Vinylogous Blaise Reaction: Conceptually New Synthesis of Pyridin-2-ones

Article abstract of DOI:10.1055/s-0037-1610171

A conceptually new synthesis of pyridine rings by a [C ₄ + CN] assembly has been developed by applying a vinylogous version of the classic Blaise reaction. The zinc-mediated reaction of (het)aryl or alkyl nitriles with ethyl-4-bromocrotonate pr

Full text of DOI:10.1055/s-0037-1610171

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
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A
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H. S. Rao et al.
Letter
Synlett
Vinylogous Blaise Reaction: Conceptually New Synthesis of
Pyridin-2-ones
H. Surya Prakash Rao*
Nandurka Muthanna
Ashiq Hussain Padder
1) Zn (2 equiv), TMSCl (3 mol%)
1,4-dioxane, reflux, 2–5 h
O
RCN
Br
R
N
H
O
OEt
2) 50% aq. K2CO3, rt,
30 min, 44–67%
R = Ar, benzyl, alkyl etc.
Vinylogous Blaise reaction
pyridine ring synthesis by [C4 + CN] assembly
Department of Chemistry, Pondicherry University,
Pondicherry-605 014, India
wide scope (12 examples) for C(6)-substituted pyridin-2-ones
FAcile synthesis of agomelatine (antidepressant) analogue
Received: 12.04.2018
Accepted after revision: 13.05.2018
Published online: 19.06.2018
and indolizidines.10 Although pyridin-2-ones are medici-
nally privileged,11 there are surprisingly few methods for
their direct synthesis.12
DOI: 10.1055/s-0037-1610171; Art ID: st-2018-v0222-l
Abstract A conceptually new synthesis of pyridine rings by a [C4 + CN]
assembly has been developed by applying a vinylogous version of the
classic Blaise reaction. The zinc-mediated reaction of (het)aryl or alkyl
nitriles with ethyl-4-bromocrotonate provided a variety of C(6)-substi-
tuted pyridin-2-ones in a single-step.
N
O
N
OH
H
1 (pyridin-2(1H)-one)
1 (pyridin-2-ol)
Me
OH
Et
O
O
Key words vinylogous Blaise reaction, pyridinones, pyridine ring
synthesis, zinc catalysis, bromoalkenoates
N
N
CN
O
O
N
N
O
Me
N
OH
The pyridine ring is a fundamental heterocycle1 that has
been known for over 170 years.2 The pyridine structural
element is present in many primary and secondary meta-
bolites, and such natural products play extremely import-
ant roles in biological processes.3 In the pyridine family,
pyridin-2(1H)-one (1) (or its tautomer, pyridin-2-ol)
(Figure 1) is a very important molecule, and its motif is well
represented as a structural unit among alkaloids, many of
which display useful biological activities.4 For example,
alkaloids with a pyridin-2-one motif (Figure 1) exhibit anti-
biotic or anticancer activities and can affect the central ner-
vous system.5 Camptothecin (2), an anticancer drug used
extensively in cancer treatment, is notable among natural
products having a pyridin-2-one motif (highlighted por-
tion).6 Some synthetic pyridin-2-ones, such as the antifun-
gal agent ciclopirox (3)7 and the vasodilator milrinone (4),
are useful drugs .8 Apart from their widespread use as drug
candidates, pyridin-2-ones have found use in technology-
driven applications in the fields of paints, pigments, fuels,
lubricants, acid–base indicators, polymers, and others.9 In
addition, pyridin-2-one derivatives have been used as inter-
mediates in the synthesis of six-membered nitrogen
heterocycles such as pyridines, piperidines, quinolizidines,
H
2 camptothecin
(anticancer)
3 ciclopirox
(antifungal)
4 milrinone
(vasodilator)
Figure 1 Structures of pyridin-2(1H)-one and its tautomer (1) and of
some natural (2) and synthetic drugs (3 and 4) containing a pyridin-2-
one motif
There are many reports on pyridine ring synthesis in
the literature.13 Among them, some have become familiar
named reactions, including the Kröhnke [C5 + N],14 Guareschi–
Thorpe [C3 + C2 + N],15 Hantzsch [C3 + C2 + N],16 Chichibabin
[C3 + C2 + N],17 and Petrenko–Kritschenko [C3 + C2 + N]18 re-
actions (Scheme 1). We have designed a conceptually new
method in which the C5N unit of the pyridin-2-one ring is
assembled through a [C4 + CN] strategy (Scheme1; Present
Work).
Recently, our group focused on the expansion of the
scope of the classical Blaise reaction. Fundamentally, the
Blaise reaction is a Zn-mediated transformation of alkyl or
aryl nitriles 5 into β-keto esters 7 by reaction with ethyl
bromoacetate (6) (Scheme 2; Equation 1).19 Because β-keto
esters provide an enormous range of opportunities for the
synthesis of a wide variety of heterocyclic compounds, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
H. S. Rao et al.
Letter
Synlett
further expanded the scope of the Blaise reaction by em-
ploying ethyl 4-bromocrotonate (12) instead of ethyl bromo-
acetate in the reaction with alkyl or aryl nitriles 5 to give
pyridin-2-ones 13. We refer to this variation as the vinylo-
gous Blaise reaction. In our pyridine-ring synthesis, four
carbon atoms originate from the 4-bromocrotonate 12 and
one carbon atom and one nitrogen atom come from the
nitrile. This is the first report of a one-step pyridine-ring
synthesis in [C4 + CN] fashion.
R
CHO
EtOOC
COOEt
Me
O
O
CHO
NH3
Me
Me
Hantzsch
[C2+C+C2+N]
H
H
O
O
O
O
CN
OH
NH3
Chichibabin
[C2+C+C2+N]
H2N
Guareschi-Thorpe
[C3+C2N]
To arrive at appropriate reaction conditions for effecting
the vinylogous Blaise reaction of ethyl 4-bromocrotonate
(12) with nitriles 5, we selected benzonitrile (5a) as a mod-
el substrate (Scheme 3). Initially, we adopted the reaction
conditions that we previously developed for the Blaise reac-
tion between nitriles and ethyl bromoacetate.22 The reac-
tion between benzonitrile (5a; 1 mmol) and ethyl 4-bromo-
crotonate (12; 2 equiv) in the presence of a catalytic
amount of trimethylsilyl chloride (TMSCl; 3 mol%) and two
equivalents of Zn in 4 mL of THF at the reflux for ten hours,
followed by hydrolysis with 3 N HCl gave 6-phenylpyridin-
2(1H)-one (13a) in 30% yield. There was no trace of the ini-
tially formed open-chain Blaise product 14. By changing
solvent from THF (bp 67 °C) to higher-boiling 1,4-dioxane
(bp 101 °C), the yield of the pyridin-2-one 13a was in-
creased to 52%.23 Replacing the acidic hydrolysis with basic
hydrolysis with 50% aq K2CO3 further increased the yield to
62%. Before, settling on 1,4-dioxane as the solvent, we
screened a few ethereal solvents such as tert-butyl methyl
ether (bp = 55 °C), dimethoxyethane (bp = 85 °C), and cyclo-
pentyl methyl ether (bp = 106 °C), but in all the cases, for
inexplicable reasons, the reaction did not proceed and
N
Krohnke
[C5+N]
Petrenko-Kritschenko
[C+C3+C+N]
O
EtOOC
COOEt
OHC
OHC
CHO
R
CHO
R
Br
NH3
NH3
COOEt
R
N
Present work
[C4+CN]
Scheme 1 Well-known methods and the present concept for the
construction of pyridine rings
Blaise reaction has recently found its rightful place in main-
stream synthetic organic chemistry. We found that by em-
ploying α-bromo ketones 8 instead of α-bromo esters, the
reaction provides extremely useful 1,3-diketones
9
(Scheme 2; Equation 2).20 In continuation of that work, we
found that when acyl nitriles 10 are employed instead of
alkyl or aryl nitriles, the reaction provides 3,5-diketo esters
11 (Scheme 2; Equation 3).21 In the present work, we have
Zn
O
RCN
BrCH2COOEt
Blaise 1901; Ref. 19 - equation 1
CO2Et
R
5
6
7
O
O
Zn
Zn
Rao and Muthanna 2015;
Ref. 20 - equation 2
R1CN
BrCH2COR2
R1
R2
5
8
9
O
O
Rao and Muthanna 2016;
Ref. 21 - equation 3
BrCH2COOEt
RCOCH2CN
CO2Et
R
10
6
11
Zn
Br
CO2Et
RCN
Present work - equation 4
R
N
H
O
5
12
13
Scheme 2 The Blaise reaction and its variants
(i) Zn (2 equiv), TMSCl (3 mol%)
1,4-dioxane, 100 °C
NH2
Br
CO2Et
PhCN
CO2Et
Ph
N
H
O
(ii) 50% aq. K2CO3, 0 °C to rt
30 min, 62%
Ph
5a
12
13a
14
Scheme 3 Synthesis of 6-phenylpyridin-2(1H)-one (13a) from benzonitrile (5a) and ethyl 4-bromocrotonate (12)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
H. S. Rao et al.
Letter
Synlett
benzonitrile remained unaltered even after 24 hours at the
reflux. We conducted a reaction in a 9:1 mixture of 1,4-di-
oxane and DMF, reasoning that the DMF might provide a
polar aprotic environment for the solvated zinc ions, but
there was no improvement in the yield of the pyridine 13a.
Next, we varied the molar ratio of ethyl 4-bromocrotonate
(12), Zn dust, and TMSCl to arrive at best reaction condi-
tions. In summary, we found that for the conversion of 1
mmol of benzonitrile, the reaction required one equivalent
of ethyl 4-bromocrotonate, two equivalents of Zn powder, 3
mol% of TMSCl (zinc activator), and 4 mL of dry 1,4-dioxane.
The product, 6-phenylpyridin-2(1H)-one (13a) was isolated
as a light-yellow solid (mp 194–195 °C)24 and was charac-
terized by means of IR and NMR spectroscopy.25
This simple, single-step, straightforward conversion of
benzonitrile into 6-phenylpyridin-2(1H)-one proved to be
general for a variety of nitriles. We employed a range of
aromatic (5a–e), heteroaromatic (5f–h), benzylic (5i–j), ali-
phatic (5k), and sterically hindered (5l) nitriles (Table 1),
which, on treatment with ethyl 4-bromocrotonate (12),
were converted into the corresponding pyridin-2-ones
13a–l in good yields (Table 1). The benzonitriles 5 included
those with various substituents at the C(4) position, such as
a strongly electron-withdrawing trifluoromethyl (5b; Table
1, entry 2), moderately electron-withdrawing but ortho–
para directing chloro (5c; entry 3), electron-donating methyl
(5d; entry 4), and strongly electron-donating methoxy (5e;
entry 5) groups. Each of these benzonitriles, when treated
with ethyl 4-bromocrotonate (12), provided the corre-
sponding pyridine 13a–e without much variation in the
yield, indicating that the rate-determining step does not in-
volve nucleophilic attack of the Reformatsky reagent on the
nitrile. The transformation of 4-(trifluoromethyl)benzoni-
trile (5b) into the corresponding pyridin-2-one 13b, how-
ever, gave the best yield (67%). The heteroaromatic nitriles
2-furonitrile (5f; entry 6), thiophene-2-carbonitrile (5g;
entry 7), and N-tosyl-1H-indol-3-carbonitrile (5h; entry 8)
underwent the one-step transformation to provide good
yields of the corresponding pyridin-2-ones 13f–h. Further-
more, phenylacetonitrile (5i; entry 9) and (4-fluoro-
phenyl)acetonitrile (5j; entry 10) provided satisfactory
yields of corresponding pyridines 13i and 13j, both of
which incorporate a central-nervous-system-active aryl-
ethylamine motif. The aliphatic nitrile butyronitrile (5k
entry 11) underwent the transformation to provide the
pyridin-2-one 13k indicating that large variations in the
C(6)-substituted aliphatic chain are possible in the present
method. The reaction of sterically hindered diphenylaceto-
nitrile (5l) with 12 provided pyridine 13l, albeit with a
reduced yield (entry 12). Finally nitrile 5m, which is a pre-
cursor to agomelatine 15 (a melatonergic antidepressant)26
reacted with ethyl 4-bromocrotonate (12) and zinc to fur-
nish the pyridin-2-one 13m (entry 13); this product incor-
porates pharmacophore features of agomelatine (15) and
might, therefore, emerge as a useful drug for the treatment
of depression.
The structures of the C(6)-substituted pyridin-2-ones
13a–m prepared in this study and that of agomelatine {N-
[2-(7-methoxy-1-naphthyl)ethyl]acetamide} (15) are given
in Table 1 of the Supplementary Information.
Table 1 Vinylogous Blaise Method for the Synthesis of C(6)-Substituted
Pyridin-2-ones 13a–i
To explain the formation of the pyridin-2-ones 13, we
propose the mechanism shown in Scheme 4. Initially, Zn
inserts into the C–Br bond of 12 to form an organozinc
intermediate 18. This intermediate is in equilibrium with
the zinc enolate 19. Intermediates 18 and 19 possess
nucleophilic C(2) and C(4) carbons. In the cases of nitriles 5,
the reaction takes place at the C(4) position to provide the
push–pull diene 14 (γ-addition). Further cyclization of 14
via the intermediate 20 with concomitant loss of ethanol
provided the C(6)-substituted pyridin-2-one 13. On the
other hand, the reaction of 19 with highly reactive 4-cyano-
pyridine 5p takes place at C(2) to provide 17 (α-addition).
In a related vinylogous Reformatsky reaction, Hudlicky and
co-workers isolated diene products similar to 17, and pro-
posed a similar mechanism.27
Although, the vinylogous Blaise reaction was successful
in many cases, there were a few failures, as noted below.
Attempts at the conversion of pyridine-2-, -3-, or -4-carbo-
nitriles (5n–p) into corresponding pyridin-2-ones were un-
successful (Scheme 5). The zinc-mediated reaction of ethyl
4-bromocrotonate (12) with pyridine-2-carbonitrile (5n)
gave pyridine-2-carbamide (16) as the sole product, gener-
ated by partial hydrolysis of the nitrile functional group.
The reaction of pyridine-3-carbonitrile (5o) did not
1) Zn (2 equiv), TMSCl (3 mol%)
1,4-dioxane, reflux, 2–5 h
O
RCN
Br
R
N
H
O
2) 50% aq. K2CO3, rt,
30 min, 44–67%
OEt
5a–l
12
13a–l
Entry
Nitrile
R
Time (h) Product
Yield (%)
1
2
5a
5b
5c
5d
5e
5f
Ph
4
4
5
5
5
2
2
5
5
4
5
5
5
13a
13b
13c
13d
13e
13f
62
67
58
61
60
54
64
60
57
64
54
44
47
4-F3CC6H4
4-ClC6H4
4-Tol
3
4
5
4-MeOC6H4
2-furyl
6
7
5g
5h
5i
2-thienyl
N-tosylindol-3-yl
Bn
13g
13h
13i
8
9
10
11
12
13
5j
CH2-4-FC6H4
Pr
13j
5k
5l
13k
13l
CHPh2
5m
(7-methoxy-2-naph-
thyl)methyl
13m
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
H. S. Rao et al.
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Synlett
proceed, even after 12 hours at the reflux. With pyridine-4-
carbonitrile (5p) the reaction provided the diene 17 as the
sole product. We reason that in the reaction of 5p, conden-
sation of the organozinc intermediate is thermodynamical-
ly controlled and proceeds through reaction at the α-car-
bon of the zinc alkoxide instead of the γ-carbon, as seen in
other cases.
In conclusion, we have discovered and elaborated a new
method for the synthesis of pyridin-2-ones by employing
the vinylogous Blaise reaction.28 The method constitutes a
new pyridine-ring synthesis through a [C4 + CN] assembly.
The vinylogous Blaise reaction with ethyl bromobut-2-
enoate on a variety of nitriles furnished C(6)-substituted
pyridin-2-ones. We expect to be able to expand the scope of
this reaction by using various substituted 4-bromocroton-
ates for the syntheses of polysubstituted pyridin-2-ones.
Central Instrumentation Facility (CIF) and Department of Chemistry
for the instrumentation facilities.
)(
Supporting Information
Detailed experimental procedures and spectra of the pyridin-2-ones
13a-m made in this study are given in the supplementary material
available online at https://doi.org/10.1055/s-0037-1610171.
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References
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ZnBr
O
γ-addition
O
O
Zn(0)
OZnBr
OEt
OEt
Br
BrZn
OEt
OEt
R
N
N
α-addition
18
12
19
R1
γ-addition
α-addition
NHZnBr
CO2Et
– EtOZnBr
NHZnBr
R
CO2Et
NH2
R
N
O
CO2Et
R
H
R
13
20
14
17
Scheme 4 Plausible mechanism for the formation of pyridin-2-ones and highly substituted 1,3-dienes
CN
5n
N
NH2
N
6 h; (ii) 50% aq. K2CO3, 52%
O
16
CN
(i) Zn (2 equiv)
TMSCl (3 mol%)
5o
N
Br
CO2Et
No reaction
CO2Et
1,4-dioxane
reflux
12 h; (ii) 50% aq. K2CO3
12
CH2
H2N
N
CN
5p
1 h; (ii) 50% aq. K2CO3, 74%
N
17
Scheme 5 Reactions of pyridine nitriles with ethyl 4-bromocrotonate
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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H. S. Rao et al.
Letter
Synlett
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A solution of TMSCl (3 mol%) in anhyd 1,4-dioxane (1 mL) was
added to a suspension of Zn dust (2 equiv) in anhyd 1,4-dioxane
(3 mL), and the resulting suspension was refluxed with vigorous
stirring for 25 min. The appropriate nitrile (2 mmol) in dry 1,4-
dioxane (1 mL) and ethyl (E)-4-bromobut-2-enoate (12; 2
equiv) in dry 1,4-dioxane (1 mL) were simultaneously added
dropwise to the refluxing suspension during 10 min by using
two syringes. The resulting light-green mixture was refluxed
until all the starting material was consumed and the color
changed to brown (TLC; 3–6 h). The mixture was cooled to r.t.
then centrifuged (700 rpm). The upper solution was decanted
and the remaining solid was washed with 1,4-dioxane (4 × 1
mL). The 1,4-dioxane solutions were combined and concen-
trated to about 1 mL under reduced pressure in a rotatory evap-
orator. The residue was treated with 50% aq K2CO3 until the pH
reached 13 (~5 mL). The resulting mixture was stirred for 30
min at r.t. (30 °C) then diluted with CH2Cl2 (10 mL) and H2O (10
mL). The organic layer was separated, washed sequentially with
H2O (2 × 10 mL) and brine (10 mL), dried (Na2SO4), and evapo-
rated under reduced pressure to give a crude product that was
purified by column chromatography [silica gel (100–200 mesh);
15–60% EtOAc–hexane].
6-Phenylpyridin-2(1H)-one (13a)
By following the general procedure, the reaction of PhCN (5a;
201 mg, 1.94 mmol) with crotonate 12 (374 mg, 1.94 mmol) in
the presence of Zn (252 mg, 3.88 mmol) and TMSCl (7 mg, 3 mol
%) in 1,4-dioxane (6 mL) for 4 h, followed by hydrolysis with 50%
aq K2CO3 (5 mL) gave a light-yellow solid; yield: 205 mg (62%);
mp 194–195 °C; Rf = 0.5 (hexanes–EtOAc, 2:1).
IR (KBr): 2904, 1643, 1612, 1550, 1493, 990, 921, 795, 761 cm–1
.
(20) Rao, H. S. P.; Muthanna, N. Eur. J. Org. Chem. 2015, 1525.
(21) Rao, H. S. P.; Muthanna, N. Synlett. 2016, 27, 2014.
(22) Rao, H. S. P.; Rafi, S.; Padmavathy, K. Lett. Org. Chem. 2008, 5,
527.
1H NMR (400 MHz, CDCl3): δ = 12.49 (br s, 1 H), 7.72 (d, J = 6.9
Hz, 2 H), 7.59–7.40 (m, 4 H), 6.55–6.47 (m, 2 H). 13C NMR (100
MHz, CDCl3): δ = 165.4, 147.1, 141.5, 133.6, 130.1, 129.2, 126.8,
118.7, 105.0. HRMS (ESI): m/z [M + H] calcd for C11H9NO:
172.0762; found: 172.0750.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E