KOtBu-mediated annulation of acetonitrile with aldehyde: Synthesis of substituted dihydropyridin-2(1H)-ones, pyridin-2(1H)-ones, and thiopyridin-2(1H)-ones

Article abstract of DOI:10.1039/c5cc02964c

The KO^tBu-mediated annulation of acetonitrile with aldehyde was observed, in which the cleavage of four C(sp³)-H bonds occurred and a total of eight new bonds were formed during the synthesis of substituted dihydropyridinones in the

Full text of DOI:10.1039/c5cc02964c

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DOI: 10.1039/C5CC02964C
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KOtBu-Mediated annulation of acetonitrile with aldehyde:
synthesis of substituted dihydropyridin-2(1H)-ones, pyridin-2(1H)-
ones, and thiopyridin-2(1H)-ones
Received 00th January 20xx,
Accepted 00th January 20xx
Abhimanyu Yadav, Ajay Verma, Saket Patel, Amit Kumar, Vandana Rathore, Meenakshi, Shailesh
Kumar and Sangit Kumar*
DOI: 10.1039/x0xx00000x
www.rsc.org/
KOtBu-Mediated annulation of acetonitrile with aldehyde was catalysed by N-heterocyclic carbene.10 Nonetheless, these
observed in which cleavage of four C(sp3)-H bonds occurred, and methods required prefunctionalized substrates to obtain
Scheme 1. Synthesis of dihydropyridin-2(1H)-ones
total eight new bonds formed during the synthesis of substituted
dihydropyridinones in the presence of peroxide. Furthermore,
dihydropyridinones have been transformed into pyridinones
utilizing KOtBu in DMSO.
Annulation by the condensation of readily available substrates,
in which formation of several new bonds occurred by the
coupling of C-H bonds in a single pot, is as an attractive
approach for the preparation of heterocycles.1 This strategy
avoids prefunctionalized coupling partners, particularly,
halogenated substrates, generates H2O as waste, and expands
the substrate scope.
Heterocycles,
particularly,
N-containing
such
as
dihydropyridin-2(1H)-ones,
pyridin-2(1H)-ones,
and
dihydropyridin-2(1H)-ones
and
pyridin-2(1H)-ones.
substituted pyridines are privilege structures with various
biological and medicinal properties.2,3 Dihydropyridin-2(1H)-
one analogues are being used as hypertensive drugs for the
blockage of calcium channel, for the treatment of diabetes,
obesity, and neuropeptide.3 Also dihydropyridin-2(1H)-one
core is present in the natural products such as
homoclausenamide, batzelladine, and carambine alkaloids
which possess HIV-gp-120CD4 inhibition and selective α1a
receptor antagonists activities.4
Prefunctionalized substrates such as α,β-unsaturated acyl
chloride, esters, sodium cyanomethanide, and β-aminonitrile
are either expensive or difficult to handle. The use of
prefunctionalized substrates in the coupling reactions restricts
the substrate scope because of difficulty in their synthesis and
also due to their incompatibility with another coupling partner.
TM-free KOtBu-mediated C-C and C-X coupling reactions have
been studied between C-H and C-X (X, halogens) bonds, and
cross coupling between two C-H bonds by us and others.14-17
Here; we present a KOtBu base mediated coupling reaction
between aldehyde and acetonitrile for the synthesis of
In view of their biological importance, several synthetic
methods have been presented in the literatures (eq 1, Scheme
1).5-13 The coupling of α,β-unsaturated acid chloride and ester
with enaminonitrile and sodium cyanomethanide, respectively,
have been studied for the synthesis of dihydropyridinones.5-
dihydropyridin-2(1H)-ones
without
employing
prefunctionalized substrates (eq 2). In this coupling reaction,
cleavage of four sp3-C-H bonds was observed, and total eight
new bonds formed. Furthermore, synthesized dihydropyridin-
2(1H)-ones have been oxidized into pyridin-2(1H)-ones using
novel approach KOtBu in DMSO.
8,11,12
Bode et al. and Biju et al. have synthesized
dihydropyridinones enantioselectively by the coupling of α,β-
unsaturated aldehydes with various imine derivatives
After screening of various bases and additives for the coupling
o
of acetonitrile with the aldehyde at 110 C in a sealed tube
a.Department of Chemistry, Indian Institute of Science Education and Research
(IISER) Bhopal, Indore By-pass Road, Bhauri, Bhopal, Madhya Pradesh, India-462
066. E-mail: sangitkumar@iiserb.ac.in
(see SI, page S2-S4 for optimization), we chose one mmol of
aldehyde, four mmol of KOtBu base and one mmol of aq. H2O2
in the excess of CH3CN (four mL) for the preparation of
dihydropyridin-2(1H)-ones. The results are summarized in
† Electronic Supplementary Information (ESI) available: [experimental procedure,
spectra, crystal data CCDC No. 1038678 (
1), 1038680 (5), 1057417 (16), 1057418
(
41), 1038679 (42)]. See DOI: 10.1039/x0xx00000x
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were reported with respect to aryl aldehyde. a Heated at 130 oC
Scheme 2. Dihydropyridin-2(1H)-one
yield by the condensation of benzaldehyde with acetonitrile.
Scheme 2. Substrate scope with regard to aromatic aldehydes
1 was obtained in 70%
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DOI: 10.1039/C5CC02964C
The formation of 4-phenyl-pyridine
2
was also observed as a
minor product and could only be confirmed by mass analysis
(See, SI page S3). After synthesis of , halogen substituted
1
benzaldehyde were subjected to the coupling reaction. Fluoro,
difluoro, chloro, bromo and even iodo are well tolerated under
the optimized reaction conditions and halogen substituted
4 (55)
3 (56)
6 (65)
5 67)
dihydropyridin-2(1H)-ones 2-7 were obtained in 55-67% yields.
Electron donating substituents such as CH3, mono, di, and tri-
OCH3, SCH3, N(CH3)2 on benzaldehyde have also shown the
compatibility under the reaction conditions and produced
respective dihydropyridin-2(1H)-ones 9-17 in 48-70% yields.
Interestingly, benzaldehyde containing acidic OH proton also
reacted with acetonitrile and formed hydroxy substituted
8 (65)
7 (67)
dihydropyridin-2(1H)-ones 18-24. Various other aromatic
aldehydes such as naphthyl, furanyl, thiophenyl, pyridyl
aldehydes also underwent coupling reaction with acetonitrile
to provide the naphthyl, heteroaryl dihydropyridin-2(1H)-ones
10 (63)
9 (62)
11 (50)
25-32 in 37-65% yields.
Scheme 3. Substrate scope with regards to alkyl aldehydes
13 (50)
16 (55)
12 (55)
14 (48)
17 (70)
37
33 R, Me (67)
34 R, Et (50)
35 n = 2 (37)
36 n = 3 (30)
(35)
15 (50)
18 (65)
40 (50)
38 (30)
39 (66)
20 (66)
19 (60)
Next alkyl aldehydes were subjected to the coupling reaction
with the acetonitrile (Scheme 3). Indeed, alkyl aldehydes
provided 4-alkyl substituted such as methyl, n-butyl, n-decyl,
iso-propyl, and cyclohexyl dihydropyridin-2(1H)-ones 33-40 in
moderate yields, though, high temperature (130 oC) is required
to accomplish the annulation (please see SI page S18).
2
1 (60)
22 (50)
25 (37)
23 (60)
26 (34)
Fig. 1. Crystal structures of dihydro and pyridin-2(1H)-ones 5 and 42
24 (37)a
Heteroaromatics
28 (43)
31 (50)
27 (45)
29 (38)
32 (55)
30 (65)
Reaction was carried by heating aldehyde (1 mmol), KOtBu (4 mmol), and H2O2 (1
mmol, 30% aq. Solution), and CH3CN (4 mL) in a sealed tube at 110 oC. Yields
Synthesized dihydro and pyridin-2(1H)-ones 1, 5, 16 and 42
were also characterized by single crystal X-ray structure study
(Fig. 1, for details see SI, pages S32-S77).18
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Scheme 6. Control reactions with CD3CN and with 2-alkene aldehyde
Under the optimized conditions, when ferrocene aldehyde was
subjected for coupling with acetonitrile, 4-ferrocene
substituted pyridine 41 was obtained in 76% yield instead of
expected ferrocenyl dihydropyridin-2(1H)-one (Scheme 4).
Structure of 41 is established by single crystal X-ray study.
View Article Online
DOI: 10.1039/C5CC02964C
Scheme 4. Synthesis of 4-ferrocenyl pyridine under optimized conditions
was also observed and could be rationalized by mechanistic
understanding (vide infra). When reaction was performed on
(E/Z)-but-2-enal substrate under the optimized conditions,
dihydropyridin-2(1H)-one 33 was obtained, which also formed
by the reaction of acetaldehyde with acetonitrile (Scheme 3,
vide supra).
Further utilities of synthesized dihydropyridin-2(1H)-ones were
explored (Scheme 5). Addition of KOtBu to dihydropyridin-
2(1H)-ones in DMSO provided selective oxidation of C-H bonds
leading to pyridin-2(1H)-ones 42-47 in 35-80% yields. It seems
DMSO not only acts as a solvent but also oxidizing agent.
Oxidation of dihydropyridin-2(1H)-ones into pyridin-2(1H)-
ones could not be achieved in acetonitrile even in the
presence of excess KOtBu and oxidant H2O2 and excess of
KOtBu led to self-coupling of acetonitrile (see SI page S29).
Scheme 7. Proposed mechanism for the coupling of CH3CN20
Scheme 5. Conversion dihydropyridin-2(1H)-ones into pyridin-2(1H)-ones
and thio analogues
In the tentative mechanism (Scheme 7), deprotonation of
acetonitrile in the presence of KOtBu would led to
cyanomethanide which adds to the second molecule of CH3CN
forming (1-cyanopropan-2-ylidene)amide I 21
This may form
.
carbanion II via proton transfer, which then adds to aldehyde
followed by H2O removal, would give (3-cyanobut-3-en-2-
ylidene)amide III. This may react with the third CH3CN
molecule to generate intermediate IV which may convert into
Next, synthesized 3,4-dihydropyridin-2(1H)-ones were
transformed into dihydropyridine-2(1H)-thiones (Scheme 5)
which exhibit vasodilator, cardiotonic, and antitumor biological
activities and also show enriched coordination chemistry as
carbanion
carbanion
V
V
by 1,3-proton transfer. Intramolecular attack of
to the benzylic carbon would furnish the cyclized
carbanion VI. This cyclized carbanion VI would undergo
resonance forming VII. Intermediate VII may be hydrolized to
ligands.8,19
Dihydropyridine-2(1H)-thiones
Lawesson’s reagent to the dihydropyridine-2(1H)-thiones gave
respective thio analogues 48 50 in 87-90% yields.
Addition
of
yield 3,4-dihydropyridin-2(1H)-one
H2O2 is not known in the reaction, however, formation of
ammonia and better yield of was observed in the presence of
1. Although, exact role of
-
1
Next, deutrated acetonitrile was reacted with the
benzaldehyde to gain mechanistic insight (Scheme 6). The
obtained heterocycle 51 shows incorporation of five
deuterium atoms as studied by mass spectrometry.
H2O2. This suggests that H2O2 facilitate the hydrolysis of NH
into C=O group.
In summary, we have shown that substituted dihydropyridin-
2(1H)-ones, can be synthesized from simple aldehyde and
Deuterium-hydrogen exchange at first and sixth position of
3
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acetonitrile employing KOtBu base without using
prefunctionalized substrates. A wide range of aldehydes,
including aliphatic, diversely substituted aromatic including
naphthalenes and heteroaromatics such as thiophenes,
pyridines, and furan coupled with the three molecules of
acetonitrile. Moreover, dihydropyridin-2(1H)-ones has been
oxidized into pyridin-2(1H)-ones by novel method using KOtBu
in DMSO. Currently, we are exploring the scope of the coupling
reaction, particularly, for the synthesis of substituted
pyridines, from readily available substrates utilizing KOtBu
base.
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Bhakuni, C. D. Prasad, S. Kumar and S. Kumar, Tetrahedron,
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We thank IISER Bhopal, DST and DRDO New Delhi for generous
funding. AY, AV, VR thank CSIR-UGC New Delhi, AK
acknowledges CSIR New Delhi, SP and Meenakshi grateful to
DRDO for fellowships.
and S. Kumar, Org. Lett., 2015, 17, 82.
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