Temperature controlled condensation of nitriles: Efficient and convenient synthesis of β-enaminonitriles, 4-aminopyrimidines and 4-amidinopyrimidines in one system

Article abstract of DOI:10.1039/c9ra10866a

A series of β-enaminonitriles, 4-aminopyrimidines and 4-amidinopyrimidines were synthesized by condensation of organonitriles in one system. A wide variety of compounds were obtained in good to excellent yields by simply controlling the reaction temperature. The base-induced transformation process is easy for production. The scope and versatility of the method have been successfully demonstrated with 72 examples. The flexible and diversified characteristics of nitriles were introduced based on electronic effect, steric effect, position of substituted groups and intermolecular hydrogen bonding. An updated reaction mechanism is proposed based on the study of the stoichiometric reaction conditions at variable temperature, and on the investigation of products with cis-trans configuration transformation.

Full text of DOI:10.1039/c9ra10866a

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Temperature controlled condensation of nitriles:
efficient and convenient synthesis of b-
enaminonitriles, 4-aminopyrimidines and 4-
amidinopyrimidines in one system†
Cite this: RSC Adv., 2020, 10, 6576
Yinghua Li, Yingzu Zhu, Shiqun Xiang,
Weibin Fan, Jiang Jin
*
and Deguang Huang
A series of b-enaminonitriles, 4-aminopyrimidines and 4-amidinopyrimidines were synthesized by
condensation of organonitriles in one system. A wide variety of compounds were obtained in good to
excellent yields by simply controlling the reaction temperature. The base-induced transformation
process is easy for production. The scope and versatility of the method have been successfully
demonstrated with 72 examples. The flexible and diversified characteristics of nitriles were introduced
based on electronic effect, steric effect, position of substituted groups and intermolecular hydrogen
bonding. An updated reaction mechanism is proposed based on the study of the stoichiometric reaction
conditions at variable temperature, and on the investigation of products with cis–trans configuration
transformation.
Received 24th December 2019
Accepted 21st January 2020
DOI: 10.1039/c9ra10866a
rsc.li/rsc-advances
b-Enaminonitriles were commonly synthesized by condensa-
tion of two functional amide/nitrile molecules under high
temperature and/or strong base conditions (Scheme 2a and b).1,12,13
Other methods were also developed to obtain b-enaminonitriles,
including the reuxing of methylenecarbonitriles with triethyl
orthoformate and amine (Scheme 2c),14 the metal-catalysed
condensation of active nitriles with isocyanides or cyclopropanes
(Scheme 2d and e),15,16 the cyclization of chloromethyl p-tolyl
sulfoxide with cyanomethyl lithium and (Scheme 2f),17 and the
Introduction
As a versatile and designable building block, b-enaminonitrile
plays an important role in the synthesis of pharmaceuticals,
fungicides, dyes and biological pesticides.1,2 Many heterocyclic
compounds, e.g. pyrimidine,3 pyridine,4 pyrrole,5 pyrazole,6
imidazole,7 isothiazole8 and pyrrolinone9 are proposed to be
synthesized from b-enaminonitriles (Scheme 1). The great
signicance of them in synthetic chemistry has consistently
stimulated the development of new methods for their prepa-
ration. Meanwhile, the base-facilitated alkylation of stabilized
carbanions, directed by functional groups, has been extensively
employed in the construction of small molecule precursors for
organic synthesis.10 Among which, the alkylation of deproto-
nated nitrile anions occupies a unique position as being
powerful nucleophiles, ideally suited for transformation into
a variety of functional groups.11 The challenging issues lie ahead
in controlling selectivity and efficiency of transformation, from
the viewpoints of practicality in laboratory synthesis and
industrial applications.
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences Fuzhou, Fujian 350002, China.
E-mail: dhuang@irsm.ac.cn
† Electronic supplementary information (ESI) available: Characterization of
compounds; X-ray crystal structures of compounds 2j, 4a and 5e; synthesis and
characterization of 2,3,3-triphenylacrylonitrile. CCDC 1956320–1956327,
1969352. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c9ra10866a
Scheme 1 Synthesis of diverse heterocycles from b-enaminonitriles.
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efficient method is desired for the synthesis of various b-enami-
nonitriles, 4-aminopyrimidines and their derivatives, consistent
with the development of heterocyclic chemistry and its related
medical synthetic chemistry.
Organonitriles possess versatile chemical properties,23 and
the nitrile group can be easily transformed into a variety of
heterocyclic groups such as amines, amides, amidines, tetra-
zoles, triazoles, oxazoles and thiazoles.24 The employment of
nitriles as nitrogen source has become a scientic interest in
the construction of nitrogenous substances and heterocyclic
compounds.1,25 We recently reported a simple and catalyst-free
method for the synthesis of b-enaminonitriles and 4-amino-
pyrimidines by using aliphatic nitriles as electron donors and
benzonitriles as electron acceptor (Scheme 2h).26 However, the
application of aliphatic nitriles and other types of aromatic
nitriles (e.g. naphthyl, pyridyl, thienyl) as electron acceptors has
not been concerned. Also, the condensation of aliphatic nitriles
only and the discussion of the cis–trans isomerization of
b-enaminonitriles was not involved in that paper. Herein, we
introduce the method for the synthesis of b-enaminonitriles by
self-condensation of aliphatic nitriles, as well as reaction of
aliphatic nitriles with N,N0-diisopropylcarbodiimide (DIC) and
various aromatic nitriles. The discussion of cis–trans isomeri-
zation of b-enaminonitriles is concluded based on the results of
condensation of various nitriles. Furthermore, the formation of
4-aminopyrimidines with various types of nitriles is examined,
and a new type condensation of four-component nitriles is
developed for the construction of novel multi-substituted
4-amidinopyrimidines.
Results and discussion
All the reactions were carried out under N2 atmosphere in Teon
screw-cap sealed tubes. The condensation of phenylacetonitrile
(1a) was selected as a model reaction and optimized by changing
reagents or reaction conditions to nd out the most suitable
condition (Table 1). Based on the experimental results obtained,
it is concluded that the reaction of substrates 1a (0.4 mmol) and
lithium hexamethyldisilazide (LiHMDS, 0.2 mmol) in dime-
ꢀ
thoxyethane (DME) at 120 C for 24 h gives the best result with
the production of compound 2a in yield up to 86% (entry 6). The
LiHMDS salt works as a highly efficient base in deprotonation of
the a-H of 1a, and it was added in stoichiometric ratio for
a completed reaction. Other alkali salts and/or organic bases of
tBuOK, EtONa, Cs2CO3, 4-dimethylaminopyridine (DMAP) and
1,8-diazabicyclo [5.4.0]-undec-7-ene (DBU) afforded the product
of 2a in lower yields (entry 1–2) or without yield (entry 3–5).
Meanwhile, the type of solvent was important for the formation
of 2a (entry 6–11). Less polar solvents such as DME, anisole and
THF would help to increase the reaction yield, among which the
DME is the best choice (entry 6). In contrast, more polar solvents
would be unfavourable for the generation of product with the
decline of yield to trace in DMF (entry 11). The existence of
hydrogen bonding interaction between solvent and inter mediate
imine/amine is suggested to be responsible for the inaction of the
self-condensation reaction in more polar solvent system.
Scheme 2 Methods and routines for the synthesis of b-enaminoni-
triles and its related 4-aminopyrimidines, 4-amidinopyrimidines.
Thorpe–Ziegler condensation of aliphatic nitriles (Scheme 2g).18
However, all these reactions show limited tolerance for the
synthesis of various enaminonitriles due to the rigorous reaction
conditions and/or limited reaction substrates.1,12–18 Thus, the
utilization of b-enaminonitriles for the synthesis of different
substituent 4-aminopyrimidines is rarely described. 4-Amino-
pyrimidines and their derivatives are an important building blocks
found in the molecules of natural products.19 The biochemical
activity of them has been discovered and explored for the treat-
ment of diseases such as T cell-mediated autoimmune and
inammatory disorders,20 external injuries21 and cancer.22 An
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Table 1 Optimization of the formation of compound 2aa
Table 2 Scope of nitriles with respect to b-enaminonitrilesa
En
Base
Solvent
Temp (ꢀC)
T (h)
Yieldb (%)
1
2
3
4
5
6
7
8
tBuOK
EtONa
Cs2CO3
DMAP
DBU
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
DME
DME
DME
DME
DME
DME
Anisole
THF
120
120
120
120
120
120
120
120
120
120
120
60
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
36
12
26
None
None
None
86
55
45
None
None
None
3
9
Dioxane
DCE
10
11
12
13
14
15
16
DMF
DME
DME
DME
DME
DME
100
140
120
120
22
61
67
71
a
Reaction conditions: 1a (0.4 mmol), base (0.20 mmol), solvent (1 mL),
b
N2.
dimethylaminopyridine, DBU
THF
dimethylformamide.
Isolated yield. DME
¼
dimethoxyethane, DMAP
1,8-diazabicyclo[5,4,0]undec-7-ene,
dichloroethane, DMF N,N-
¼
4-
¼
¼
tetrahydrofuran, DCE
¼
¼
The percent conversion of nitrile was examined in
a temperature range of 60–140 ꢀC (entry 6, 12–14), and the
temperature of 120 ꢀC was determined as standard condition
according to the transformation efficiency of compound 2a.
Lower temperature would decrease the yield dramatically down
to 3% at 60 ꢀC (entry 12), and higher temperature might not
help to improve the efficiency of production (entry 14). In
addition, the inuence of reaction time on the production of 2a
was monitored at points of 12 h, 24 h and 36 h (entry 6, 15–16).
It was found that 24 h would be a right time for the achievement
of reaction. Shorter or longer time would be disadvantageous
for the transformation of 1a to 2a with yields decreased to 67%
at 12 h and 71% at 36 h, respectively.
Encouraged by the above results, we started to examine the
scope of the reaction system as to other nitrile substrates (Table 2).
A total of 29 organonitriles were chosen for analysis of the impli-
cation of reaction, including aliphatic nitriles, aromatic nitriles,
heteroaromatic nitriles, dinitriles. The reactions produced 37 b-
enaminonitrile compounds in the same way as phenylacetonitrile
(1a) worked. The yield distribution and production efficiency of b-
enaminonitriles were discussed based on the electronic effect,
steric effect and the synergic effect of functional groups on the
nitriles. It was found that all the aliphatic nitriles could work both
as electron donors and electron acceptors in the above reaction
system, by means of deprotonation of the a-H of nitriles and
polarization of the carbon atom on the CN triple bond. By
contrast, the aromatic nitriles could only work as electron accep-
tors owing to the absence of a-H. Firstly, 25 alkyl organonitriles
(2a–2y) were deprotonated and performed to study the electronic
a
Reaction conditions: (1) 1 (0.40 mmol), LiHMDS (0.20 mmol), 120 ꢀC,
24 h, N2; (2) 1 (0.20 mmol), 10 (0.20 mmol), LiHMDS (0.20 mmol), 120 ꢀC,
24 h, N2; (3) isolated yield. b LiHMDS (0.4 mmol). c 60 ꢀC. d 140 ꢀC. The
absence of E/Z ratio means that no Z-form of product was found.
effect of functional groups in manner of self-condensation. The
experimental results showed that electronic effect of substituted
groups on the aliphatic nitriles had a signicant impact on the
production of b-enaminonitriles. The reaction of phenyl-
acetonitrile derivatives with electron-donating groups and weak
electron-withdrawing substituted groups on the para-position of
phenyl ring afforded the product of b-enaminonitriles in high
yields (2a–2g, 70–86%). The electron-withdrawing uoro group
would offer the product in lower yield (2h, 63%) compared to its
analogous bromo and chloro groups (2f, 2g). No product of b-
enaminonitrile could be isolated when the strong electron-
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withdrawing groups (nitro and/or triuoromethyl) substituted
phenylacetonitrile derivatives were used for reaction. This point of
view was consistent with the results presented in the formation of
compounds 2p–2w, in which the reaction of naphthyl groups and
various alkyl groups substituted nitriles generated the products in
yields 62–78%. Secondly, the steric hindrance to the reaction was
studied by employment of methoxyl group (2e, 2j), uoro group
(2h, 2k, 2m) and methyl group (2c, 2i, 2l) in the para-, meta- and
ortho-positions, respectively. The result showed that the yields of
reaction decreased dramatically from the substitution of para-
position (2c, 2h) to ortho-position (2l, 2m), and no self-
condensation product was found when the methoxyl group was
employed in the ortho-position of the phenyl ring of phenyl-
acetonitrile. This conclusion was in accordance with the fact that
the dimethyl groups substituted nitriles (2n, 2o) provided the
products in much lower yields (47% and 34%). Finally, the
condensation reaction was examined with mixed nitriles by using
Fig. 1 Crystal structures of compounds 2x (CCDC number: 1969352)
(a) and 3c (1956321) (b), showing the strong intermolecular hydrogen
bondings between amine and pyridine groups (N2/H–N3 ¼ 1.998 A˚
for compound 2x and 2.010 A˚ for compound 3c).
97% (Table 3). The scope of phenylacetonitriles substrates was
explored by changing functional groups on the phenyl ring,
including electron donating groups (MeOꢁ, tBuꢁ, Meꢁ; 4b–4d),
electron withdrawing groups (Phꢁ, Brꢁ, Clꢁ, Fꢁ; 4e–4h),
difunctional groups (dimethyl, dimethoxyl, dioxolane, diuoro;
the
deprotonated
n-butyronitrile,
3-phenylpropionitrile,
2-pyridylacetonitrile as electron donors and benzonitrile, 2-cya-
nopyridine, 2-thiophenecarbonitrile, 2-naphthonitrile as electron
ꢀ
acceptors (3a–3l). All the reactions were carried out at 60 C and
the products were obtained in good to excellent yields, except for
those reactions using 2-pyridylacetonitrile as electron donor. The
experiments of 2-pyridylacetonitrile were run at 140 ꢀC for
a complete transformation of starting materials to compounds (3c,
3f, 3i, 3l) with the yields above 70%. It is supposed that the
interaction of hydrogen bonding between the pyridine group of
starting material and the amine group of product decreased the
free degree of molecules, which would lead to the difficulty in the
molecular collision at lower temperature.
Table 3 Scope of nitriles with respect to compound 4a
In addition, it was found that the cis–trans isomerization was
less evident in the formation of b-enaminonitriles in our reac-
tion, since all the reactions produced trans isomers as main
products. The yields of (Z)-b-enaminonitriles was less than 10%
in the condensation of aliphatic nitriles only (worked as both
electron donor and electron acceptor). The proportion of cis
isomers turned out to be higher in the reaction of aliphatic
nitriles (electron donors) with aromatic nitriles (electron
acceptors). The yields could reach 16% in the formation of
compound 3k. It is thought that the aryl group on the aromatic
nitriles decreased the energy barrier of C^N bond cleavage,
which would lead to decreasing energy consumption for C–C
bonding again steric hindrance for the generation of cis-form
products. Beyond that, no cis-form compounds was found in the
formation of pyridyl group contained b-enaminonitriles. The
strong intramolecular hydrogen bonding would bring the
reaction to the generation of (E)-b-enaminonitriles during this
process (Fig. 1). There was a special case: the condensation of
acetonitrile in our conditions afforded cis–trans isomers of
3-aminocrotononitrile (2y) in a ratio of about 1 : 1, which could
be due to the similar steric effect of methyl group and amine
group to the cyanide group on the other carbon atom.
Our condensation reaction also demonstrates good reactivity
and stability towards the formation of functional b-enamino-
nitriles with N]C]N type substrates (Table 3 and Fig. S1†).
The reaction of phenylacetonitrile with N,N0-diisopropylcarbo-
diimide (DIC) in THF (60 ꢀC, 6 h) afforded compound 4a in yield
a
Reaction conditions: 1 (0.20 mmol), DIC (0.20 mmol), LiHMDS (0.20
mmol), 60 ꢀC, 6 h, N2, isolated yield. DIC ¼ N,N0-diisopropylcarbodiimide.
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Table 4 Investigation of b-enaminonitriles for the construction of
4p–4t) and aromatic groups (pyridyl, naphthyl; 4o, 4u and 4v).
All the reactions showed high production efficiency with the
yields obtained from 84% to 97%, this result indicated that the
above electron groups had weak impacts on the yield of the
reaction. The difunctional substituted groups such as
3,5-dimethyl (4p), 2,5-dimethyl (4q), 2,4-diuoro (4t) and
3,4-dimethoxyl (4s) could reduce the generation of product by
ca. 10%. Larger substituted group might be disadvantageous for
the production of compound 4 and its derivative. Meanwhile,
the reaction of DIC with 2-pyridylacetonitrile (4o), 1-naphthyl-
acetonitrile (4u) and 2-naphthylacetonitrile (4v) gave the target
products in good yields of 97%, 90% and 92%, respectively. It
shows that our reaction have a good tolerance in the trans-
formation of various aryl acetonitriles to b-enaminonitriles. The
reactivity of nitrile in our system was also examined by reaction
of phenylacetonitrile with benzophenone. The reaction afforded
the product of 2,3,3-triphenylacrylonitrile in yield 80% aer
dehydroxylation (Fig. S2†). In addition, the synthetic utility of
our reaction was also examined by running the experiments on
gram scale. The self-condensation of phenylacetonitrile (1a) or
cross-coupling of 1a with DIC on 5 gram scale yielded the
products of 2a and 4a in high overall yields of 80% and 95%
(Scheme 3), respectively.
variable substituted 4-aminopyrimidinesa
In order to explore the application of b-enaminonitriles for
the construction of various substituted 4-aminopyrimidines,
the condensation of b-enaminonitrile with another portion of
nitrile was examined under base condition (Table 4). The
reactions were carried out at 120 ꢀC and 140 ꢀC for the
condensation of two-species (5b–5d, 5f) and three-species
organonitriles (5e, 5g–5i) respectively. The self-condensation
a
Reaction conditions: 1 (0.20 mmol), 2 or 3 (0.20 mmol), LiHMDS (0.22
mmol), 120 ꢀC, 24 h, N2, isolated yield. b 140 ꢀC.
3l) with aromatic nitriles did not yield the target products under
the same conditions. It is thought that the strong hydrogen
bonding between the pyridine and amine group in the molecule
limits the change of conformation from ‘trans’ to ‘cis’ (Fig. 1).
The inversion of conguration is critical for the construction of
pyrimidine core through cycloaddition with another portion of
nitrile.
Interestingly, our method also provides an efficient way to
synthesize 4-amidinopyrimidines by further condensation of
4-aminopyrimidines with a fourth portion of nitriles (Scheme
4).
To our best knowledge, the synthesis of 4-amidinopyr-
imidine was rarely reported, and the only example of
(2,6-dimethyl-4-acetamidine)-pyrimidine was obtained as a by
product in the condensation of acetonitrile under pressure of
a few thousand atmosphere.27 The preparation of different
component 4-amidinopyrimidine has not been reported so far.
In our lab, the reactions run smoothly with four typical type of
4-amidinopyrimidines and the products were obtained in yields
ꢀ
of acetonitrile was also completed at a temperature of 140 C
(5a). Nine types of 4-aminopyrimidines were obtained in yields
63–77%, which reected that the reaction had a wide range of
application in the synthesis of nitrogen containing heterocy-
cles. Higher temperature was required for the achievement of
multi-substituted 4-aminopyrimidines. It showed that the
condensation of multi-components of nitriles was more diffi-
cult than that of fewer-components. Also, the eletrophilicity of
nitrile has an impact on the formation of 4-aminopyrimidine.
The CN groups of aliphatic nitriles posses less electrophilicity to
be attacked than aromatic nitriles, and the condensation of
aliphatic nitriles for the synthesis of 4-aminopyrimidines needs
ꢀ
higher temperature ($140 C). Furthermore, it was found that
the component of 2-pyridylacetonitrile might not be suitable for
the building of pyrimidine core, since the reactions of
pyridylacetonitrile-contained b-enaminonitriles (2w, 3c, 3f, 3i,
1
over 76%. All the compounds were characterized by H NMR,
13C NMR, mass spectra and X-ray crystallography (Fig. 2).
The bond lengths and bond angles of heterocyclic rings are
comparable to those presented in the analogous compounds,26
indicating the formation of pyrimidine cores and peripheral
amidine function groups.
Based on the above experimental results, an updated
mechanism is proposed in Scheme 5. One of hydrogen atoms
on the methylene group of aliphatic nitrile is deprotonated by
Scheme 3 Studies of the synthetic utility of b-enaminonitriles.
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Scheme 4 Studies of the synthetic utility of b-enaminonitriles.
Scheme
5
Plausible mechanism of the condensation of various
nitriles under base conditions.
LiHMDS to form a cyanoalkylide anion (a). The anion attacks an
adjacent nitrile molecule on the carbon atom of cyanide group
to generate an intermediate imine species (b) and (c). The
species (c) attacks another nitrile molecule to produce the imine
species (d), following by an intramolecular cycloaddition reac-
tion to form the intermediate (e). The imine species (e) attacks
a fourth nitrile molecule to form the four-component interme-
diate (f). The chemical shi of hydrogen atom (H1) and the
electron transfer of C–H bond to the terminal imine nitrogen
affords the product of 6 spontaneously. In addition, the inter-
mediates (b), (c) and (e) would transform to compounds 2, 20
and 5 by controlling the addition of nitriles and the reaction
temperature.
Conclusions
In summary, we have described a simple and efficient method
for the synthesis of b-enaminonitriles, 4-aminopyrimidines and
4-amidinopyrimidines in a total of 72 samples by means of
condensation of organonitriles. The products can be obtained
gradually by simply controlling the reaction temperature and
the addition of nitrile substrates. The presence of various
products in one system indicates the exible and diversied
characteristics of nitriles as electron donor and/or electron
acceptor under base conditions. The extra reactivity and
stability were studied based on electronic effect, steric effect,
position of substituted groups and intermolecular hydrogen
bonding. The employment of easily available reagents and mild
reaction condition makes this method useful for synthesis
chemistry. This work is superior in simple reaction condition,
low-cost materials, broad substrate applicability and wide
adaptability of production. It might provide a clue to synthesize
various multi-substituted 4-aminopyrimidines and/or 4-amidi-
nopyrimidines in favour of the development of biological
chemistry, pharmaceutical chemistry and pesticide chemistry.
Experimental section
General information
Unless otherwise stated, the loading of starting materials were
completed in a glove box. The sealed Teon screw-cap tube
(50 mL) was moved out of glove box, and heated to react under
N2 atmosphere. All the liquid nitriles were distilled before use.
Other commercial-grade chemicals were used without further
purication. DME was distilled over Na and degassed before
use. Flash chromatography was performed on silica gel (200–
Fig. 2 Crystal structures of compounds 6a–6d (CCDC number:
1956324–1956327).
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300 mesh). The single crystal data of compounds were collected petroleum ether/acetone (4 : 1 v/v) to afford compound 6 in
by a Cu-Ka rotating anode source at 100 K, using a Supernova yields up to 86% (6a).
diffractometer with the u-scan method. ESI-MS were obtained
using a Bruker Impact II quardrupole time-of-ight mass
spectrometer. The 1H NMR and 13C NMR spectra were recorded Conflicts of interest
on Bruker Avance III (400 MHz) and chemical shis were
There are no conicts to declare.
expressed in d ppm values with reference to tetramethylsilane
(TMS) as internal standard. The NMR spectra were recorded in
solvent of CDCl3 (Safety Note: along with standard practice (eye
protection, fume hood, laboratory coat) the use of LiHMDS requires
Acknowledgements
no water, far away from the environment of re source and training
for the operator.).
This research was supported by the National Natural Science
Foundation of China (Grant No. 21371171) and the Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant No. XDB20000000).
General experimental procedures
Synthesis of compounds 2 or 3. Nitrile 1 (0.40 mmol) (1/10 ¼
0.20/0.20 mmol for 3), lithium bis(trimethylsilyl)-amide (0.20
mmol) and dried DME (1 mL) were mixed in a 50 mL Teon
Notes and references
screw-cap sealed tube. The tube was charged with N2 (1 atm)
and the mixture was vigorously stirred at 60–120 C for 24 h.
1 (a) A. W. Erian, Chem. Rev., 1993, 93, 1991–2005; (b)
S. Bondock, A. E. Tarhoni and A. A. Fadda, Curr. Org.
Chem., 2011, 15, 753–781.
ꢀ
Aer cooling to room temperature, the reaction mixture was
diluted with dichloromethane (20 mL), ltered through a pad of
silica gel and concentrated under reduced pressure. The crude
product was puried on a silica gel column eluted with petro-
leum ether/acetone (4 : 1 v/v) to afford b-enaminonitriles in
yields up to 90% (3c).
Synthesis of compounds 4. Phenylacetonitrile (0.20 mmol),
N,N0-diisopropylcarbodiimide (0.2 mmol), lithium bis(-
trimethylsilyl)amide (0.20 mmol) and dried THF (1 mL) were
mixed in a 50 mL Teon screw-cap sealed tube. The tube was
charged with N2 (1 atm) and the mixture was stirred at 60 ꢀC for
6 h. Aer cooling to room temperature, the reaction mixture was
diluted with dichloromethane (20 mL), ltered through a pad of
silica gel and concentrated under reduced pressure. The crude
product was puried on a silica gel column eluted with petro-
leum ether/acetone (4 : 1 v/v) to afford compound 4 in yields up
to 97% (4a).
2 (a) M. A. A. Radwan and M. El-Sherbiny, Bioorg. Med. Chem.,
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Synthesis of compounds 5. b-Enaminonitrile (0.20 mmol),
aromatic nitrile (0.2 mmol), lithium bis(trimethylsilyl)amide
(0.20 mmol) and dried DME (1 mL) were mixed in a 50 mL
Teon screw-cap sealed tube. The tube was charged with N2 (1
ꢀ
atm) and the mixture was stirred at 120–140 C for 24 h. Aer
cooling to room temperature, the reaction mixture was diluted
with dichloromethane (20 mL), ltered through a pad of silica
gel and concentrated under reduced pressure. The crude
product was puried on a silica gel column eluted with petro-
leum ether/acetone (4 : 1 v/v) to afford compound 5 in yields up
to 85% (5f).
Synthesis of compounds 6. 4-Aminopyrimidine (0.20 mmol),
aromatic nitrile (0.2 mmol), lithium bis(trimethylsilyl)amide
(0.20 mmol) and dried DME (1 mL) were mixed in a 50 mL
Teon screw-cap sealed tube. The tube was charged with N2
(1 atm) and the mixture was stirred at 140 ꢀC for 24 h. Aer
cooling to room temperature, the reaction mixture was diluted
with dichloromethane (20 mL), ltered through a pad of silica
gel and concentrated under reduced pressure. The crude
product was puried on a silica gel column eluted with
˜
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