N-3-oxoalkylamides and -thioamides in the synthesis of heterocyclic compounds. 7*. Study of the cyclization of N-(3-oxoalkyl)amides of tosylacetic acid

Article abstract of DOI:10.1023/A:1026146421293

Alkyl-substituted N-(3-oxoalkyl)amides of tosylacetic acid are cyclized under the action of bases with the formation of 3-tosyl-3,6-dihydropyridin-2(1H) -ones. In the presence of a phenyl substituent at position C₍₁₎ of the 3-oxoalkyl chain the

Full text of DOI:10.1023/A:1026146421293

Chemistry of Heterocyclic Compounds, Vol. 39, No. 7, 2003
N-3-OXOALKYLAMIDES AND -THIOAMIDES
IN THE SYNTHESIS OF HETEROCYCLIC COMPOUNDS.
7*. STUDY OF THE CYCLIZATION OF N-(3-OXOALKYL)-
AMIDES OF TOSYLACETIC ACID
A. S. Fisyuk and N. V. Poendaev
Alkyl-substituted N-(3-oxoalkyl)amides of tosylacetic acid are cyclized under the action of bases with
the formation of 3-tosyl-3,6-dihydropyridin-2(1H)-ones. In the presence of a phenyl substituent at
position C(1) of the 3-oxoalkyl chain the reaction proceeds with the formation of 2-pyridones. The
principles influencing the regiodirection of cyclization are explained.
Keywords: N-(3-oxoalkyl)amides, 2-pyridones, 3-tosyl-3,6-dihydropyridin-2(1H)-ones, intramolecular
cyclization.
We previously reported [2] that N-(3-oxoalkyl)phenylacetamides are capable of cyclization in basic
media, proceeding according to an aldol type reaction with the formation of 5,6-dihydropyridin-2(1H)-ones. As
in the case of the crotonization, where the reaction products may be not only α,β-unsaturated but also
β,γ-unsaturated carbonyl compounds, the cyclization of N-(3-oxoalkyl)phenyl-acetamides may lead to the
formation of 3,6-dihydropyridin-2(1H)-ones [3]. It might have been assumed that any factors destabilizing the
double bond in the C(3)=C(4) position of the ring of 5,6-dihydropyridin-2(1H)-ones will be capable of isomerizing
it into the C(4)=C(5) position. It is known [4] that if the substituent displays πp-πd conjugation and a large -I effect
then it destabilizes the adjacent double bond and the equilibrium is displaced in the direction of the compound
in which the double bond is removed from this substituent. The tosyl group possesses such qualities,
consequently as a result of cyclizing N-(3-oxoalkyl)amides having a tosyl substituent in α-position in relation to
the carbamoyl group, the formation of 3,6-dihydropyridin-2(1H)-ones might have been expected. Calculated
data (MNDO/MOPAC 7.0) indicate that the energy of formation of 4,6,6-trimethyl-3-tosyl-5,6-dihydropyridin-
2(1H)-one (3a) proves to be 2.8 kcal/mol higher than that of 3,6-dihydropyridin-2(1H)-one (4a).
Ts
Me
Me
O
H
O
H
N
H
N
Me
Me
Ts
H
Me
Me
4a
3a
_______
* For Part 6 see [1].
__________________________________________________________________________________________
Omsk State University, Omsk 644077, Russia; e-mail: fis@univer.omsk.su. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 1037-1042, July, 2003. Original article submitted September 18,
2000.
0009-3122/03/3907-0895$25.00©2003 Plenum Publishing Corporation
895

In this connection we have studied the possibility of the directed synthesis of 3,6-dihydropyridin-2(1H)-
ones 4a-d by the cyclization of N-(3-oxoalkyl)amides of tosylacetic acid 2a-d and have established that the
reaction of N-(3-oxoalkyl)chloroacetamide 1a with sodium p-toluenesulfinate in reality leads to the formation of
compound 4a. Under analogous conditions cis- and trans-3,6-dihydropyridin-2(1H)-ones (4b) in a ratio of 2:3
were obtained from a mixture of anti and syn isomers of 1b. The yields of compounds 4b and 4a were 45 and
70%. At the same time compound 1c is converted under analogous conditions into 4-methyl-6-phenylpyrid-2-
one (6c). For the synthesis of compounds 4,6 the sodium p-toluenesulfinate used was obtained from an aqueous
solution of p-toluenesulfinic acid by salting out with Na2CO3 [5] and contains 10-15% sodium carbonate.
Heating N-(3-oxo-1,3-diphenylpropyl)-2-(p-toluenesulfonyl)acetamide (2d), synthesized by substituting
the halogen atom in compound 1d by a tosyl group, in an alcoholic solution of EtONa, also leads to the
formation of 4,6-diphenyl-2-pyridone (6d). It should be noted that a mixture of cis and trans isomers of 4b was
not converted into 3,6-dimethylpyrid-2-one under analogous conditions. Probably the increase in acidity of the
proton at position 6 aids isomerization of dihydropyridin-2(1H)-ones 4c,d into 5c,d, which form pyrid-2-ones
6c,d after cleavage of p-toluenesulfinic acid.
R1
Ph
R2
R3
Ts
Cl
O
O
O
NaSO2C6H4Me
EtOH, NaI
N
H
O
N
H
Ph
R4
1a–d
2d
:B
NaSO2C6H4Me
EtOH, ∆
R1
R1
Ph(Me)
Ph(Me)
R2
R3
R4
R2
R3
Ts
Ts
O
Ts
Ts
N
H
O
N
H
O
N
H
O
N
H
O
Ph
Ph
R4
3a–d
2a–c
4c,d
,
5c d
–HSO2C6H4Me
R1
Ph(Me)
H
R2
R3
Ts
N
H
O
N
H
O
Ph
R4
4a,b
6c,d
1–4 a R1 = R3 = R4 = Me, R2 = H; b R1 = R2 = R3 = Me, R4 = H; c R1 = Me, R2 = R4 = H,
R3 = Ph; d R1 = R3 = Ph, R2 = R4 = H
In the IR spectra of compounds 4a,b in CDCl3 solution systems of bands were present at 1140-1330 cm-1
for the vibrations of the sulfo group (Table 1). The vibrations of the C=C and NH bonds were located at 1600
and 3400 and of the N–C=O group at 1680 cm-1.
1
In the H NMR spectrum of compound 4a a multiplet signal was present at 5.84 ppm for the C(5)–H
proton with 4J5,4-CH = 1.5 and 4J5,NH = 1.5 Hz. The character of the splitting of the C(4)–CH3 methyl group signals
3
in 4a,b confirms the presence of an allylic interaction with the C(5)–H proton in compound 4a and a homoallylic
interaction with the C(5)–CH3 methyl substituent in compound cis-4b (5J5-CH ,4-CH = 0.9 Hz). The C(3)–H proton
3
3
of compound 4a is recorded as a singlet at 4.31 ppm. The absence of long-range spin-spin interactions of C(5)–H
896

TABLE 1. Spectral Characteristics and Yields of Compounds 1a,b, 2d, 4a,b, and 6s,d
IR spectrum, ν, cm-1*
Found, %
——————
Com-
Empirical
formula
Yield,
%
1H [13C] NMR spectrum, δ, ppm (J, Hz)**
Calculated, %
(NH)
(N–C=O)
SO2
pound
С=S, C=O
C
5
H
6
1
2
3
4
7
8
1680
1670
(3410) 1710 С8H14ClNO
(3420) 1710 С8H14ClNO2
—
—
7.29 (1H, br. s, NH); 3.98 (2Н, s, CH2Cl); 2.99 (2H, s, CH2CO);
59
39
1a
2.15 (3H, s, COCH3); 1.43 (6H, s, 2CH3)
anti-1b,
sin-1b
49.98
50.14
7.35
7.36
anti-1b, 6.94 (1H, br. s, NH); 4.30 (1H, m, 3J = 9.5, 3J = 7.0, 3J = 5.5, С(1)–H);
4.03 (2H, s, CH2Cl); 2.72 (1H, dd, 3J = 7.3, 3J = 5.5, С(2)–H ); 2.21 (3H, s, COCH3);
1.22 (3Н, d, 3J = 7.0, С(1)–СН3); 1.18 (3Н, d, 3J = 7.3, С(2)–СН3)
sin-1b, 7.50 (1H, br. s, NH); 4.18 (1H, m, С(1)–H); 4.04 (2H, s, CH2Cl);
2.83 (1H, dd, 3J = 7.3, 3J = 4.2, С(2)–H); 2.22 (3H, s, COCH3);
1.19 (3Н, d, 3J = 6.8, С(1)–СН3); 1.17 (3Н, d, 3J = 7.3, С(1)–СН3)
1690
1690
(3410) 1730 С12H14ClNO2
(3410) 1730 С17H16ClNO2
(3280) 1685 С24H23NO4S
60.15
60.13
5.88
5.89
7.84 (1H, d, 3J = 8.3, NH); 7.35-7.19 (5H, m, Ph); 5.38 (1H, m, 3J = 8.3, 3J = 6.0,
3J = 6.0, С(1)–H); 3.96 (2H, s, CH2Cl); 3.12 (1H, dd, 2J = 17.0, 3J = 6.0, С(2)–H);
2.91 (1H, dd, 2J = 17.0, 3J = 6.0, С(2)–H); 2.06 (3H, s, COCH3)
56
81
87
1c
1d
2d
67.71
67.66
5.48
5.34
7.90-7.21 (11H, m, NH, 2Ph); 5.58 (1H, m, 3J = 6.0, 3J = 5.5, 3J = 5.5, С(1)–H);
4.00 (2H, s, CH2Cl); 3.75 (1H, dd, 2J = 17.2, 3J = 5.5, С(2)–H);
3.43 (1H, dd, 2J = 17.2, 3J = 6.0, С(2)–H)
(1655) 1155,
1300, 1325
68.43
68.39
5.39
5.50
8.72 (1H, d, 3J = 7.8, NH); 7.97-7.24 (14H, m, 2Ph, C6H4); 5.35 (1Н, m, С(1)-4);
4.24 (1Н, d, 2J = 13.7, NCOCH2Ts); 4.27 (1Н, d, 2J = 13.7, NCOCH2Ts);
3.55 (1Н, dd, 2J = 17.6, 3J = 7.6, PhCOCH2); 3.41 (1Н, dd, 2J = 17.6, 3J = 7.6,
PhCOCH2); 2.37 (3H, s, CH3)
(1690) 1145,
(3400) 1600 С15H19NO3S
61.44
61.41
6.50
6.53
7.80 (2Н, d, 3J = 8.0, Ar); 7.34 (2Н, d,3J = 8.0, Ar); 6.42 (1H, br. s, NH);
5.84 (1H, m, 4J = 1.5, 4J = 1.5, 5-H); 4.31 (1H, s, 3-H); 2.44 (3H, s, Ar–CH3);
2.10 (3H, d, 4J = 1.5, 4-СН3); 1.38 (3Н, s, 6-СН3); 1.28 (3Н, s, 6-СН3)
[162.2 (NCO); 145.0, 136.1, 2 × 129.5, 2 × 129.3 (Ar); 135.2 (C(5)); 122.4 (C(4));
71.7 (C(3)); 55.2 (C(6)); 31.3 (6-CH3); 30.2 (4-CH3); 22.5 (6-CH3); 21.7 (Ar–CH3)]
70
4a
1290, 1310, 1325

TABLE 1 (continued)
1
2
3
4
5
6
7
8
cis- and
trans-
4b*3
(1680) 1140,
1290, 1300,
1320, 1330
(3400) 1600 С15H19NO3S
61.32
61.41
6.59
6.53
trans-4b 7.80 (2Н, d, 3J = 8.2, Ar); 7.34 (2Н, d, 3J = 8.2, Ar); 7.13 (1H, br. s, NH);
4.34 (1H, br. s, 3-H); 3.81 (1Н, br. q, 3J = 6.7, 6-Н); 2.44 (3H, s, Ar–CH3);
43
1.98 (3H, s, 4-СН3); 1.82 (3Н, s, 5-СН3); 1.41 (3Н, d, 3 = 6.7, 6-СН )
J
3
[163.2 (NCO); 144.8, 136.3, 2 × 129.5, 2 × 129.2 (Ar); 136.3 (C(5)); 117.1 (C(4));
73.6 (C(3)); 54.9(C(6)); 21.8 (Ar–CH3); 21.7 (4-CH3); 19.5 (6-CH3); 16.8 (5-CH3)]
cis-4b 7.75 (2Н, d, 3J = 9.2, Ar); 7.34 (2Н, d, 3J = 8.2, Ar); 7.03 (1H, br. s, NH);
4.33 (1H, br. s, 3-H); 3.70 (1Н, br. q, 3J = 7.0, 6-Н); 2.44 (3H, s, Ar–CH3);
1.98 (3H, s, 4-СН3); 1.74 (3Н, q, 5J = 0.9, 5-СН3); 1.15 (3Н, d, 3J = 7.0, 6-СН3)
[163.1 (NCO); 145.1, 136.1, 2 × 129.6; 2 × 129.3 (Ar); 135.0 (C(5)); 118.1 (C(4));
74.2 (C(3)); 52.1 (C(6)); 21.8 (Ar–CH3); 21.7 (4-CH3); 20.4 (6-CH3); 15.5 (4-CH3)]
1645
1645
(3370)
(3380)
С12H11NO
77.82
77.81
6.09
5.99
12.7 (1H, br. s, NH); 7.80-7.20 (5H, m, Ph); 6.33 (1H, d, 4J35 = 1.2, C(3)–H);
79
87
6c
6.32 (1H, d, 4J35 = 1.2, C(5)–H); 2.23 (3H, s, CH3)
[165.5 (NCO); 152.9 (С(4)), 146.0 (С(6)), 133.6, 129.8, 129.0, 126.8 (Ph) 117.2 (C(3)
)
107.5 (C(5)), 21.7 (CH3)]
—
—
—
7.80-7.28 (10H, m, 2Ph); 6.84 (1H, d, 4J35 = 1.6, C(3)–H);
6.50 (1H, d, 4J35 = 1.6, C(5)–H)
6d
_______
* The IR spectra were taken in CHCl3.
*2 The 13C NMR spectra for compounds 4a,b and 6c are given in square brackets; the 1H NMR spectra of compounds 2d
and 6d were taken in DMSO-d6, the 1H and 13C NMR spectra of the remaining compounds in CDCl3.
*3 Ratio of cis:trans isomers was 63:37.

and C(3)–H is characteristic of allylic protons [6] and indicates the closeness of the value of the dihedral angle
C(5)=C(4)–C(3)–H to θ ~180°, and consequently the pseudoequatorial orientation of C(3)–H. The C(6)–CH3 protons
of cis-4b (δ 1.15 ) are shielded by the tosyl group, and in comparison with trans-4b (δ 1.41), give a doublet
13
signal towards higher field. In the C NMR spectrum of compounds 4a,b characteristic signals are present for
the nuclei of the carbon atoms of the NC=O group (δ 163.2-162.2), double bond (δ 136.3-135.0 and
122.4-117.1), the aromatic ring (δ 145.1-129.2), and the C(3) atom (δ 74.2-71.7 ppm). It is known that the
presence of van der Waals interactions between spatially adjacent alkyl groups leads to a high field chemical
shift of the carbon atom nuclei [7]. In the spectrum of trans-4b having the interaction between C(6)–CH3 and
C(5)–CH3 the signals of the carbon nuclei of the respective methyl groups are present at 19.5 and 16.8 ppm.
Ts
Ts
Me
H
H
O
H
O
H
N
H
N
H
Me
Me
Me
cis-4b
Me
Me
trans-4b
The absence of such an interaction in cis-4b leads to a low field displacement of the shift of the C(5)–CH3
signal (15.5 ppm). At the same time the signal of C(6)–CH3 of compound cis-4b is located at high field
(20.4 ppm) as a result of spatial interactions with the tosyl group.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on a Bruker AC 200 P instrument (200 and 50 MHz).
Internal standard was TMS. The IR spectra were recorded on a Specord IR-75 spectrometer. A check on the
progress of reactions and the purity of the compounds obtained was carried out by TLC on Silufol UV 254
plates, visualizing with iodine vapor or UV light.
Compounds 1a,b were obtained by the acylation of 1,3-amino ketones with chloroacetyl chloride [2],
and 1c,d from the corresponding 1,3-chloroketones and chloroacetonitrile in the presence of SnCl4 [2, 8].
Compound 1b had mp 56-76°C (hexane), 1c mp 90-91°C (ethanol). The properties of compounds 1a,d are given
in [9].
2-[(4-Methylphenyl)sulfonyl]-N-(3-oxo-1,3-diphenylpropyl)acetamide (2d).
A
solution of
chloroacetamide 1d (0.88 g, 2.92 mmol), KI (0.50 g, 3.01 mmol), and sodium p-toluenesulfinate dihydrate
(1.918 g, 6.00 mmol) in DMSO (25 ml) was stirred at room temperature for 48 h. The reaction mixture was then
poured into water (150 ml), the solid filtered off, washed with water, dried in the air, and crystallized from
C6H6–EtOH, 1:4. Compound 2d (1.037 g) was obtained; mp 190-191°C.
4,4,6-Trimethyl-3-[(4-methylphenyl)sulfonyl]-3,6-dihydropyridin-2(1H)-one (4a). Compound 1a
(1.00 g, 5.2 mmol) and tetrabutylammonium iodide (0.10 g) were added to a solution of sodium
p-toluenesulfinate dihydrate (2.44 g, 11.2 mmol) in 50% aqueous ethanol (15 ml). The reaction mixture was
boiled under reflux for 2 h, cooled, and the precipitated solid was filtered off. After crystallization from 50%
ethanol compound 4a (1.07 g) was obtained; mp 231-232°C.
4,5,6-Trimethyl-3-[(4-methylphenyl)sulfonyl]-3,6-dihydropyridin-2(1H)-one (4b) was obtained
analogously to compound 4a from a mixture of the syn and anti isomers of compound 1b (0.153 g, 0.83 mmol),
sodium p-toluenesulfinate dihydrate (0.295 g, 1.35 mmol), and KI (0.276 g) in alcohol (10 ml), and boiling for
24 h. The reaction mixture was evaporated, chloroform (5 ml) added, the salt was filtered off, and the product
purified by column chromatography on silica gel with a solvent gradient of CHCl3 → CHCl3–AcOEt–EtOH,
6:3:1. A mixture of cis- and trans-4b (0.104 g) was obtained; mp 198-203°C.
899

4-Methyl-6-phenylpyridin-2(1H)-one (6c) was obtained analogously to compound 4a from compound
1c by boiling for 6 h. The product was purified by recrystallization from a mixture of ethyl acetate–benzene.
Mp 159-160°C.
4,6-Diphenylpyridin-2(1H)-one (6d). Potassium hydroxide (0.20 g) was added to a solution of
compound 2d (0.20 g, 0.474 mmol) in a mixture (20 ml) of benzene and alcohol (1:5). The reaction mixture was
boiled for 1 h, evaporated, and diluted with water. The precipitated solid was filtered off, and crystallized from
alcohol. Compound 6d (0.102 g) was obtained; mp 211-212°C (lit. 211-212°C [10]).
The work was carried out with the financial support of the Russian Fund for Fundamental Investigations
(Grant No. 99-03-33013a).
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