Simple Synthesis of 3-Oxopropanenitriles via Electrophilic Cyanoacetylation of Heterocycles with Mixed Anhydrides

Article abstract of DOI:10.1002/jhet.2511

A simple and efficient method for the synthesis of 3-oxopropanenitriles from variously substituted heterocyclic compounds via direct electrophilic cyanoacetylation is described. A series of heterocyclic 3-oxopropanenitriles (2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k) have been synthesized using mixed anhydride (acetic or trifluoroacetic anhydride:cyanoacetic acid) in the presence of Mg(ClO₄)₂·2H₂O as catalyst. This method can be extended also for the cyanoacetylation of electron poor aromatic compounds.

Full text of DOI:10.1002/jhet.2511

Month 2015
Simple Synthesis of 3-Oxopropanenitriles via Electrophilic
Cyanoacetylation of Heterocycles with Mixed Anhydrides
a
b
c
*
Anita Andicsovà-Eckstein, Erika Kozma, and Daniel Végh
aPolymer Institute, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 41 Bratislava, Slovak Republic
bIstituto per lo Studio delle Macromolecole, Consiglio Nazionale delle Ricerche, Via Bassini 15, 20133 Milano, Italy
cInstitute of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovak Republic
*
E-mail: anita.andicsova@savba.sk
Received December 3, 2014
DOI 10.1002/jhet.2511
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient method for the synthesis of 3-oxopropanenitriles from variously substituted
heterocyclic compounds via direct electrophilic cyanoacetylation is described. A series of heterocyclic
3-oxopropanenitriles 2(a–k) have been synthesized using mixed anhydride (acetic or trifluoroacetic
anhydride:cyanoacetic acid) in the presence of Mg(ClO4)2·2H2O as catalyst. This method can be extended
also for the cyanoacetylation of electron poor aromatic compounds.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
acylation of an acid chloride with the lithium salt of
cyanoacetic acid [6]. The straightforward electrophilic sub-
stitution of nitrogen containing heteroaromatic compounds
(indoles, pyrroles) with cyanoacetic acid in acetic
anhydride was discovered for the first time in 2004 [7].
The synthesis of 3-oxopropanenitrile by using a mixed anhy-
dride from cyanoacetic acid–acetic anhydride mixture with
electron rich aromatics in presence of indium trichloride as
a Lewis acid was described by Elnagdi et al [8].
Recently, several new methods have been developed,
such as indium-mediated coupling of bromoacetonitriles
with acyl cyanides or palladium-catalyzed carbonylation of
aryl iodides and trimethylsilylacetonitrile [9]. In all cases,
these synthetic methods are strictly exploitable for
electron-rich aromatic compounds, and additional synthetic
steps for the preparation of the starting materials are needed.
In this work we report the preparation of
3-oxopropanenitriles by direct cyanoacetylation of
different heterocycles, including electron poor aromatic
compounds, with mixed anhydride (cyanoacetic acid:acetic
anhydride or cyanoacetic acid:trifluoroacetic anhydride) in
the presence of Mg(ClO4)2·2H2O as catalyst, using
commercially available starting materials.
Substituted 3-oxopropanenitriles are versatile synthetic
intermediates or reactants with a great interest in organic
chemistry. Suitably situated keto- and cyano- strong elec-
tron withdrawing groups are favorable for reactions with
common bidentate reagents to form a variety of heterocy-
clic compounds possessing biological and pharmaceutical
activities [1]. Moreover, because of the presence of active
hydrogen on C-2, these compounds can participate in a
variety of condensation and substitution reactions.
Recently, using 3-oxopropanenitriles as starting materials,
the synthesis of different heterocycles and their derivatives
such as pyrazoles, 4-cyano pyrroles, pyridines, isoxazoles,
pyrimidines, pyridazines, pyrans, thiazoles, π-conjugated
thiophene derivatives, and optically active β-hydroxy
carboxylic nitriles has been reported [2]. Because most
of these heterocycles are potentially bioactive materials,
facile synthetic procedures for the preparation of
3-oxopropanenitriles are needed.
Several synthetic pathways for the preparation of
3-oxopropanenitriles are present in literature (Scheme 1).
The oldest method involves the reaction of α-haloketones
with cyanide [3], while the classical method uses the
Claisen type reaction [4] of appropriate aromatic or
heteroaromatic esters with in situ generated metallated
nitriles. The synthesis of 3-oxopropanenitriles can be
accomplished also by the Guareshi–Thorpe condensation
of aromatic or heteroaromatic nitriles with acetonitrile in
the presence of bulky bases [5]. Another approach is the
The present study was initiated because of the continuous
growing demand of heteroaromatic 3-oxopropanenitriles,
used as starting materials for the Vilsmeier-Haack Arnold
haloformylation. Our study was focused on the introduction
of 3-oxopropanenitriles on electron reach and electron poor
heterocycles, such as furan, thiophene, pyrrole, and their
derivatives.
© 2015 HeteroCorporation

A. Andicsovà-Eckstein, E. Kozma, and D. Végh
Vol 000
Scheme 1. Known synthetic approaches towards 3-oxopropanenitriles.
RESULTS AND DISCUSSION
a phenyl group at the nitrogen atom (1c and 1d) or in the
alpha position (1e) leads to a significant yield decrease,
as a direct consequence of the strong steric hindrance.
The heteroaromatic 3-oxopropanenitriles used in our
research were prepared by using two different types of
mixed anhydrides: cyanoacetic acid:acetic anhydride or
cyanoacetic acid:trifluoroacetic anhydride. Generally, the
mixed anhydride was prepared via the common procedure
by heating the mixture of several equivalents of cyanoacetic
acid and anhydrides [10].
In the first approach, the synthesis of 3-
oxopropanenitriles was performed by the addition of
cyanoacetic acid–acetic anhydride, without catalyst, using
pyrrole, thiophene, and furan derivatives as starting mate-
rials. In these conditions, no reaction was observed for
thiophene and furan derivatives, and therefore, Scheme 2
represents only the synthetic pathways for the pyrrole
based molecules.
Table 1
Substituted 3-oxopropanenitriles 2(a-e) synthesized by cyanoacetic acid:
acetic anhydride mixture.
Substrate
Product (2)
Yield
85%
1a
2a
2b
2c
1b
1c
57%
36%
Using 1(a–e) as substrates, 3-oxopropanenitriles 2(a–e)
were obtained in 30–85% yield, with a cyanoacetylating
agent containing 2:3 ratio between cyanoacetic acid and
acetic anhydride (Table 1).
1d
1e
2d
2e
30%
48%
The highest yields were obtained for pyrrole, because of
its high reactivity; it can be noticed that the introduction of
Scheme 2. Synthesis of 3-oxopropanenitriles using cyanoacetic acid:
acetic anhydride mixture
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Simple Synthesis of 3-Oxopropanenitriles via Electrophilic Cyanoacetylation of
Heterocycles with Mixed Anhydrides
Except for compounds 1c and 1d, where secondary products
were isolated 1-(1-phenyl-1H-pyrrol-2-yl)ethan-1-one (3c)
[11] in 5% and 1-(1-(perfluorophenyl)-1H-pyrrol-2-yl)
ethan-1-one (3d) [12] in 24% yields, in the other cases these
compounds were not found.
suitable also for the cyanoacetylation of the unsubstituted
thiophene 1f and furan 1j, in 39% and respectively, 23%.
Obviously the reaction of activated derivatives 1(g–i, k)
proceeded in a higher yields (43–49%).
Table 2
In order to extend the applicability of this reaction to less
reactive electron poor aromatic compounds, stronger con-
ditions are necessary. Therefore, in a our second approach,
the acetic acid anhydride is replaced with trifluoroacetic
anhydride and Mg(ClO4)2·2H2O is added as catalyst.
We have already noticed in our previous work that Mg
(ClO4)2·2H2O acts as a Lewis acid and improves the
eaction yield [13].
Using mixed anhydride derived from cyanoacetic acid:
trifluoroacetic anhydride together with the perchlorate
catalyst, 3-oxopropanenitriles of different heteroaromatic
compounds were obtained with satisfactory yields
(Scheme 3).
Substituted 3-oxopropanenitriles 2(a–k) synthesized by mixed anhydride–
cyanoacetic acid:trifluoroacetic anhydride.
Substrate
Product (2)
Yield
31%a
1a
2a
1b
1c
2b
2c
85%a
61%a
Different anhydride:acid ratios were used in order to op-
timize the reaction yields. If the ratio of the trifluoroacetic
anhydride:cyanoacetic acid is 1:2 and the reaction
underwent at 25°C for 30 min, trifluoroacetyl derivatives
4(c, d, h) were isolated as secondary products in 32%,
10%, and respectively 28% yields. In order to eliminate
the by-product formation, the reaction conditions were ap-
propriately modified. Therefore, during the preparation of
the mixed anhydride at 50°C for 30 min, the generated
trifluoroacetic acid was removed via vacuum distillation
during the reaction, monitored by TLC, and the formation
of by-product 4 was avoided. The complete conversion of
the starting materials 1(a–k) was not achieved in any
presented compounds. The best results obtained for differ-
ent heterocyclic compounds are summarized in Table 2.
Several interesting features are coming out from the results
shown in Table 1 and Table 2.
Regarding the pyrrole derivatives with bulky phenyl or
pentafluorophenyl substituents (1c and 1d), the
trifluoroacetic anhydride:cyanoacetic acid is more efficient
(61–65% yields) with respect to acetic anhydride:
cyanoacetic acid (30–36% yields). The scope and limita-
tions of a direct cyanoacetylation were overcome, because
the reaction works well with different active five-
membered heterocycles. The reaction conditions were
1d
1e
2d
2e
65%a
65%a
1f
2f
39%b
48%a
29%b
49%b
23%a
43%a
1g
1h
1i
2g
2h
2i
1j
2j
Scheme 3. Synthesis of 3-oxopropanenitriles 2(a–k) by cyanoacetic
acid:trifluoroacetic anhydride mixture, in the presence of 0.01 eqv. of
Mg(ClO4)2·2H2O.
1k
2k
aIsolated yield using cyanoacetic acid:trifluoroacetic anhydride 1:2, Mg
(ClO4)2·2H2O (0.01 equiv.).
bIsolated yield using cyanoacetic acid:trifluoroacetic anhydride 1:2, Mg
(ClO4)2·2H2O (0.01 equiv.), removing the trifluoroacetic acid from the
reaction media.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Andicsovà-Eckstein, E. Kozma, and D. Végh
Vol 000
The structures of all synthesized compounds were
established on the basis of their spectroscopic data. The
IR spectrum of compounds 2(a–k) showed a strong absorp-
by-products 3 were in concordance with that reported in
the literature.
General procedures for the synthesis of heterocyclic
3-oxopropanenitrile. Cyanoacetic acid–acetic anhydride
1
tion at 2210–2259 cmÀ1 because of the CN group. The H
method.
The mixed anhydride was prepared from
NMR spectrum of 2(a–k) showed a singlet at 3.8–3.9ppm
corresponding to CH2 groups. The carbon signals of the tar-
get 3-oxopropanenitrile group are appeared with shift
around 29 (CH2), 113 (CN), and 175 (CO) ppm. 19F
NMR spectra displayed two triplets and one doublet in a
2:1:2 ratios which characterize the pentafluorophenyl group
of 2d and 4d derivatives and one singlet from CF3 which
characterize the trifluoroacetic group of byproducts 4c, 4d,
and 4h.
cyanoacetic acid and acetic anhydride (in 3:2 ratio) the
appropriate heterocyclic derivative (1a–j, 1.0 equiv.) was
added at 80°C under argon atmosphere and stirred at this
temperature for a further 4 h. The reaction mixture was
then poured into ice water, and then saturated solution of
NaHCO3 was added (pH = 7). The product was extracted
by CH2Cl2. The extract was washed with water, dried
over Na2SO4, and the solvent removed in vacuo to
dryness to give the crude product.
Cyanoacetic acid–trifluoroacetic anhydride method.
The
CONCLUSIONS
mixed anhydride was prepared from cyanoacetic acid and
trifluoroacetic anhydride (in 2:1 ratio); the appropriate
heterocyclic derivative (1a–k) and catalytic amount of
Mg(ClO4)2·2H2O (0.01 equiv.) were added at 25°C
under argon atmosphere and stirred at this temperature for
4–20h. The reaction mixture was then poured into water,
and then saturated solution of NaHCO3 was added
(pH=7). The product was extracted by CH2Cl2. The
extract was washed with water, dried over Na2SO4, and the
solvent was removed in vacuo to dryness to give the crude
In summary, we have described an efficient method
which allows a facile and direct synthesis of heteroaryl
3-oxopropanenitriles. These synthetic procedures are valu-
able because mixed anhydrides are employed and almost in
all cases commercially available starting materials were
used. These synthetic pathways represent new methods
for the direct preparation of 3-oxopropanenitriles of
thiophene and furan derivatives, which are less reactive
comparing to the substituted pyrroles. Moreover, the
target compounds 2(a–k) may be used as intermediates
to develop novel heterocyclic compounds with potential
biological activity.
product.
3-Oxo-3-(1H-pyrrole-2-yl)propanenitrile (2a). Crystallized
from ethanol, colorless solid, mp 78–81°C (Lit. [7] mp 78°C).
3-Oxo-3-(1-methyl-1H-pyrrole-2-yl)propanenitrile (2b).
Crystallized from ethanol, colorless solid, mp 109–110°C
(Lit. [7] mp 109–110°C).
3-Oxo-3-(1-phenyl-1H-pyrrole-2-yl)propanenitrile (2c). Purified
by column chromatography (hexane:ethyl acetate, 5:1) and
EXPERIMENTAL
General.
All starting materials and substrates are
commercially available (Sigma-Aldrich), except 1-phenyl-
1H-pyrrole (1c) [14] which was synthesized from aniline
hydrochloride and 2,5-dimethoxytetrahydrofuran, 1-
pentafluorophenyl-1H-pyrrole (1d) [12] prepared by a
modified Clauson–Kass cyclization and 2-((9H-
fluorenylidene)methyl)-1-methyl-1H-pyrrole (1e) [2] was
obtained as a condensation product from the reaction of 1-
methyl-1H-pyrrole-2-carbaldehyde and fluorene. Compounds
1c, 1d, and 1e were purchased from Georganics.
Melting points were recorded on a Kofler block and are
uncorrected. Infrared spectra (KBr) were determined on a
Perkin-Elmer 1600 FT-IR system. NMR spectra (1H at 300,
13C at 75, and 19F at 300MHz) were obtained in
deuterochloroform using VARIAN VXR 300 spectrometer
with tetramethylsilane as internal standard. Chemical shifts
are reported in parts per million (ppm). Coupling constants
are reported in Hertz (Hz). Elemental analyses were
measured with Carlo Erba Elemental Analyzer 1108. Silica
gel 60 (230–400mesh, Merck) was used for column
chromatography. Reactions and the collected fraction
samples were monitored by TLC (Merck 60F254 silica
gel). The 1H NMR spectra of the isolated acetyl
recrystallized from methanol, colorless solid, mp 95°C.
IR (KBr) υ: 720, 900, 1050, 1105, 1270, 1325, 1380,
1
1490, 1679, 1684, 2210, 3490 cmÀ1; H NMR (CDCl3) δ
3.86 (2H, s, CH2), 6.37–6.35 (1H, dd, J= 2.8 Hz, 3.4 Hz),
7.12–7.05 (2H, m), 7.27–7.24 (2H, m), 7.43–7.41 (3H,
m); 13C NMR (CDCl3) δ: 29.5, 110.4, 114.2, 121.3,
126.5, 128.3, 128.5, 129.1, 133.6, 139.9, 175.3. Anal.
Calcd. for C13H10N2O: 74.27; H, 4.79; N, 13.33. Found:
C, 74.32; H, 4.81; N, 13.35.
3-Oxo-3-(1-(perfluorophenyl)-1H-pyrrole-2-yl)propanenitrile
(2d). Purified by column chromatography (hexane:ethyl
acetate, 5:1) and recrystallized from methanol, colorless
solid, mp 105–106°C. IR (KBr) υ: 750, 810, 990, 1050,
1100, 1175, 1405, 1510, 1530, 1675, 2220, 3430cmÀ1
;
1H NMR (CDCl3) δ 3.94 (2H, s, CH2), 6.52 (1H, dd,
J = 2.7 Hz, 3.4 Hz), 7.02 (1H, s), 7.21 (1H, d, J = 1.5Hz);
13C NMR (CDCl3) δ: 29.1, 112.0, 113.5, 121.8, 129.0,
132.7, 145.4–135.9 (5 × s, C–F), 176.1; 19F NMR
(CDCl3) δ: À83.90 (2F, t, J = 8.7 Hz), À75.17 (1 F, t,
J = 11.4Hz), À69.45 (2 F, d, J =9.0 Hz). Anal. Calcd. for
C13H5F5N2O: C, 52.01; H, 4.68; N, 9.33. Found: C,
52.32; H, 4.70; N, 9.57.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Simple Synthesis of 3-Oxopropanenitriles via Electrophilic Cyanoacetylation of
Heterocycles with Mixed Anhydrides
3-Oxo-3-(5-((9H-fluorene-9-ylidene)methyl)-1-methyl-1H-
pyrrole-2-yl)propanenitrile (2e). Yellow solid, mp 133–
135°C (Lit. [2i] mp 133–135°C).
3-Oxo-3-(thiophene-2-yl)propanenitrile (2f). Crystallized
from ethanol, colorless solid, mp 123–126°C, (Lit. [15]
mp 124–126°C; ethanol).
3-Oxo-3-(5-methylthiophene-2-yl)propanenitrile (2g). Crystallized
1-(2,2′-Bithiophene-5-yl)-2,2,2-trifluoroethanone (4h). Purified
by column chromatography (hexane/ethyl acetate, 9/1),
and recrystallized from ethanol, colorless solid, yield 28%
1
(0.44g), mp 65–67°C. H NMR (CDCl3) δ 7.11 (1H, dd,
J=4.2Hz, 4.5Hz), 7.26 (1H, d, J= 4.2Hz), 7.43–7.41
(2H, m), 7.87–7.85 (1H, m); 13C NMR (CDCl3) δ: 116.4 (q,
JF-C =288.5Hz, COCF3), 124.9, 127.0, 128.1, 128.6, 133.9,
135.3, 137.5, 150.2, 173.1 (q, JC-F=36.4 Hz, COCF3); 19F
NMR (CDCl3) δ À96.4 (s, 3F, COCF3). Anal. Calcd. for
C10H5F3OS2: C, 45.79; H, 1.92. Found: C, 46.62; H, 1.90.
from ethanol, colorless solid, mp 111–112°C (Lit. [16] mp
108–109°C).
3-Oxo-3-(2,2′-bithiophene-5-yl)propanenitrile (2h). Purified
by column chromatography (dichloromethane) and
recrystallized from ethanol, yellow solid, mp 127–128°C.
IR (KBr) υ: 668, 723, 772, 796, 841, 879, 1075, 1227,
1336, 1393, 1455, 1507, 1541, 1558, 1666, 1699, 2259,
Acknowledgments. The authors are grateful to the Slovak Grant
Agency for Science (contract No. 2/0112/13, 1/0829/14), to Slovak
Research and Development Agency (contract APVV-0038-11), and
for Accordo Quadro between Regione Lombardia and CNR—
Cluster Project ‘Energy’ no 17348 for the financial support.
1
2340cmÀ1; H NMR (CDCl3) δ 3.97 (2H, s, CH2), 7.08
(1H, dd, J=4.2Hz, 4.3Hz), 7.22 (1H, d, J=4.2Hz), 7.39–
7.36 (2H, m), 7.67 (1H, d, J=3.9Hz,); 13C NMR (CDCl3)
δ: 29.1, 113.5, 124.4, 126.5, 127.5, 128.5, 134.6, 135.5,
138.3, 148.5, 178.9. Anal. Calcd for C11H7NOS2: 56.63;
REFERENCES AND NOTES
H, 3.02; N, 6.00. Found: C, 56.51; H, 3.00; N, 6.01.
3-Oxo-5′-methyl-(2,2´-bithiophene-5-yl)propanenitrile (2i).
[1] Elnagdi, M. H.; Elmoghayar, M. R. H.; Elgemeie, G. E. H.
Synthesis 1984, 1.
Purified by column chromatography (dichloromethane) and
recrystallized from ethanol, yellow solid, mp 172–174°C.
IR (KBr) υ: 668, 798, 897, 1074, 1233, 1330, 1442, 1472,
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1521, 1507, 1540, 1684, 1699, 2258, 2340 cmÀ1 1H
;
NMR (CDCl3) δ 2.51 (3H, s, CH3), 3.95 (2H, s, CH2),
6.73 (1H, d, J=3.6Hz), 7.12 (1H, d, J=4.2Hz), 7.17 (1H,
d, J=3.6Hz), 7.64 (1H, d, J=4.2Hz); 13C NMR (CDCl3)
δ: 15.5, 29.1, 113.6, 123.6, 126.6, 126.7, 133.2, 134.7,
137.6, 142.9, 149.1, 178.7. Anal. Calcd. for C12H9NOS2:
58.27; H, 3.67; N, 5.66. Found: C, 58.30; H, 3.68; N, 5.65.
3-Oxo-3-(furan-2-yl)propanenitrile (2j). Crystallized from
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ethanol, colorless solid, mp 77–79°C (Lit.4 mp 74–75°C).
3-Oxo-3-(5-methylfuran-2-yl)propanenitrile (2k). Crystallized
from ethanol, colorless solid, mp 89–92°C. 1H NMR (CDCl3)
δ 2.43 (3H, s, CH3), 3.92 (2H, s, CH2), 6.27 (1H, d,
J=3.0Hz), 7.30 (1H, d, J=3.6Hz); 13C NMR (CDCl3) δ:
14.1, 28.4, 110.2, 113.6, 121.4, 149.1, 159.6, 174.7. Anal.
Calcd. for C8H7NO2: C, 64.42; H, 4.73; N, 9.39. Found C,
64.57; H, 4.88; N, 9.41.
2,2,2-Trifluoro-1-(1-phenyl-1H-pyrrole-2-yl)ethanone (4c).
Purified by column chromatography (hexane:ethyl
acetate, 5:1) and recrystallized from hexane, colorless
solid, yield 32% (0.5 g), mp 36–37°C. (Lit. [17]).
2,2,2-Trifluoro-1-(1-(perfluorophenyl)-1H-pyrrole-2-yl)ethanone
(4d). Purified by column chromatography (hexane:ethyl
acetate, 5:1) and recrystallized from hexane, colorless
1
solid, yield 10% (0.08g), mp 48–49°C. H NMR (CDCl3)
δ 6.62–6.60 (1H, dd, J =2.6Hz), 7.15–7.13 (1H, m), 7.49–
7.46 (1H, m); 13C NMR (CDCl3) δ: 110.7, 113.1, 116.4 (q,
JF-C =288.3Hz, COCF3), 125.2, 134.5, 145.5–141.9
(5 × C–F), 169.9 (q, JF-C =36.5Hz, COCF3); 19F NMR
(CDCl3, HFB) δ À73.1 (3F, s, COCF3); À147.9 (2F, t),
À153.3 (1F, t), À162.4 (2F, d). Anal. Calcd. for
C12H3F8NO: C, 43.79; H, 0.92; N, 4.26. Found: C, 44.52;
H, 0.94; N, 4.31.
[17] Chadwick, D. J.; Meakins, G. D.; Rhodes, C. A. J Chem
Research 1980, 2, 878.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet