β-Chlorocinnamonitriles in a new synthesis of 3-functionally substituted 6-amino-1,2-dihydropyridin-2-ones

Article abstract of DOI:10.1080/00397910801997777

β-Chlorocinnamonitriles react with methylene-active compounds containing N-substituted carboxamide group in DMSO solution in the presence of potassium hydroxide, forming 3-functionally substituted 1,2-dihydropyridin-2- ones. Copyright Taylor & Francis Group, LLC.

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β-Chlorocinnamonitriles
in a New Synthesis of 3-
Functionally Substituted 6-
amino-1,2-Dihydropyridin-2-
ones
Sergii A. Trofymchuk a , Andrij O. Tolmachov a
,
Kostàntyn M. Kondratyuk a , Yulian M. Volovenko a
Pavlo S. Lebed b & Mykhaylo V. Vovk b
,
a National Taras Shevchenko University, Kyiv, Ukraine
b Institute of Organic Chemistry, National Academy
of Sciences of Ukraine, Kyiv, Ukraine
Version of record first published: 12 Jun 2008
To cite this article: Sergii A. Trofymchuk, Andrij O. Tolmachov, Kostàntyn M.
Kondratyuk, Yulian M. Volovenko, Pavlo S. Lebed & Mykhaylo V. Vovk (2008): β-
Chlorocinnamonitriles in a New Synthesis of 3-Functionally Substituted 6-amino-1,2-
Dihydropyridin-2-ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:12, 1984-1989
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Synthetic Communications1, 38: 1984–1989, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801997777
b-Chlorocinnamonitriles in a New Synthesis of
3-Functionally Substituted 6-Amino-
1,2-dihydropyridin-2-ones
Sergii A. Trofymchuk,1 Andrij O. Tolmachov,1
1
Kostantyn M. Kondratyuk, Yulian M. Volovenko,
1
`
Pavlo S. Lebed,2 and Mykhaylo V. Vovk2
1National Taras Shevchenko University, Kyiv, Ukraine
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Kyiv, Ukraine
Abstract: b-Chlorocinnamonitriles react with methylene-active compounds
containing N-substituted carboxamide group in DMSO solution in the presence of
potassium hydroxide, forming 3-functionally substituted 1,2-dihydropyridin-2-ones.
Keywords: Anilides of malonic and acetoacetic acids; b-chlorocinnamonitriles;
3-functionally substituted 1,2-dihydropyridin-2-ones; N-monosubstituted cya-
noacetamides
b-Chlorocinnamonitriles, easily available by a one-pot procedure starting
from acetophenones,[1,2] are convenient electrophilic reagents for obtain-
ing various five-membered heterocyclic systems. In particular, their cyclo-
condensations with esters of a-mercaptoacetic acid are widely used for the
effective synthesis of 3-amino-2-thiophenecarboxylic acid derivatives,[3–7]
reactions with hydrazine afford 3-aminopyrazoles,[8] and interaction with
sodium hydrosulfite gives 3-aminoisothiazoles.[9] At the same time, utiliza-
tion of mentioned reagents for obtaining six-membered heterocycles (for
instance, highly functionalized aminopyridines) remains unexplored.
Meanwhile, compounds of 6-amino-1,2-dihydropyrimidin-2-one series
Received in the U. K. June 26, 2007
Address correspondence to Sergii A. Trofymchuk, National Taras Shevchenko
University, Volodymyrska str. 64, 01033, Kyiv, Ukraine. E-mail: trofimchuk_s@
ukr.net
1984

b-Chlorocinnamonitriles
1985
exhibit high pharmacological activity[10] and are valuable precursors for
azo-dyes synthesis.[11]
It is also important to note that the presence of an enamine fragment
in their structure (absence of a substituent in the C-5 position within the
pyridine ring together with an amino group in the C-6 position) gives a
chance to use them for obtaining annulated heterocyclic systems.
In the literature, there is only one method of direct formation of a
1,2-dihydropyridin-2-one cycle containing an amino group at the 6-
position and electron-withdrawing CꢀN group at the 3-position, based
on condensation of S,N-ketene acetals with cyanoacetate.[12] Other meth-
ods for synthesis of such types of compounds are multistep and include
amination of primarily formed 6-chloropyridin-2-ones[10,13,14] or scission
of 6-cyano-1,8-naphthyridin-7-ones upon action of secondary amines.[15]
The approach proposed by us profitably differs from that described
previously, and we propose a new synthetic methodology based on cyclo-
condensation of b-chlorocinnamonitriles 1a–c with methylene-active
compounds containing an N-substituted carboxamide group, that is,
N-monosubstituted cyanoacetamides 2a–c, anilide ester 2d and dianilide
2e of malonic acid, and acetoacetic acid anilide 2f. It is demonstrated that
in the presence of potassium hydroxide the reaction between 1a–c and
2a–f proceeds in dimethyl sulfoxide (DMSO) solution at room tempera-
ture and leads to the formation of target 3-functionally substituted 1,2-
dihydropyridin-2-ones 3a–l in 50–76% yields (Scheme 1).
Taking into consideration the experimental conditions found, it may
be assumed that interaction of reagents 1a–c and 2a–f is realized via the
stage of formation of primary C-alkenylation products A, which then
undergo intramolecular cyclization into the products 3a–l.
The structure of synthesized compounds is confirmed by results of
1
chromatography mass analysis, H NMR, and IR spectra. It should be
Scheme 1. Reaction between b-chlorocin namonitriles 1a-c and methylene-active
compounds containing an N-substituted carboxamide group 2a-f.

1986
S. A. Trofymchuk et al.
Table 1. Physical properties of 3-functionally substituted 1,2-dihydropyridin-2-
ones 3a-l prepared
Entry
R
Ar
X
Yield (%)
Mp (ꢂC)
a
b
c
d
e
f
g
h
i
Me
Me
Me
Ph
Ph
Ph
4-ClC6H4
4-MeOC6H4
4-PhC6H4
4-ClC6H4
4-MeOC6H4
4-PhC6H4
4-ClC6H4
4-MeOC6H4
4-PhC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
CN
CN
CN
CN
CN
CN
CN
CN
65
62
61
60
51
66
67
56
66
59
72
75
221–222
270–272
310–311
>310
>310
>310
>310
>310
>310
282–284
281–283
>310
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
4-ClC6H4
Ph
CN
j
k
l
MeC(O)
EtOC(O)
PhNHC(O)
Ph
1
noted that in H NMR spectra, singlets of C5-H pyridine cycle protons
observed in the range of 5.43–5.7 ppm are distinctive. Yields and melting
points of synthesized compounds are shown in Table 1.
In conclusion, we showed a possibility of using b-chlorocinnamoni-
triles for the convenient preparative synthesis of 3-functionally substituted
1,2-dihydropyridin-2-ones.
EXPERIMENTAL
Melting points were measured with Tomas Hoover apparatus and are
uncorrected. IR spectra were recorded on a Nexus-470 spectrophot-
1
ometer in KBr tablets. H NMR spectra were registered in D6-DMSO
on a Brucker-400 instrument with TMS as an internal standard.
Starting compounds were synthesized according to reported proce-
dures: 1a–c,[2] 2a,[16] 2b,[17] 2c,[18] 2d,[19] 2e,[20] and 2f [21]
.
6-Amino-3-R-1,2-dihydropyridin-2-ones 3a–l: General Procedure
To a mixture of b-chlorocinnamonitrile 1 (0.02 mol) and amide 2
(0.02 mol) in 15 mL of freshly distilled DMSO, the solution of KOH
(2.3 g, 0.041 mol) in 5 mL of water was added dropwise with intensive
stirring and cooling with ice water. The reaction mixture was stirred
for 1 h, left for 24 h, and then poured onto water (100 mL). The pre-
cipitate formed was filtered, washed with water (50 ꢁ 3 mL), dried, and

b-Chlorocinnamonitriles
1987
recrystallized from acetic acid (compounds 3a–c, f–i, k), DMF (com-
pounds 3d, e, l), or MeOH (compound 3j).
Data
1
=
Compound 3a. IR: 1713 (C O), 2220 (CꢀN), 3450 (NH2). H NMR d 3.39
(s, 3H, CH3), 5.61 (s, 1H, C5ꢃH), 7.63 (d, 2HAr, J ¼ 7.6 Hz), 7.78 (d, 2HAr
,
J ¼ 7.8 Hz), 7.84 (s, 2H, NH2). Anal. calculated for C13H10ClN3O: C,
60.13; H, 3.88; N, 16.18. Found: C, 60.25; H, 3.80; N, 16.02.
1
=
Compound 3b. IR: 1715 (C O), 2200 (CꢀN), 3430 (NH2). H NMR
d 3.42 (s, 3H, CH3), 3.81 (s, 3H, CH3O), 5.60 (s, 1H, C5ꢃH), 7.08 (d,
2HAr, J ¼ 7.6 Hz), 7.38 (d, 2HAr, J ¼ 7.7 Hz), 7.45 (s, 2H, NH2). Anal.
calculated for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found: C,
66.05; H, 5.08; N, 16.32.
1
=
Compound 3c. IR: 1675 (C O), 2200 (CꢀN), 3460 (NH2). H NMR
d 3.40 (s, 3H, CH3), 5.69 (s, 1H, C5ꢃH), 7.43 (t, 1HAr, J ¼ 8.0 Hz), 7.52
(t, 2HAr, J ¼ 7.9 Hz), 7.64 (d, 2HAr, J ¼ 7.9 Hz), 7.70 (s, 2H, NH2), 7.76
(d, 2HAr, J ¼ 7.8 Hz), 7.85 (d, 2HAr, J ¼ 7.9 Hz). Anal. calculated for
C19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found: C, 75.97; H, 4.99; N,
13.96.
1
=
Compound 3d. IR: 1670 (C O), 2200 (CꢀN), 3460 (NH2). H NMR
d
5.67 (s, 1H, C5ꢃH), 7.35 (d, 2HAr, J ¼ 8.0 Hz), 7.57–7.66
(m, 9HAr þ NH2). Anal. calculated for C18H12ClN3O: C, 67.19; H,
3.76; N, 13.06. Found: C, 67.15; H, 3.88; N, 12.99.
1
=
Compound 3e. IR: 1670 (C O), 2200 (CꢀN), 3480 (NH2). H NMR,
d 3.82 (s, 3H, CH3O), 5.70 (s, 1H, C5ꢃH), 6.72 (s, 2H, NH2), 6.99 (d,
2HAr, J ¼ 7.8 Hz), 7.34 (d, 2HAr, J ¼ 7.8 Hz), 7.58–7.66 (m, 5HAr). Anal.
calculated for C19H15N3O2: C, 71.91; H, 4.76; N, 13.24. Found: C, 71.97;
H, 4.65; N, 13.35.
1
=
Compound 3f. IR: 1655 (C O), 2200 (CꢀN), 3455 (NH2). H NMR
d 5.61 (s, 1H, C5ꢃH), 7.34–7.75 (m, 16HAr þ NH2). Anal. calculated
for C24H17N3O: C, 79.32; H, 4.72; N, 11.56. Found: C, 79.28; H, 4.67;
N, 11.50.
1
=
Compound 3g. IR: 1665 (C O), 2210 (CꢀN), 3465 (NH2). H NMR
d 3.84 (s, 3H, CH3O), 5.6 (s, 1H, C5ꢃH), 6.83 (s, 2H, NH2), 7.22–7.65 (m,
8HAr). Anal. calculated for C19H14ClN3O2: C, 64.87; H, 4.01; N, 11.94.
Found: C, 65.07; H, 3.95; N, 11.87.
1
=
Compound 3h. IR: 1665 (C O), 2210 (CꢀN), 3460 (NH2). H NMR d
3.80 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 5.60 (s, 1H, C5ꢃH), 6.75 (s, 2H,
NH2), 7.10 (d, 2HAr, J ¼ 7.6 Hz), 7.14–2.20 (m, 3HAr), 7.49 (t, 1H,
J ¼ 7.2 Hz), 7.55 (d, 2HAr, J ¼ 7.7 Hz). Anal. calculated for C20H17N3O3:
C, 69.15; H, 4.93; N, 12.10. Found: C, 69.01; H, 5.00; N, 12.21.

1988
S. A. Trofymchuk et al.
1
=
Compound 3i. IR: 1665 (C O), 2205 (CꢀN), 3470 (NH2). H NMR
d 3.80 (s, 3H, CH3O), 5.70 (s, 1H, C5ꢃH), 7.12–7.66 (m, 13HAr þ NH2),
7.82 (d, 2H, J ¼ 8.0 Hz). Anal. calculated for C25H19N3O2: C, 76.32; H,
4.87; N, 10.68. Found: C, 76.19; H, 4.99; N, 10.60.
=
1
Compound 3j. IR: 1680 (C O), 3480 NH2. H NMR d 2.34 (s, 3H,
CH3), 5.43 (s, 1H, C5ꢃH), 6.85 (s, 2H, NH2), 7.20 (d, 2HAr, J ¼ 7.8 Hz),
7.32 (d, 2HAr, J ¼ 7.4 Hz), 7.40 (d, 2HAr, J ¼ 7.3 Hz), 7.61 (d, 2HAr
,
J ¼ 7.8 Hz). Anal. calculated for C19H14Cl2N2O2: C, 61.14; H, 3.78; N,
7.51. Found: C, 61.02; H, 3.85; N, 7.44.
1
=
Compound 3k. IR: 1705 (C O), 3470 (NH2). H NMR, d 1.26 (t,
3H, CH3), 3.82 (q, 2H, CH2), 5.54 (s, 1H, C5ꢃH), 6.52 (s, 2H, NH2),
7.31 (d, 2HAr, J ¼ 7.4 Hz), 7.40 (d, 2HAr, J ¼ 7.3 Hz), 7.6 (m, 5H). Anal.
calculated for C20H17ClN2O3: C, 65.13; H, 4.65; N, 7.60. Found: C,
65.34; H, 4.59; N, 7.45.
1
=
Compound 3l. IR: 1650 (C O), 3400 (NH2). H NMR, d 5.62 (s, 1H,
C5ꢃH), 6.96–7.61 (m, 16HAr þ NH2), 11.47 (s, 1H, NH). Anal. calculated
for C24H18ClN3O2: C, 69.31; H, 4.36; N, 10.10. Found: C, 69.52; H, 4.44;
N, 10.02.
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