1-butyl-3-methylimidazolium bromide as a solvent and precatalyst for stetter reaction

Article abstract of DOI:10.14233/ajchem.2020.22711

Stetter reaction between aromatic aldehydes and acrylonitrile/ethyl acrylate performing in [Bmim]Br in the presence of NaOH is described. N-Heterocyclic carbene (NHC) generates in situ is shown to be an efficient catalyst. Benzoin condensation also occured as side reaction.

Full text of DOI:10.14233/ajchem.2020.22711

Asian Journal of Chemistry; Vol. 32, No. 8 (2020), 2028-2032
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22711
1-Butyl-3-methylimidazolium Bromide as a Solvent and Precatalyst for Stetter Reaction
1,*,
2
BARAMEE PHUNGPIS
and VIWAT HAHNVAJANAWONG
1Faculty of Natural Resources, Rajamangala University of Technology, Isan Sakonnakhon Campus, Sakonnakhon 47160, Thailand
2Department of Chemistry and Centre of Excellence for Innovation in Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002,
Thailand
*Corresponding author: E-mail: barameephungpis@yahoo.com
Received: 5 March 2020;
Accepted: 25 May 2020;
Published online: 27 July 2020;
AJC-19985
Stetter reaction between aromatic aldehydes and acrylonitrile/ethyl acrylate performing in [Bmim]Br in the presence of NaOH is described.
N-Heterocyclic carbene (NHC) generates in situ is shown to be an efficient catalyst. Benzoin condensation also occured as side reaction.
Keywords: [Bmim]Br, N-Heterocyclic carbene, catalyst, Stetter reaction.
Liberation of NHC 2 from the resulting intermediate 8 provides
1,4-dicarbonyl adduct 9 [2] (Scheme-I).
INTRODUCTION
Stetter reaction is the cross-coupling reaction between
aldehydes and Michael acceptors. The reaction is generally
catalysed by N-heterocyclic carbenes (NHCs) generated in situ
by deprotonation of azolium salts [1], i.e. thiazolium, triazolium
and imidazolium salts (Fig. 1).
Stetter reaction proceeds through addition of NHC 2,
generated in situ from deprotonation of corresponding azolium
ion 1, to aldehyde 3 follows by a proton transfer process of
adduct 4 to form Breslow intermediate 5. Subsequent conjugate
addition of 5 to the Michael acceptor 6 leads to the conjugate
adduct 7, which undergoes another proton transfer process.
N-heterocyclic carbene catalyzed-Stetter reaction is a
simple synthetic method for affording 1,4-dicarbonyl compounds,
which are important intermediates in synthesis of various
natural and medicinal compounds, such as cis-jusmon and
dihydrojusmon, ( )-trans-sabinene hydrate and haloperidol
[3-5] (Schemes II-IV).
Upon treatment with base, 1-butyl-3-methylimidazolium
bromide ([Bmim]Br), commonly used as reaction medium,
has been reported to provide an effective NHC catalyst for benzoin
condensation [6]. In continuation of our studies on performing
Stetter reaction in ionic liquids [7,8] herein, we wish to report
R1
R1
X
H
R1
N
X
R4
X
N
R3
N
N
H
H
N
R3
R3
N
R2
S
R2
R2
Imidazolium salt
Thiazolium salt
X = I, Br, Cl, BF4, ClO4
Triazolium salt
Fig. 1. Azolium salts generally utilized as precatalyst for Stetter reaction
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Vol. 32, No. 8 (2020)
1-Butyl-3-methylimidazolium Bromide as a Solvent and Precatalyst for Stetter Reaction 2029
O
R1
R1
R1
HN
N
Y
Y
N
R3
H
Y
Base
O
3
R2
R2
R2
Deprotonation
H
X
X
Addition
H
X
R3
2
4
1
X = S, NR; Y = CH, N
O
R1
R1
R4
O
HN
Y
R4
R5
N
Y
Proton transfer
OH
Proton transfer
6
R2
R2
R5
X
X
R3
OH
R3
Conjugate addition
7
5
Breslow intermediate
R1
R1
O
R4
O
HN
Y
HN
Y
Liberation of 2
R5
R3
+
R2
R2
R5
X
X
R4
O
R3
O
2
9
8
Scheme-I: The reaction pathway for Stetter reaction catalysed by NHCs catalyst
Me
Et
N
Br
O
O
HO
S
R
O
O
R
NaOH
H2O, EtOH
(10 mol%)
R
+
O
H
Me
Et3N, 80 oC, 12 h
62-69%
Me
Me
Et
cis-jusmon, R =
Dihydrojusmon, R = n-penty
Scheme-II: Synthesis of cis-jusmon and dihydrojusmon
Me
Bn
Cl
N
O
Me
HO
HO
S
Me
O
O
3 steps
(1 mol%)
Me
O
+
Me
R
Me
Et3N, EtOH, 48 h
82%
Me
(+)-trans-Sabinene hydrate
Me
Me
Me
Scheme-III: Synthesis of ( )-trans-sabinene hydrate
a successful employment of [Bmim]Br as a solvent and NHC
precursor in Stetter reaction.
points were determined in capillary tubes in a Buchi B 545
apparatus. The products were identified by comparison of their
melting points and spectral data (IR, 1H & 13C NMR) with those
in the authentic samples. FT-IR spectra were obtained as KBr
disks on a Shimadzu spectrometer. The 1H and 13C NMR spectra
were recorded using aVarian Mercury plus (400 MHz FT-NMR).
EXPERIMENTAL
All chemicals in the experiment were commercially avail-
able and used directly without further purification. Melting

2030 Phungpis et al.
Asian J. Chem.
Cl
OH
Me
Bn
Cl
N
O
CHO
HO
S
4 steps
(20 mol%)
+
CO2Me
F
F
CO2Me
[Bmim]BF4
Et3N, 80 oC
67%
O
F
Haloperidol
Scheme-IV: Synthesis of haloperidol
General procedure for the Stetter reaction between aro-
matic aldehydes (10a-d) and acrylonitrile (11)/ethyl acrylate
(15): To a grinding mixture of [Bmim]Br (12) (0.219 g, 1 mmol)
and NaOH (0.008 g, 0.2 mmol) was added corresponding
aromatic aldehyde 10 (1.0 mmol) and acrylonitrile (11)/ethyl
acrylate (15) (2 mmol) and the mixture was heated at 80 ºC for
8-13 h. After completion of the reaction (monitored by TLC,
eluant hexane/dichloromethane, 1:1), the mixture was cooled to
room temperature and extracted with dichloromethane (3 × 30
mL). The organic phase was dried over anhydrous Na2SO4 and
the solvent was removed under reduced pressure. The residue
was purified by preparative thin layer chromatography (silica
gel, elution with dichloromethane).
Benzoin (14a): White crystals; m.p.: 134-136 ºC (lit.134-
136 ºC) [11]; IR (KBr, νmax, cm-1): 3418, 2935, 1678, 1597,
1
1450, 1341, 1207 and 757; H NMR (CDCl3, 400 MHz) δ:
7.92 (2H, d, J = 7.6 Hz, 2- and 6-H), 7.53 (1H, t, J = 7.6 Hz, 4-
H), 7.39 (2H, t, J = 7.6 Hz, 3- and 5-H), 7.25–7.32 (5H, m,
ArH), 5.96 (1H, s, CH), 4.53 (1H, br s, OH); 13C NMR (CDCl3)
δ: 76.1, 127.7, 128.6, 128.7, 129.2, 133.6, 133.9, 139.1, 198.8.
4,4′-Dichlorobenzoin (14b): White crystals; m.p.: 87-88
ºC (lit.87-88 °C) [10]; IR (KBr, νmax, cm-1): 3423, 3070, 2928,
1674, 1590, 1487, 1401, 1251, 1091, 977 and 812; 1H NMR
(CDCl3, 400 MHz) δ: 7.76 (2H, d, J = 8.8 Hz, 2- and 6-H),
7.33 (2H, d, J = 8.8 Hz, 3- and 5-H), 7.23 (2H, d, J = 8.4 Hz,
3- and 5′-H), 7.17 (2H, d, J = 8.4 Hz, 2′- and 6′-H), 5.82 (1H,
s, CH); 13C NMR (CDCl3) δ: 75.6, 129.0, 129.2, 129.5, 130.5,
131.5, 134.8, 137.2, 140.7, 197.5.
4,4′-Dimethylbenzoin (14c): White crystals; m.p.: 75-76
ºC (lit. 75 ºC) [12]; IR (KBr, νmax, cm-1): 3410, 3059, 2931,
1679, 1594, 1447, 1263, 1092 and 753; 1H NMR δ: 7.82 (2H,
d, J = 8.8 Hz, 2- and 6-H), 7.22 (2H, d, J = 8.8 Hz, 3- and 5-
H), 7.17 (2H, d, J = 8.4 Hz, 2′-H and 6′-H), 7.12 (2H, d, J =
8.4 Hz, 3′- and 5′-H), 5.89 (1H, s, CH), 2.34 (3H, s, Ar-CH3),
2.29 (3H, s, Ar-CH3); 13C NMR (CDCl3) δ: 21.2, 21.7, 75.9,
127.7, 129.3, 129.5, 129.8, 131.0, 136.4, 138.4, 144.9, 198.4.
4,4′-Pyridoin (14d): Yellow crystals; m.p.: 154-156 ºC;
IR (KBr, νmax, cm-1): 3463, 3075, 2981, 2843, 1667, 1597, 1513,
1465, 1314, 1266, 1169, 1075, 828; 1H NMR δ: 8.76 (2H, d, J
= 8.4 Hz, 2- and 6-H), 8.56 (2H, d, J = 8.4 Hz, 3- and 5-H),
7.93 (2H, d, J = 8.8 Hz, 2′-H and 6′-H), 7.19 (2H, d, J = 8.8
Hz, 3′- and 5′-H), 6.09 (1H, s, CH); 13C NMR (CDCl3) δ: 75.6,
122.1, 122.6, 135.0, 137.4, 145.1, 150.4, 197.9.
4-Phenyl-4-oxobutanenitrile (13a):White crystals; m.p.:
74-76 ºC (lit. 74-76 ºC) [9]; IR (KBr, νmax, cm-1): 3069, 2955,
1
2257, 1692, 1596, 1450, 1332, and 1218; H NMR δ: 7.97
(2H, d, J = 7.8 Hz, 2′- and 6′-H), 7.63 (1H, t, J = 7.8 Hz, 4′-
H), 7.51 (2H, t, J = 7.8 Hz, 3′- and 5′-H), 3.40 (2H, t, J = 7.2
Hz, CH2CH2CN), 2.79 (2H, t, J = 7.2 Hz, CH2CH2CN); 13C
NMR δ: 11.9, 34.4, 119.4, 128.1, 128.9, 133.9, 135.7, 195.5.
4-(4′-Chlorophenyl)-4-oxobutanenitrile (13b): White
crystals; m.p.: 72-73 ºC (lit. 72-73 ºC) [10]; IR (KBr, νmax, cm-1):
3136, 2951, 2257, 1676, 1562, 1466, 1327 and 1259; 1H NMR
δ: 7.88 (2H, d, J = 8.8 Hz, 2′- and 6′-H), 7.48 (2H, d, J = 8.8
Hz, 3′- and 5′-H), 3.34 (2H, t, J = 7.2 Hz, CH2CH2CN) and
2.78 (2H, t, J = 7.2 Hz, CH2CH2CN); 13C NMR δ: 11.8, 34.2,
119.1, 129.3, 129.4, 133.9, 140.6, 194.2.
4-(4′-Tolyl)-4-oxobutanenitrile (13c): White crystals;
m.p.: 75-77 ºC (lit. 75-77 ºC) [9]; IR (KBr, νmax, cm-1): 3065,
2920, 2252, 1689, 1399, 1331, 1225, 1184 and 1006; 1H NMR
δ: 7.85 (2H, d, J = 8.4 Hz, 2′- and 6′-H), 7.28 (2H, d, J = 8.4 Hz,
3′- and 5′-H), 3.38 (2H, t, J = 7.2 Hz, CH2CH2CN), 2.78 (2H,
t, J = 7.2 Hz, CH2CH2CN), 2.43 (3H, s, Ar-CH3); 13C NMR δ:
11.9, 29.8, 34.2, 119.1, 128.1, 129.5, 133.3, 144.9, 201.2.
4-(Pyridin-4-yl)-4-oxobutanenitrile (13d):Yellow crystals;
m.p.: 135-137 ºC; IR (KBr, νmax, cm-1): 3069, 2955, 2923, 2257,
Ethyl 4-phenyl-4-oxobutanoate (16a):Yellow liquid; IR
(neat, νmax, cm-1): 3032, 2955, 1724, 1640, 1569, 1446, 1392,
1260, 1183; 1H NMR δ: 7.98 (2H, d, J = 7.6 Hz, 2′- and 6′-H),
7.56 (1H, t, J = 7.6 Hz, 4′-H), 7.46 (2H, t, J = 7.6 Hz, 3′- and
5′-H), 4.16 (2H, q, J = 7.6 Hz, OCH2CH3), 3.31 (2H, t, J = 6.8
Hz, CH2CH2CO2CH2CH3), 2.74 (2H, t, J = 6.8 Hz,
CH2CH2CO2CH2CH3), 1.26 (3H, t, J = 7.6 Hz, CO2CH2-CH3);
13C NMR δ: 14.2, 28.4, 33.5, 60.6, 128.1, 128.6, 133.3, 136.7,
172.9, 198.2.
1
2681, 1692, 1580, 1450, 1332, 1218 and 1002; H NMR δ:
8.75 (2H, d, J = 8.4 Hz, 2′- and 6′-H), 7.88 (2H, d, J = 8.4 Hz,
3′- and 5′-H), 3.00 (2H, t, J = 7.2 Hz, CH2CH2CN), 2.75 (2H, t,
J = 7.2 Hz, CH2CH2CN); 13C NMR δ: 14.9, 38.8, 119.3, 122.6,
135.0, 135.3, 150.4, 198.8.
Ethyl 4-(4′-dichlorophenyl)-4-oxobutanoate (16b):White
crystals; m.p.: 55-57 ºC (lit. 56-58 ºC) [9]; IR (KBr, νmax, cm-1):

Vol. 32, No. 8 (2020)
1-Butyl-3-methylimidazolium Bromide as a Solvent and Precatalyst for Stetter Reaction 2031
3004, 2955, 1745, 1689, 1599, 1443, 1330 and 1273; 1H NMR
δ: 7.86 (2H, d, J = 8.4 Hz, 2′- and 6′-H), 7.37 (2H, d, J = 8.4 Hz,
3′- and 5′-H), 4.08 (2H, q, J = 7.6 Hz, CO2CH2CH3), 3.21
(2H, t, J = 6.8 Hz, CH2CH2CO2CH2CH3), 2.68 (2H, t, J = 6.8
Hz, CH2CH2CO2CH2CH3), 1.21 (3H, t, J = 7.6 Hz,
CO2CH2CH3); 13C NMR δ: 14.2, 28.2, 33.3, 60.7, 128.9, 129.4,
134.9, 139.6, 172.7, 197.0.
Ethyl 4-(4′-tolyl)-4-oxobutanoate (16c): White crystals;
m.p.: 64-65 ºC; IR (KBr, νmax, cm-1): 3066, 2956, 1741, 1691,
1596, 1451, 1323, 1175, 1005, 748; 1H NMR δ: 7.86 (2H, d, J
= 8.8 Hz, 2′- and 6′-H), 7.38 (2H, d, J = 8.8 Hz, 3′- and 5′-H),
4.08 (2H, q, J = 7.6 Hz, CO2CH2CH3), 3.20 (2H, t, J = 6.8 Hz,
CH2CH2CO2CH2CH3), 2.68 (2H, t, J = 6.8 Hz,
CH2CH2CO2CH2CH3 ), 2.11 (3H , s, CH3Ar), 1.22 (3H, t, J =
7.6 Hz, CO2CH2CH3); 13C NMR δ: 14.3, 28.4, 30.9, 33.1, 60.7,
128.9, 129.5, 134.9, 139.7, 172.8, 196.8.
Ethyl 4-(pyridin-4-yl)-4-oxobutanoate (16d): Yellow
liquid; IR (neat, νmax, cm-1): 3086, 2993, 2909, 1734, 1680,
1590, 1450, 1361, 1222, 1165, 1037; 1H NMR δ: 8.75 (2H, d,
J = 8.4 Hz, 2′- and 6′-H), 7.88 (2H, d, J = 8.4 Hz, 3′- and 5′-
H), 4.12 (2H, q, J = 7.6 Hz, CO2CH2CH3), 3.00 (2H, t, J = 6.8
Hz, CH2CH2CO2CH2CH3), 2.71 (2H, t, J = 6.8 Hz, CH2-
CH2CO2CH2CH3), 1.15 (3H, t, J = 7.6 Hz, CO2CH2CH3); 13C
NMR δ: 14.1, 27.7, 33.4, 60.7, 122.8, 135.0, 150.4, 173.0,
196.8.
RESULTS AND DISCUSSION
In this study, we conducted Stetter reaction using [Bmim]Br
as a solvent and precatalyst was conducted under reaction
conditions similar to those reported by Grée et al. [5]. We began
to briefly examine an effective amount of [Bmim]Br required
for the nucleophilic coupling of benzaldehyde (10a) with
acrylonitrile (11) in the presence of 20 mol% of NaOH at 80
ºC. Employment of 100 mol% of [Bmim]Br (12) was revealed
to be optimal, satisfactorily affording the 1,4-addition product
13a in 72% yield; benzoin (14a) resulted from benzoin
condensation was obtained in 19% yield (Table-1, entry 3).
Under optimized condition, Stetter reaction between aromatic
aldehydes 10b-d and acrylonitrile (11) went on well to produce
good yields of corresponding 1,4-addition products 13b-d
(Table-2, entries 1-3). Corresponding aroins 14b-d also occurred
as minor side products. Treatment of aromatic aldehyde 10a-d
with ethyl acrylate (15) similarly afforded corresponding 1,4-
addition products 16a-d as well as corresponding aroins 14a-d
as major and minor products, respectively (Table-2, entries 4-7).
Lower yields (ca. 10%) of 1,4-addition products 16a-dcomparing
with those of 1,4-adducts 13a-d indicates that ethyl acrylate
(15) is less reactive than acrylonitrile (11) towards Stetter reaction
which in turn results in providing slightly increasing yields
(3-11%) of aroins from benzoin condensation.
TABLE-1
BRIEF EXAMINATION OF EFFECTIVE AMOUNT OF [Bmim]Br (12) REQUIRED FOR STETTER
REACTION BETWEEN BENZALDEHYDE (10a) AND ACRYLONITRILE (11) AT 80 °C
O
O
CHO
+
+
NaOH(20 mol%), 80 oC
CN
CN
OH
[Bmim]Br 12
14a
10a
Entry
11
13a
Mol% 12
Yield 13a (%)
Yield 14a (%)
1
2
3
20
50
100
39
70
72
13
19
19
TABLE-2
STETTER REACTION OF AROMATIC ALDEHYDES 10a-d WITH ACRYLONITRILE (11)/ETHYL
ACRYLATE (15) IN [Bmim]Br (12) (100 mol%) IN THE PRESENCE OF NaOH (20 mol%) AT 80 °C
O
O
[Bmim]Br 12
Ar
Ar-CHO
+
Z
+
Ar
Z
Ar
NaOH, 80 0C
OH
14
10
11/15
13/16
Entry
Ar
Z
Yield (%)
76 (13b)
60 (13c)
74 (13d)
61 (16a)
64 (16b)
51 (16c)
63 (16d)
Yield (%)
14 (14b)
26 (14c)
7 (14d)
27 (14a)
25 (14b)
30 (14c)
10 (14d)
1
2
3
4
5
6
7
4-ClC6H4 (10b)
4-MeC6H4 (10c)
4-C5H4N (10d)
C6H5 (10a)
4-ClC6H4 (10b)
4-MeC6H4 (10c)
4-C5H4N (10d)
CN (11)
CN (11)
CN (11)
CO2Et (15)
CO2Et (15)
CO2Et (15)
CO2Et (15)

2032 Phungpis et al.
Asian J. Chem.
Catalytic activity of [Bmim]Br (12) results from deproto-
nation of the 2H proton of imidazolium cation to give NHC
17. Nucleophilic attrack on aromatic aldehyde 10 produces
the adduct intermediate 18, which proton transfer leads to
Breslow intermediate 19. Subsequent 1,4-addition to the
Michael acceptor 11/15 generates 1,4-adduct intermediate 20.
Tranformation to intermediate 21 by proton transfer and liber-
ation of 1,4-addition products 13/16regenerates the NHC catalyst
17 (Scheme-V).
[Bmim]Br 100 mol% proceeded well, with N-heterocyclic carbene
(NHC) derived from [Bmim]Br as catalyst. Benzoin conden-
sation also took place besides good yields of corresponding
1,4-addition products, giving corresponding aroins as side
products. Ethyl acrylate was found to be less reactive than
acrylonitrile towards the Stetter reaction.
ACKNOWLEDGEMENTS
The authors are grateful to the National Research Council of
Thailand: NRCT and Faculty of Natural Resources, Rajamangala
University of Technology Isan Sakonnakhon Campus, Thailand
for financial support.
Me
Br
+
N
N
CONFLICT OF INTEREST
12
Bu
The authors declare that there is no conflict of interests
regarding the publication of this article.
NaOH
Me
O
O
N
Ar
H
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Ar
Z
:
10
13/16
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Scheme-V: Catalytic cycle for [Bmim]Br catalyzed Stetter reaction
Conclusion
Stetter reaction between aromatic aldehydes and acrylo-
nitrile/ethyl acrylate in the presence of NaOH 20 mol% in