Synthesis of 3-S-hetaryl-substituted pyridin-2(1H)-ones and 5,6-dihydropyridin-2(1H)-ones

Article abstract of DOI:10.1007/s10593-010-0592-0

A method has been developed for the synthesis of 3-S-hetaryl-substituted pyridin-2(1H)-ones and 5,6-dihydropyridin-2(1H)-ones based on the base catalyzed cyclization of N-(3-oxoalkyl)- and N-(3-oxoalkenyl)amides which contain a divalent sulfur atom in an

Full text of DOI:10.1007/s10593-010-0592-0

Chemistry of Heterocyclic Compounds, Vol. 46, No. 7, 2010
SYNTHESIS OF 3-S-HETARYL-SUBSTITUTED PYRIDIN-
2(1H)-ONES AND 5,6-DIHYDROPYRIDIN-2(1H)-ONES*
A. S. Fisyuk1**, Y. P. Bogza1, N. V. Poendaev1, and D. S. Goncharov1
A method has been developed for the synthesis of 3-S-hetaryl-substituted pyridin-2(1H)-ones and
5,6-dihydropyridin-2(1H)-ones based on the base catalyzed cyclization of N-(3-oxoalkyl)- and N-(3-
oxoalkenyl)amides which contain a divalent sulfur atom in an -position to a carbamoyl group and
bound to the heterocycle.
Keywords: 5,6-dihydropyridin-2(1H)-ones, N-(3-oxoalkenyl)amides, N-(3-oxoalkyl)amides, pyridin-2(1H)-
ones, intramolecular cyclization.
We have previously reported that N-(3-oxoalkenyl)- and N-(3-oxoalkyl)amides containing a mobile
hydrogen atom in an -position to the carbamoyl group can undergo an aldol type intramolecular ring closure to
give pyridin-2(1H)-ones [1] or their hydrogenated derivatives [2]. In order to increase the acidity, various
acceptors including a pyridine ring [3, 4], triphenylphosphonium group [5, 6], halogen atom [7], and a tosyl [8]
or aryl [9] substituent were introduced to the -carbamoyl position. It is possible to introduce a divalent sulfur
atom in order to stabilize the carbanion and so increase the acidity at the -carbamoyl position. In our case, this
can be achieved by the nucleophilic substitution of the halogen in N-(3-oxoalkenyl)- and N-(3-oxoalkyl)-
chloroacetamides by a thio group. At the same time the use of thiophenol and thiols in the synthesis is not
without the drawback of an unpleasant odor. The introduction of a divalent sulfur atom in the molecule is
possible by the S-alkylation of cyclic thioamides, thiocarbamates, or thiourea. The compounds are generally
crystalline and do not have an objectionable odor. We have previously reported such a possible route [10].
With the aim of studying the cyclization of N-(3-oxoalkenyl)- and N-(3-oxoalkyl)amides containing a
divalent sulfur atom in an -carbamoyl position we have prepared the compounds 4a, 5a-e by treating the
chloroacetamides 1, 2 (synthesized by known methods [1, 9]) with the thio derivatives 3a-e. The reactions were
carried out in DMF at room temperature in the presence of potassium carbonate and potassium iodide. The
completion of the reaction was monitored by TLC. The yields of compounds 4a and 5a-e were 54-88% (Table 1).
It was found that cyclization of compounds 5a,d occurs even at room temperature over 2-3 h with the
action of sodium ethylate in ethanol to give the 5,6-dihydropyridin-2(1H)-ones 7a,d in 80-90% yield.
Cyclization of compounds 5b,c,e occurs more slowly and it is necessary to carry out the reaction with heating.
The yield of compounds 7b,c,e is 57-73% (Table 1). It should be noted that cyclization of compound 4a occurs
_______
* Dedicated to the memory of the prominent scientist and wise teacher, Reva S. Sagitullin.
** To whom correspondence should be addressed, e-mail: fis@orgchem.univer.omsk.su.
1F. M. Dostoevsky Omsk State University, Omsk 644077, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1044-1049, July, 2010. Original
article submitted April 27, 2010.
844
0009-3122/10/4607-0844©2010 Springer Science+Business Media, Inc.

under analogous conditions to yield a hard to separate mixture of products, evidently as a result of the
alcoholysis of the starting compound. The pyridin-2(1H)-one 6a was prepared in 88% yield by carrying out the
reaction in anhydrous THF with the use of potassium tert-butylate as base.
Me
Me
Me
HSHet
SHet
O
3a
t-BuOK
O
O
THF
K2CO3, KI
DMF
Me
NHCOCH2Cl
Me
NHCOCH2SHet
Me
N
H
6a
1
4a
Me
Me
Me
O
HSHet
3a–e
SHet
EtONa
EtOH
O
Me
Me
Me
Me
Me
Me
K2CO3, KI
DMF
NHCOCH2SHet
N
H
7a–e
O
NHCOCH2Cl
5a–e
2
Me
H
N
H
N
Ph
Ph
S
S
N
N
c
,
,
b
a
,
,
d
e
3–7 Het =
N
N
N
N
N
The IR spectra of compounds 6a and 7a-e show the absence of absorption bands for the carbonyl group.
The 1H and 13C NMR spectra confirm the structures of compounds 6a and 7a-e (Tables 2 and 3).
TABLE 1. Characteristics and Conditions for Preparing Compounds 4-7
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Reaction Reaction
mp, °С* Yield, %
time, h
T, °C
C
H
N
4a
5a
5b
5c
5d
5e
6a
7a
7b
7c
7d
7e
С14H14N2O2S2
C15H18N2O2S
C23H24N2O2S
C15H19N3O2S
C16H21N3O2S
C10H16N4O2S
С14H12N2OS2
C15H16N2OS2
C23H22N2OS2
C15H17N3OS
C16H19N3OS
C10H14N4OS
54.67
54.88
55.62
55.87
65.18
65.06
58.71
58.99
60.35
60.16
46.69
46.86
58.43
58.31
59.35
59.18
67.82
67.95
62.53
62.69
63.92
63.76
50.54
50.40
4.66
4.61
5.56
5.63
5.77
5.70
6.35
6.27
6.58
6.63
6.38
6.29
4.25
4.19
5.41
5.30
5.34
5.45
5.88
5.96
6.42
6.35
5.81
5.92
9.07
9.14
8.62
8.69
6.64
6.60
13.68
13.76
13.07
13.16
21.69
21.86
9.62
9.71
9.14
9.20
6.95
6.89
14.51
14.62
13.86
13.94
23.34
23.51
72
30
30
72
72
30
1
25
25
142-143
71-72
78
80
88
54
64
62
88
79
68
73
90
57
25
175-176
175-176
97-98
25
25
25
75-76
25
> 245
2
25
180-181
244-245
232-233
202-203
243-244
3
75-80
75-80
25
1
3
2
75-80
_______
* Solvents: 70% ethanol (compounds 4a, 5a-d), 40:70 mixture of ethyl
acetate and petroleum ether (compound 5e), ethanol (compound 6a) or
50% ethanol (compounds 7a-e).
845

846

847

Hence we have developed a method for the preparation of pyridin-2(1H)-ones and 5,6-dihydropyridin-
2(1H)-ones which contain a divalent sulfur atom at position C(3) and bound to a heterocycle. It was found that
cyclic thioureas and thiocarbamates can be successfully used to increase the acidity at the -carbamoyl position.
EXPERIMENTAL
IR spectra were recorded on an Infralum FT-801 spectrometer. 1H and 13C NMR spectra were taken on a
Bruker DRX-400 instrument (400 and 100 MHz respectively) with TMS as internal standard. Mass spectra were
obtained on an Agilent 5973N instrument (ionization energy 70 eV, evaporator temperature 230-250ºC).
Monitoring of the reaction course and the purity of the compounds obtained was carried out by TLC on Sorbfil
UV-254 plates and revealed using iodine vapor or UV light. Melting points were determined on a Koffler stage.
Compounds 1 and 2 were synthesized by acylation of the corresponding amino ketone [9] and enamino
ketone [1] using monochloroacetic acid chloride. With the exception of the commercially available
mercaptobenzothiazole 3a the starting thiocarbamates and thioureas were prepared by a known method: 3b [11],
3c,d [12], or 3e [13].
N-(1,1-Dimethyl-3-oxobutyl)-2-(hetarylsulfanyl)acetamides 5a-e (General Method). A solution of
the chloroacetamide 2 (0.192 g, 1.0 mmol), the corresponding thiocarbamate or thiourea 3a-e (1.0 mmol),
anhydrous K2CO3 (0.138 g, 1.0 mmol), and KI (0.017 g, 0.1 mmol) in absolute DMF (2 ml) was stirred at room
temperature for 30-72 h while the reaction was monitored by TLC. The reaction product was diluted with water
(10 ml), neutralized with 10% HCl solution, and the precipitate was filtered off. The compound was
recrystallized from 70% ethanol. Compound 5e was recrystallized from a 40:70 mixture of ethyl acetate and
petroleum ether.
2-(1,3-Benzothiazol-2-ylsulfanyl)-N-(1-methyl-3-oxobut-1-en-1-yl)acetamide (4a) was prepared
similarly to compounds 5a-e.
3-(1,3-Benzothiazol-2-ylsulfanyl)-4,6-dimethylpyridin-2(1H)-one (6a). Potassium tert-butylate
(0.17 g, 1.5 mmol) was added with stirring and cooling in ice to a solution of the acetamide 4a (0.306 g,
1.0 mmol) in anhydrous THF (5 ml) and stirred for 10-15 min. Cooling was removed and stirring was continued
at room temperature for 1 h (TLC monitoring). Solvent was removed in vacuo and the reaction product was
treated with water, neutralized with a 10% solution of HCl, and the precipitate formed was filtered off. The
compound was recrystallized from ethanol.
3-(Hetarylsulfanyl)-4,6,6,-trimethyl-5,6-dihydropyridin-2(1H)-ones (7a-e) (General Method). A
solution of sodium ethylate was prepared by dissolving sodium (1 mmol) in absolute ethanol (3 ml) and added
dropwise with stirring to a solution of compound 5a-e (1 mmol) in absolute ethanol (3 ml). The reaction product
was stirred for 2-3 h at room temperature (7a,d) or refluxed for 1-3 h (7b,c,e) and then neutralized with 10%
HCl solution. Solvent was evaporated in vacuo and the residue was washed with water (10 ml) and filtered off.
The compound was recrystallized from 50% ethanol.
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