.-Q. Shang, X.-X. Wang, W.-J. Xia, T. Yang, Y. Xin, Y.-M. Li, Org. Lett.
2019, 21, 2227–2230.
[10] S.-L. Zhang, X.-J. Wang, Z.-L. Yu, Org. Lett. 2017, 19, 3139.
[11] Y. Zhu, J. Gong, Y. Wang, J. Org. Chem. 2017, 82, 7428.
[12] X.-W. Lan, N.-X. Wang, C.-B. Bai, C.-L. Lan, T. Zhang, S.-L. Chen, Y. Xing,
Org. Lett. 2016, 18, 5986.
[16]
A. Bhunia, S. R. Yetra, S. S. Bhojqude, A. T. Biju, Org. Lett. 2012, 14, 2830–
2833.
A. Patra, A. Bhunia, A. T. Biju, Org. Lett. 2014, 16, 4798–4801.
S. Esposti, D. Dondi, M. Fagnoni, A. Albini, Angew. Chem. Int. Ed. 2007,
46, 2531–2534; Angew. Chem. 2007, 119, 2583.
[17]
[18]
[19]
[20]
M. Ociepa, O. Baka, J. Narodowiec, D. Grykoa, Adv. Synth. Catal. 2017,
359, 3560–3565.
a) P. Shukla, A. Asati, S. R. Bhardiya, M. Singh, V. K. Rai, A. Rai, J. Org.
Chem. 2020, 85, 7772–7780; b) F. Verma, P. Shukla, S. R. Bhardiya, M.
Singh, A. Rai, V. K. Rai, Adv. Synth. Catal. 2019, 361, 1247–1252; c) F.
Verma, P. Shukla, S. R. Bhardiya, M. Singh, A. Rai, V. K. Rai, Catal. Commun.
2019, 119, 76–81; d) F. Verma, A. Sahu, P. K. Singh, A. Rai, M. Singh, V. K.
Rai, Green Chem. 2018, 20, 3783–3789; e) V. K. Rai, F. Verma, G. P. Sahu,
M. Singh, A. Rai, Eur. J. Org. Chem. 2018, 2018, 537–544.
a) C. Liu, D. Liu, A. Lei, Acc. Chem. Res. 2014, 47, 3459–3470; b) S. Selva-
kumar, R. Sakamoto, K. Maruoka, Chem. Eur. J. 2016, 22, 6552–6555.
a) S. Verma, R. B. Nasir Baig, C. Han, M. N. Nadagouda, R. S. Varma, Chem.
Commun. 2015, 51, 15554–15557; b) S. Verma, R. B. Nasir Baig, C. Han,
M. N. Nadagouda, R. S. Varma, Green Chem. 2016, 18, 251–254; c) S.
Huang, Y. Zhao, R. Tang, RSC Adv. 2016, 6, 90887–90896.
[21]
[22]
[13] E. B. Knott, J. Chem. Soc. 1947, 1190.
[14] Q. Wu, Y. Li, C. Wang, J. Zhang, M. Huang, J. K. Kim, Y. Wua, Org. Chem.
Front. 2018, 5, 2496–2500.
[15] H. Stetter, Angew. Chem. Int. Ed. Engl. 1976, 15, 639; Angew. Chem. 1976,
88, 695.
Received: July 7, 2020
Eur. J. Org. Chem. 2020, 5841–5846
www.eurjoc.org
5846
© 2020 Wiley-VCH GmbH