Polish J. Chem., 74, 1101–1114 (2000)
Reactions of Secondary b-Ketothioamides with
Ethyl Bromoacetate and Ethyl 2-Bromopropionate.
The Synthesis of N-Substituted
2-Acylmethylidene-1,3-thiazolidin-4-ones
by T.S. Jagodziñski*, A. Weso³owska and J.G. Soœnicki
Department of Organic Chemistry, Technical University of Szczecin,
71-065 Szczecin, Aleja Piastów 42, Poland
(Received February 3rd, 2000; revised manuscript April 14th, 2000)
4-Morpholinocoumarin (2) was obtained in the reaction of 4-(2-hydroxythiobenzoyl)morpholine (1) with ethyl bromoacetate in the presence of triphenylphosphine and
triethylamine. Analogous reactions of 3-keto thioamides with ethyl bromoacetate and
ethyl 2-bromopropionate, carried out in THF or acetone, yielded cyclic derivatives of
N-substituted 2-acylmethylidene-1,3-thiazolidin-4-ones (4, 7, 8). In the reaction with
ethyl 3-bromopropionate only S-alkylation of the thioamide was observed. The reaction
of the indandione-derived thioamides 6 with ethyl bromoacetate in acetone gave the condensation products of 2-acylmethylidene-1,3-thiazolidin-4-ones with acetone. 2-Acylmethylidene-1,3-thiazolidin-4-ones 4, 7, 8 condensed with benzaldehyde to give the
5-benzylidene derivatives.
Key words: b-ketothioamides, 2-acylmethylidene-1,3-thiazolidin-4-ones
Two active centers determine the chemical and physical properties of thioamides.
One of them is attributed to the nitrogen atom with an unshared electron pair, the other
one, to the sulfur atom. In most cases, substitution on either the nitrogen or the
thiocarbonyl carbon atom markedly changes the properties of these compounds. The
class of thioamides includes in fact a wide variety of relatively readily available compounds. Owing to their ability to react in most cases with both electrophiles and
nucleophiles, thioamides and their functionalized derivatives may be considered as
highly versatile reagents. For those reasons they are still gaining in importance as useful synthons in the synthesis of heterocyclic compounds, including regio- and
stereoselective synthesis of natural products [1,2].
The synthesis of thioamides and their physical and chemical properties and use in
the organic synthesis have been extensively reviewed [1,2].
Simple methods for the Friedel-Crafts synthesis of the N-ethoxycarbonylthioamide derivatives of phenols and of the N-allylthioamide derivatives of aromatic and
heteroaromatic compounds and for converting these products into heterocyclic
* Author for correspondence.
1102
T.S. Jagodziñski, A. Weso³owska and J.G. Soœnicki
compounds have been described earlier [3–5]. In the present paper we report on the reaction of secondary b-keto thioamides with ethyl bromoacetate and 2- and 3-bromopropionates.
RESULTS AND DISCUSSION
In most papers concerned with the reaction of 3-oxo-3,N-disubstituted propanethioamides with electrophilic reagents, such as malonyl dichloride [6], phenacyl
bromide [7], chloroacetone [8], chloroacetic acid [7], N¢-(4-chlorophenyl)oxalomonohydrazonoyl chloride [9], and 1,2-dibromoethane and 1,3-dibromopropane [10], only the thioamide nitrogen and sulfur atoms were considered as directly engaged in the heterocyclization process. In some other reactions, for example
in that of b-keto thioamides with the derivatives of 2-nitrostyrene or with
benzylidenemalononitrile, heterocyclization occurred with participation of the carbon atom adjacent to the thiocarbonyl group and of the thioamide nitrogen or sulfur
atom [11].
Our recent studies of the reaction of salicylic acid-derived thioamides with ethyl
bromoacetate under the Eschenmoser reaction conditions [12] were directed towards
the preparation of 4-aminocoumarin derivatives. However, a positive result was obtained only with 4-(2-hydroxythiobenzoyl)morpholine (1), which gave 4-morpholinocoumarin (2) in 17% yield. Other thioamides, such as salicylthioanilide and
4-(2-hydroxythiobenzoyl)-piperidine, were converted into the corresponding amides, which were also obtained in experiments carried out under strictly anhydrous
conditions.
Scheme 1
O
N
S
N
1
O
OH
BrCH2CO2C2H5
benzene / r.t.
S
CH2CO2C2H5
OH
O
N
P(C6H5)3 / N(C2H5)3
Br
C2H5OH
O
N
CO2C2H5
CH2Cl2 / r.t.
OH
O
2
SCHEME 1
O
Reactions of secondary b-ketothioamides with ethyl bromoacetate...
1103
In an attempt to obtain the derivatives of 4-amino-2-pyranone, the reaction of
secondary b-keto thioamides was studied under analogous conditions. Instead of
the expected derivatives of 2-pyranone, the reaction products contained only fivemembered compounds with the structure of N-substituted 2-acylmethylidene-1,3thiazolidin-4-ones (4a–e) (Scheme 2). Therefore, heterocyclization involved both
heteroatoms of the thioamide function. Participation of the enol oxygen atom was observed in neither of the reactions investigated.
In several cases alkylation of the sulfur atom followed by cyclization was found
to occur in the initial stage of the reaction, i.e., when ethyl bromoacetate reacted with
the b-keto thioamide (3) in anhydrous benzene. Usually, only alkylation of the sulfur
atom with the formation of the appropriate thiuronium salt is known to take place under analogous reaction conditions [1,2]. The same products were obtained, when the
reaction was carried out in the presence of triphenylphosphine and triethylamine in
methylene chloride. No formation of the derivatives of 2-pyranone or the cyclic derivative of 1,4-oxathiepine was observed in these reactions.
Scheme 2
1104
T.S. Jagodziñski, A. Weso³owska and J.G. Soœnicki
The research was extended in scope by modifying the secondary thioamide reagents 3,5,6 and by altering the reaction conditions. Thus, irrespective of the structure of the starting thioamide (linear b-keto thioamides 3a–c or b-keto thioamide
derivatives of tetralone 5 and indanedione 6a,b), only N-substituted 2-acylmethylidene-1,3-thiazolidin-4-ones 4a–e, 7a,b, 8a,b were obtained in the reactions carried
out in anhydrous THF in the presence of potassium carbonate. Similar products 4a–e,
7a,b were obtained, when acetone was used as the reaction solvent. There is little
doubt that the S-alkylation proceeds in all investigated reactions as the initial step,
which is followed by acylation of the nitrogen atom to yield 4a–e, 7a,b, 8a,b. It seems
noteworthy that the cyclization occurs easily even at room temperature. Analogous
cyclic products 4d,e, 7b were obtained in the reaction of the thioamides 3a,b, 5 with
ethyl 2-bromopropionate (Schemes 2 and 3).
An one-step synthesis of similar systems was reported earlier [13]. Acyl derivatives of thiophene or furan, phenyl isothiocyanate, and ethyl bromoacetate were used
as the starting materials, while sodium hydride served as a base. In our hands this reaction proved to be multidirectional and therefore rather useless for preparative purposes.
Scheme 3
O
S
BrCH2CO2C2H5
O
NHC6H5 or CH3CHBrCO2C2H5
THF / K2CO3
or acetone / K2CO3
5
O
1
CNHR
C6H5
7a, R = H
7b, R = CH3
S
BrCH2CO2C2H5
THF / K2CO3
O
1
O
N
O
S
R
S
O
N
1
R
O
1
6a, R = CH3
1
6b, R = allyl
8a, R = CH3
1
8b, R = allyl
CH3
O
O
S
1
CNHR
BrCH2CO2C2H5
N
acetone / K2CO3
O
1
R
O
1
CH3
S
1
6a, R = CH3
12a, R = CH3
1
1
6b, R = allyl
12b, R = allyl
SCHEME 3
O
Reactions of secondary b-ketothioamides with ethyl bromoacetate...
1105
The reaction of the thioamides 3a,5,6a with ethyl 3-bromopropionate rather unexpectedly yielded only the S-alkylation products 9–11. In accord with the Baldwin
rule [14] the formation of six-membered rings should proceed as readily as that of
five-membered ones. In this case, however, all attempts to obtain cyclic products
9–11, either by heating or by treatment with bases, failed.
In the case of the thioamides 6a,b derivatives of indanedione, the reaction with
ethyl bromoacetate carried out in acetone in the presence of potassium carbonate also
gave unexpected results. The cyclization yielding 2-acylmethylidene-1,3-thiazolidin-4-ones was accompanied by condensation of the cyclic products 8a,b with acetone to give only the 5-isopropylidene derivatives 12a,b as final products.
Acidity of the methylene protons in the thiazolidine moiety is well evidenced by
the reaction of 4a–c, 7a, 8a,b with benzaldehyde. In refluxing ethanol in the presence
of triethylamine the corresponding 3-benzylidene derivatives 13a–c, 14, 15a,b were
obtained in high yields.
Scheme 4
1106
T.S. Jagodziñski, A. Weso³owska and J.G. Soœnicki
The results of the present study do not answer the question of how the reaction
would proceed with tertiary b-ketothioamides. A separate study will be dealing with
this problem.
The structures of compounds 2, 4, 7–15 were elucidated by means of 1D NMR
(1H, 13C, 13C-DEPT,), 2D NMR (13C, 1H COSY, 13C, 1H COLOC), IR spectroscopy,
and mass spectrometry. The spectroscopic data are presented in Table 1. Both the IR
and 13C NMR spectra give a convincing evidence for the five-membered structure of
4a–e, 7a,b, 8a,b and thus excluded the possible formation of a seven-membered cycle
of type A (Scheme 2). The IR absorption bands and the 13C NMR signals observed in
1630–1740 cm–1 range and in 185–192 ppm range, respectively, were characteristic
for the carbonyl function in a,b-unsaturated ketones.
The 1H, 1H NOESY NMR technique has been recently found as a useful tool for
determining the configuration and conformation of 3-acylmethylidene-2,2,3-trisubstituted-2,3-dihydrofurans [15]. The same technique has been applied to make the
stereochemical assignments in the 2-acylmethylidene moiety of 4a-e, 7a,b, 13a,c and
14. The correlation observed in the 1H,1H NOESY spectra of 4d, 4e, 7b, 13a, 13c, 14
made possible to estimate the through-space interaction between the following protons or groups of protons: =CH vs. NCH3, =CH vs. C6H5CO- 4d and 13a; =CH vs.
H3CCO-, =CH vs. C6H5N- 13c; CH2 vs. C6H5N- 7b and 14, and =CH vs. C6H5CO,
=CH vs. C6H5N, 4e (Figure 1). These results indicate that all the compounds exist as
the Z-isomers and that the s-cis conformation is clearly preferred. Unfortunately, the
NOESY spectra and other applied methods did not allow to determine the configuration on the double bond of the 5-phenylmethylene substituent in these compounds.
O
S
5 4
2 3
1'
H
H
CH3
1
N
H3C
CH3
O
O
H
NOE
1
1'
H
S
H
4
N
O
O
NOE
13a (Z, s-cis)
S
O
H
2
5 4
3
O
CHC6H5
O
S
O
N
H
NOE
13c (Z, s-cis)
Figure 1.
Figure 1
O
N
7b (Z, s-cis)
N
H3C
S
NOE
CHC6H5
O
N
H3C
1'
H
4e (Z, s-cis)
CHC6H5
H
5
2 3
NOE
4d (Z, s-cis)
O
S
CH3
1
NOE
14 (Z, s-cis)
R = C6H5
R1 = CH3
R2 = H
R = C6H5
R 1 = C 6 H5
R2 = H
R = CH3
R 1 = C 6 H5
R2 = H
4a
4b
4c
2
Compounds
(CDCl3): 3.91 (s, 2H, 5-CH2),
6.32 (s, 1H, =CH), 7.31 (d, J =
7.1, 2H, C6H5), 7.37 (t, J = 7.8,
2H, C6H5), 7.47 (t, J = 7.3, 1H,
C6H5),
7.54–7.63 (m, 3H, C6H5), 7.71
(d, J = 7.3, 2H, C6H5).
(CDCl3): 2.08 (s, 3H, CH3), 3.84
(s, 2H, 5-CH2), 5.58 (s, 1H,
=CH), 7.21–7.25 (m, 2H, C6H5),
7.50–7.60 (m, 3H, C6H5).
211–214(dec)
(toluene)
(CDCl3): 3.29 (s, 3H, NCH3),
3.69 (s, 2H, 5-CH2), 6.67 (s,
1H, =CH), 7.46 (t, J = 7.6, 2H,
C6H5), 7.53, (t, J = 7.3, 1H,
C6H5), 7.94 (d, J = 7.2, 2H,
C6H5).
H NMR
d (ppm)
(CDCl3): 3.26 (pseudo t,
J = 4.6, 4H, 2CH2N), 3.94
(pseudo t, J = 4.7, 4H,
2CH2O), 5.75 (s, 1H, =CH),
7.24–7.28 (m, 1H, C6H4), 7.35
(d, J = 7.6, 1H, C6H4),
7.49–7.53 (m, 1H, C6H4), 7.61
(dd, J = 1.3, 8.0, 1H, C6H4).
1
260–261(dec)
(toluene)
270 lit. [17]
172–174(dec)
(toluene)
169–170
(ethanol)
lit. [16]
m.p. °C
(solvent)
138–141
(ethanol)
(CDCl3): 30.1 (q, CH3), 31.9
(t, C-5), 101.2 (d, C-1¢),
127.9, 129.8, 130.2, 135.0
(C6H5), 159.7 (s, C-2), 172.5
(s, C-4), 196.0 (s, C=O).
(CDCl3): 32.1 (t, C-5), 97.8
(d, C-1’), 127.5, 127.9,
128.5, 130.0, 130.3, 132.2,
135.1, 138.2 (2C6H5), 162.7
(s, C-2), 172.6 (s, C-4),
188.8 (s, C=O).
(CDCl3): 30.3 (q, NCH3),
31.8 (t, C-5), 95.7 (d, C-1¢),
127.5, 128.5, 132.2, 138.3
(C6H5), 161.8 (s, C-2), 172.7
(s, C-4),188.5 (s, C=O).
C NMR
d (ppm)
(CDCl3): 51.4 (t, 2CH2N),
66.3 (t, 2CH2O), 98.0 (d,
C-3), 115.9, 117.7, 123.5,
124.6, 131.5, 154.1 (C6H4),
161.0, (s, C-2)*, 162.3 (s,
C-4)*.
13
IR
n (cm–1)
3090–3040
(=C–H)
1715 (C=O)
1610–1600
(C=C)
1250–1240
(C–N)
1730 (C=O)
1630 (C=O)
1580, 1530
(C=C),
1350 (CH3)
1720 (C=O)
1630 (C=O)
1510 (C=C)
1350 (CH2)
1620 (C=O)
lit. [17]
1710 (C=O) lit.
[17]
1730 (C=O)
1650 (C=O)
1510 (C=C)
1360 (CH3)
Mass spectra
m/z (%Imax)
231 (M+.,100), 230 (53),
216 (16), 214 (14), 202
(19), 174 (23), 172 (58),
145 (31), 118 (27), 89
(20)
233(100; M+), 232(46),
216(46), 156(81),
128(7), 105(47),
100(25), 82(24), 77(50),
51(13)
295(63;M+), 278(61),
252(48), 221(78),
190(52), 162(14),
117(33), 105(95),
77(100), 51(22)
233 (42;M+), 218(41),
216(56), 190(100),
176(27), 159(42),
144(40), 132(28),
77(51), 51(19)
Table 1. Yields and physical properties of the 2-acylmethylidenethiazolidin-4-one derivatives and S-alkyl derivatives (9–11).
40 (THF)
25 (acetone)
54 (THF)
43 (acetone)
75 (THF)
64 (acetone)
17
Yield
%
Reactions of secondary b-ketothioamides with ethyl bromoacetate...
1107
R = C6H5
R 1 = C 6 H5
R2 = CH3
R=H
R = CH3
4e
7a
7b
147–149
(hexane/ethyl
ether)
259–261(dec)
(toluene)
185–188
(hexane/ethyl
acetate)
Table 1. (continuation)
4d
R = C6H5 136–137
R1 = CH3 (hexane/ethyl
R2 = CH3 acetate)
(CDCl3): 1.69 (d, J = 7.22, 3H,
5-CH3), 1.97–2.06 (m, 2H,
CH2), 2.56–2.59 (m, 2H, CH2),
4.99 (q, J = 7.22, 1H, H-5), 7.07
(d, J = 7.3, 2H, NC6H5),
7.18–7.59 (m, 5H, C6H5, C6H4),
8.02 (dd, J = 1.05, J = 7.65, 2H,
C6H4).
(CDCl3): 2.01 (pseudo t, J =
6.5, 2H, CH2), 2.57 (pseudo t,
J = 6.9, 2H, CH2), 3.83 (s, 2H,
5-CH2), 7.08 (d, J = 7.3, 1H,
C6H4), 7.21–7.52 (m, 7H,
C6H5, C6H4), 8.01 (dd, J = 1.1,
7.6, 1H, C6H4).
(CDCl3): 1.75 (d, J = 7.3, 3H,
5-CH3), 4.07 (q, J = 7.3, 1H,
H-5), 6.31 (s, 1H, H-1¢), 7.30
(d, J = 7.1, 2H, C6H5), 7.36
(t, J = 7.7, 2H, C6H5), 7.45 (t,
J = 7.4, 1H, C6H5), 7.52–7.61
(m, 3H, C6H5), 7.71 (d, J = 7.3,
2H, C6H5).
(CDCl3): 1.63 (d, J = 7.3, 3H,
5-CH3), 3.20 (s, 3H, N-CH3),
3.87 (q, J = 7.3, 1H, H-5),
6.67 (s, 1H, H-1), 7.46
(t, J = 7.7, 2H, C6H5), 7.53
(t, J = 7.3, 1H, C6H5), 7.95
(d, J = 7.2, 2H, C6H5).
(CDCl3): 18.74 (t, 5-CH3),
26.81, 28.20 (2CH2), 40.14
(d, C-5), 109.83 (s, C-1¢),
126.94, 127.22 (br), 127.32,
127.51, 127.67 (br), 128.75,
129.45, 132.41, 133.87,
138.02, 141.49 (C6H5, C6H4),
152.56 (s, C-2), 177.49 (s,
C-4), 187.35 (s, C=O).
(CDCl3): 26.6 (t, CH2), 28.2
(t, CH2), 32.4 (t, C-5), 110.1
(s, C-1¢), 127.0, 127.3,
127.5, 128.9, 129.5, 132.5,
133.8, 137.7, 141.5
(C6H5, C6H4), 154.1
(s, C-2), 174.3 (s, C-4),
187.4 (s, C=O).
(CDCl3): 18.98 (q, 5-CH3),
40.98 (d, C-5), 97.26 (d,
C-1¢), 127.45, 127.91,
128.44, 129.85, 130.23,
132.13, 135.20, 138.29
(2 C6H5), 160.83
(s, C-2), 175.78 (s,
C-4),188.72 (s, C=O).
(CDCl3): 18.67 (q, 5-CH3),
30.38 (q, N-CH3), 40.26 (d,
C-5), 95.34 (d, C-1¢),
127.51, 128.55, 132.17,
138.47, (C6H5), 160.42 (s,
C-2), 176.01 (s, C-4),
188.56 (s, C=O).
1720 (C=O)
1630 (C=O)
1600, 1500
(C=C)
1400 (CH2)
1710 (C=O)
46 (acetone)
1625 (C=O)
1590, 1490–1470
br (C=C)
1390 (CH3)
321(24;M+), 304(100),
278(28), 247(36),
218(19), 143(5),
115(26), 90(13), 77(16),
51(7)
335 (18;M+), 319(23),
318(100), 290(14),
278(20), 247(28),
246(26), 218(16),
115(24), 77(14)
32 (THF)
30 (acetone)
56 (THF)
1720–1710 br
(C=O)
1630 (C=O)
1590,
1520–1480 br
(C=C),
1350 (CH3)
309(57; M+), 292(72),
252(38), 221(65),
204(62), 176(23),
144(23), 105(100),
77(93), 51(19)
68 (acetone)
1710 (C=O)
1630 (C=O)
1580, 1515
(C=C)
1420 (N–CH3)
1350 (CH3)
247 (100; M+), 230
(48), 170 (81), 142 (18),
131 (10), 105 (52), 82
(34), 77 (50), 59 (5), 51
(12)
1108
T.S. Jagodziñski, A. Weso³owska and J.G. Soœnicki
oil
10
(CDCl3): 14.15 (CH2CH3), decomposition
26.87, 28.25, 29.25, 34.38
(4CH2), 60.75 (CH2CH3),
110.36 (CH-2), 123.58,
124.83, 126.75, 127.09,
127.47, 129.01, 131.75,
135.14, 140.35, 142.05
(C6H4, C6H5), 156.09 (C-3),
171.24 (C=O), 185.33 (C-1).
(CDCl3): 1.21 (t, J = 7.1, 3H,
CH2CH3), 2.48 (t, J = 7.0, 2H,
CH2), 2.70 (t, J = 7.0, 2H, CH2),
2.88–3.00 (m, 4H, 2CH2), 4.10
(quartet, J = 7.1, CH2CH3),
7.13–7.40 (m, 8H, C6H5, C6H4),
8.02 (d, J = 6.6, 1H, C6H4), 13.30
(br s, 1H, NH).
decomposition
285(100; M+), 256(17),
214(52), 210(36),
186(25), 172(14),
154(29), 104(22),
76(25), 41(22)
259 (100; M+), 260
(16), 230 (7), 190 (30),
189 (37), 188 (32), 186
(14), 158 (7), 104 (14),
76 (22)
(CDCl3): 14.15 (CH2CH3),
26.63, 33.50 (2CH2), 61.07
( CH2CH3), 89.72 (CH-2),
125.28, 126.47, 127.09,
128.38, 129.05, 131.05,
138.08, 139.95 (2C6H5),
165.10 (C-#), 170.99
(C=O), 186.34 (C-1).
(CDCl3): 31.3 (t, C-5), 49.3
(t, NCH2), 107.2 (s, C-1¢),
117.7 (t, =CH2), 122.1,
122.9, 134.1, 134.4, 139.4,
139.9 (C6H4), 131.3 (d,
=CH), 167.0 (s, C-2),173.8
(s, C-4), 185.5 (s, C=O);
191.9 (s, C=O).
(CDCl3): 31.3 (t, C-5), 36.2
(q, NCH3), 107.1 (s, C-1¢),
121.7, 122.6, 133.9, 134.2,
139.4, 139.8, (C6H4), 168.6
(s, C-2), 174.2, (s, C-4),
185.2, (s, C=O), 191.3 (s,
C=O).
(CDCl3): 1.25 (t, J = 7.1, 3H,
CH2CH3), 2.72 (t, J = 7.4, 2H,
CH2), 3.19 (t, J = 7.4, 2H ,
CH2), 4.16 (quartet, J = 7.1,
2H, CH2CH3), 5.98 (s, 1H,
2H), 7.24 (t, J = 7.2, 1H,
C6H5), 7.31 (d, J = 7.3, 2H,
C6H5), 7.35–7.39 (m, 2H,
C6H5), 7.42–7.48 (m, 3H,
C6H5), 7.90 (dd, J = 1.6, 7.6,
2H, C6H5), 13.51 (br.s., 1H,
NH).
218–221 (dec) (CDCl3): 3.87 (s, 2H, 5-CH2),
5.10–5.17 (m, 2H, CH2), 5.34
(toluene)
(d, J = 5.2, 2H, CH2),
5.76–5.86 (m, 1H, =CH),
7.65–7.72 (m, 2H, C6H4),
7.80–7.85 (m, 2H, C6H4).
59–60
(hexane/ethyl
acetate)
R1 = allyl
9
8b
Table 1. (continuation)
8a
R1 = CH3 284–286 (dec) (CDCl3): 3.80 (s, 3H, NCH3),
3.86 (s, 2H, 5-CH2), 7.67–7.72
(toluene)
(m, 4H, C6H4), 7.81–7.84
(m, 2H, C6H4).
1735 (C=O)
1700 (C=O)
1600, 1550
(C=C)
1460 (CH2)
1390 (CH3)
1730 (C=O)
1590,
1550–1500 br
(C=C)
1460 (CH2)
1370 (CH3)
1740 (C=O)
1710 (C=O)
1600, 1500
(C=C)
1430 (CH2)
1730 (C=O)
1705 (C=O)
1670, 1590
(C=C)
1430 (CH3)
48 (acetone)
41 (acetone)
30 (THF)
32 (THF)
Reactions of secondary b-ketothioamides with ethyl bromoacetate...
1109
195–197 (dec) (CDCl3): 2.20 (s, 3H, CH3),
(heptane/ethyl 2.50 (s, 3H, CH3), 5.06–5.14
(m, 2H, CH2), 5.39 (d, J = 5.1,
acetate)
2H, CH2), 5.80–5.90 (m, 1H,
=CH), 7.63–7.67 (m,.2H,
C6H4), 7.77–7.82 (m, 2H,
C6H4).
201–204
(ethanol)
R1 = allyl
R = C6H5
R1 = CH3
12b
13a
(CDCl3): 3.46 (s, 3H, NCH3),
6.77 (s, 1H, =CHCOC6H5), 7.41
(t, J = 7.3, 1H, C6H5), 7.47–7.52
(m, 4H, C6H5), 7.56 (t, J = 7.3,
1H, C6H5), 7.68 (d, J = 7.3, 2H,
C6H5), 7.79 (s, 1H, =CHC6H5),
8.00 (d, J = 7.2, 2H, C6H5).
254–257 (dec) (CDCl3): 2.17 (s, 3H, CH3),
(nitromethane) 2.48 (s, 3H, CH3), 3.84 (s, 3H,
NCH3), 7.63–7.69 (m, 2H,
C6H4), 7.76–7.82 (m, 2H,
C6H4).
R1 = CH3
(CDCl3): 1.25 (t, J = 7.1, 3H,
CH2CH3), 2.70 (t, J = 6.8, 2H,
CH2), 3.26 (d, J = 5.2, 3H,
NCH3), 3.52 (t, J = 6.8, 2H,
CH2), 4.15 (quartet, J = 7.1,
2H, CH2CH3), 7.55–7.59 (m,
2H, C6H4), 7.66–7.70 (m, 2H,
C6H4), 10.82 (br s, 1H, NH).
12a
Table 1. (continuation)
11
124–125
(toluene)
73
1710 (C=O)
1640 (C=O)
1600, 1530, 1500
(C=C)
1420 (N–CH3)
321(100; M+), 322(23),
320(28), 304(38),
244(51), 134(53),
105(20), 82(33), 77(21),
51(5)
(CDCl3): 30.4 (q, NCH3),
95.0 (d, C-1¢), 122.8 (s, C-5),
127.6, 128.7, 129.2, 130.1,
130.8, 132.5, 133.9, 138.3
(2C6H5), 133.6 (d, =CH2),
155.8 (s, C-2), 166.8 (s, C-4),
188.4 (s, C=O).
21 (acetone)
20 (acetone)
36 (acetone)
1710 (C=O)
1670 (C=O)
1600–1500
(C=C)
1380–1360
((CH3)2)
1710 (C=O)
1670 (C=O)
1590, 1510
(C=C),
1360 (C(CH3)2)
1740 (C=O)
1720 (C=O)
1650–1630 br
(C=C)
1600–1550 br
(C=C)
1420–1390 br
(CH2 and CH3)
325(100; M+), 296(44)
280(12), 268(11),
212(66), 182(17),
154(33), 127(9),
104(10), 86(56)
299(100; M+), 300(18),
271(14), 207(9),
186(22), 158(7), 128(6),
104(6), 86(30), 71(16)
decomposition
21.8 (q, CH3), 26.8, (q,
CH3), 49.4 (t, NCH2), 104.5
(s, C-1¢), 116.9 (t, =CH2),
117.9 (s, C-5), 121.8, 122.7,
133.8, 134.0, 139.4, 140.1,
(C6H4), 131.7 (d, =CH),
154.8 [s, =C(CH3)2], 160.1
(s, C-2), 165.0 (s, C-4),
185.8 (s, C=O), 191.9 (s,
C=O).
21.7 (q, CH3), 26.8 (q, CH3),
36.3 (q, NCH3), 104.6 (s,
C-1¢), 117.9 (s, C-5), 121.7,
122.5, 133.7, 134.0, 139.5,
140.1,(C6H4), 154.6 [s,
=C(CH3)2], 160.9 (s,
C-2),165.4 (s, C-4), 185.8
(s, C=O); 191.5 (s, C=O).
(CDCl3): 14.17 (CH2CH3),
31.53 (CH2), 31.98 (NCH3),
35.13 (CH2), 60.93
(CH2CH3), 104.14 (CH-2),
121.29, 132.98, 138.95,
(C6H4), 169.86, 171.14
(C-1, C=O).
1110
T.S. Jagodziñski, A. Weso³owska and J.G. Soœnicki
15a
14
13c
R1 = CH3
R = CH3
R 1 = C 6 H5
234–236
(ethanol)
246–249
(ethanol)
233–235
(ethanol)
(CDCl3): 3.95 (s, 3H, NCH3),
7.47–7.55 (m, 3H, C6H5),
7.65–7.73 (m, 4H, C6H5, C6H4),
7.86–7.88 (m, 2H, C6H4), 7.92
(s, 1H, =CHC6H5).
(CDCl3): 2.11–2.15 (m, 2H,
CH2), 2.61 (pseudo t, J = 6.9,
2H, CH2), 7.10 (d, J = 6.9, 1H,
C6H4), 7.32–7.54 (m, 10H,
C6H4, 2C6H5), 7.73 (d, J = 7.3,
2H, C6H5), 7.77 (s, 1H,
=CHC6H5), 8.05 (dd, J = 1.3,
7.7, 1H, C6H4).
(CDCl3): 2.15 (s, 3H, CH3),
5.70 (s, 1H, =CHCOCH3),
7.27–7.32 (m, 2H, C6H5), 7.43
(tt, J = 2.1, 7.4, 1H, C6H5),
7.47–7.53 (m, 2H, C6H5),
7.56–7.63 (m, 3H, C6H5), 7.68
(d, J = 7.3, 2H, C6H5), 7.80
(s, 1H, =CHC6H5).
Table 1. (continuation)
13b R = C6H5 267–269 (dec) (CDCl3): 6.45 (s, 1H,
=CHCOC6H5), 7.35–7.55
R1 = C6H5 (ethanol)
(m, 8H, C6H5), 7.58–7.68 (m,
3H, C6H5), 7.73 (d, J = 7.42,
2H, C6H5), 7.77 (d, J = 7.3, 2H,
C6H5), 7.85 (s, 1H, =CHC6H5).
(CDCl3): 36.5 (q, NCH3),
106.2 (s, C-1¢), 120.1 (s, C-5),
122.1, 122.8, 129.4, 131.1,
133.3, 134.1, 134.5, 139.7,
140.4 (C6H4, C6H5), 136.8 (d,
=CHC6H5), 160.5 (s, C-2),
167.8 (s, C-4), 185.6 (s,
C=O), 191.4 (s, C=O).
1710 (C=O)
1630 (C=O)
1600, 1500,
1525 (C=C)
66
64
98
347(100; M+), 319(10), 1720 (C=O)
75
274(6), 190(8), 158(5), 1660 (C=O)
143(56), 102(7), 76(13),
1590, 1500–1450
50(4), 32(6)
(C=C)
1420 (N–CH3)
decomposition
1710 (C=O)
1650 (C=O)
1610, 1600
1500 (C=C),
1360 (CH3)
321(100; M+), 306(96),
304(48), 281(40),
278(66), 253(10),
207(82), 144(50),
134(99), 77(34)
(CDCl3): 30.5 (q, CH3),
100.3 (d, C-1¢), 122.5 (s,
C-5), 128.0, 129.1, 129.8,
130.0, 130.2, 130.7, 133.8,
135.1 (2C6H5), 133.2 (d,
=CH), 153.6 (s, C-2),166.5
(s, C-4), 196.0 (s, C=O).
(CDCl3): 26.9 (t, CH2), 28.1
(t, CH2), 109.5 (s, C-1¢),
127.1 127.4, 127.5, 127.7,
128.9, 129.1, 129.5, 129.7,
130.9, 132.6, 132.7, 134.3,
137.9, 141.7 (C6H4, 2C6H5),
133.8 (d, CHC6H5), 148.3
(s, C-2), 168.9 (s, C=O),
187.4 (s, C=O).
1710 (C=O)
1640 (C=O)
1600, 1580
1520 (C=C)
decomposition
(CDCl3): 96.8 (d, C-1¢),
122.6 (s, C-5), 127.6, 128.0,
128.6, 129.2, 129.9, 130.1,
130.3, 130.8, 132.4, 135.1,
138.1 (3C6H5), 133.8 (d,
=CH), 156.2 (s, C-2), 166.5
(s, C-4), 188.5 (s, C=O).
Reactions of secondary b-ketothioamides with ethyl bromoacetate...
1111
*could be interchanged.
Table 1. (continuation)
15b R1 = allyl 202–205
(ethanol)
(CDCl3): 5.10–5.17 (m, 2H,
CH2), 5.50 (dt, 2H, J = 1.4,
5.2, =CH2), 5.82–5.94
(m, 1H, =CH), 7.45–7.55 (m,
3H, C6H5), 7.68–7.74 (m, 4H,
C6H4, C6H5), 7.81–7.88
(m, 2H, C6H4), 7.93 (s, 1H,
=CHC6H5).
(CDCl3): 49.5 (t, NCH2),
106.1 (s, C-1¢), 117.3 (t,
=CH2), 120. (s, C-5), 122.1,
123.0, 129.4, 131.0, 131.1,
133.3, 134.2, 134.5, 139.5,
140.3 (C6H4, C6H5), 131.6
(d, =CHCH2), 137.1
(d, =CHC6H5), 159.7 (s,
C-2), 167.4 (s, C-4), 185.6
(s, C=O), 191.7 (s, C=O).
decomposition
1720 (C=O)
1660 (C=O)
1600, 1500
(C=C)
77
1112
T.S. Jagodziñski, A. Weso³owska and J.G. Soœnicki
Reactions of secondary b-ketothioamides with ethyl bromoacetate...
1113
EXPERIMENTAL
Melting points were determined on a digital apparatus Electrothermal model IA9300 and are uncorrected. The IR spectra were taken with a Specord M80 instruments in KBr pellets. The 1H- and 13C-NMR
spectroscopic measurements were performed on a Bruker DPX 400 MHz spectrometer in CDCl3 with
TMS as an internal standard. The starting thioamides 1, 3a–c, 5, 6a,b were prepared as described earlier
[2,11]. Purity and molecular mass determinations were carried out by gas chromatography – mass spectrometry (GC/MS) on a Hewlett-Packard instrument model HP 6890 equipped with a mass detector HP
5973. The analytical procedure was developed for a 30 m long capillary column, 0.2 mm in diameter, with
methylsiloxane modified with phenyl groups (5% Ph, Me siloxane) in the 0.25 Xm thick active phase
layer. The results of elemental analyses (C, H, S) data were within ±0.3% of the calculated values.
4-Morpholinocoumarin (2): To 4-(2-hydroxythiobenzoyl)morpholine (1, 8 g, 0.036 mol), dissolved in dry benzene (60 ml), ethyl bromoacetate (9.01 g, 0.054 mol) was added. The mixture was left
standing in a closed flask for 3–4 days at room temperature. The precipitated crystals (2 g) of the
S-alkylation product were filtered and without purification treated with methylene chloride (60 ml) followed with triphenylphosphine (1.47 g, 0.0056 mol) and triethylamine (1.3 g, 0.013 mol). All the operations were carried out under an argon atmosphere. The mixture was stirred for 1 h and left standing at room
temperature for 24 h, washed with 10% aqueous sodium hydroxide (20 ml) and (2´30 ml) with water, and
finally dried over magnesium sulfate. Upon evaporation of the solvent the crude product was dissolved in
ethyl acetate and passed through a 10-cm thick layer of neutral aluminum oxide. The solid left after evaporation of ethyl acetate was recrystallized from ethanol. Colorless crystals (0.2 g, 17% yield), m.p.
138–141°C.
2-Acylmethylidene-1,3-thiazolidin-4-ones (4a-e, 7a,b, 8a,b) and 2-acylmethylidene-5-isopropylidene-1,3-thiazolidin-4-ones (12a,b). General procedure: Anhydrous K2CO3 (3.45 g, 0.025 mol)
and ethyl bromoacetate (1.84 g, 0.011 mol) or ethyl bromopropionate (1.99 g, 0.011 mol) were added to
the solution of the b-keto thioamide (3a–c, 5, 6a,b, 0.01 mol) in dry THF or acetone (30 ml). The mixture
was stirred for 2 h at room temperature and then left overnight. A gradual discoloration of the solution was
observed. The progress of the reaction was monitored by TLC (silufol/hexane:ethyl acetate 3:2). Upon
filtering off the solid parts the solvent was removed under reduced pressure and the semi-solid residue
was dissolved in ethyl acetate and passed through a 10-cm column packed with neutral aluminum oxide,
activity II. Evaporation of ethyl acetate left the crude product, which was purified by recrystallization
from an appropriate solvent. Detailed physico-chemical data of isolated products are given in Table 1.
2-Acylmethylidene-5-benzylidene-3-alkyl(aryl)-1,3-thiazolidin-4-ones (13a–c, 14, 15a,b). General procedure: The 2-acylmethylidene-1,3-thiazolidin-4-one (4a–c, 7a, 8a,b, 0.01 mol), benzaldehyde
(1.2 g, 1.1 ml, 0.011 mol), and triethylamine (5.05 g, 7 ml, 0.05 mol) were refluxed in ethanol (20 ml) until
the thiazolidinone substrate disappeared. The progress of the reaction was monitored by TLC (silufol/hexane:ethyl acetate 3:2). Thorough cooling initiated crystallization. The crystals of crude product
were purified by recrystallization from ethanol. Detailed physico-chemical data of the products are given
in Table 1.
Acknowledgments
We express thanks to Professor Jerzy Lange (Warsaw University of Technology) for helpful discussions
and assistance in preparation of the manuscript.
REFERENCES
1. Takahata H. and Takao Y., Heterocycles, 27, 1953 (1988).
2. Bauer W. and Kuhlein K., in Houben-Weyl “Methoden der Organischen Chemie”, Ed. Georg Thieme
Verlag, Stuttgartd - NY 1985, E5, p. 1218.
3. Jagodziñski T., Org. Prep. Proc. Int., 22, 755 (1990).
4. Jagodziñski T.S., Soœnicki J.G. and Nowak-Wydra B., Polish J. Chem., 67, 1043 (1993).
1114
T.S. Jagodziñski, A. Weso³owska and J.G. Soœnicki
5. Jagodziñski T., Soœnicki J. and Królikowska M., Heterocyclic Communications, 1, 355 (1995).
6. ¯ankowska-Jasiñska W. and Eilmes J., Roczn. Chem., 50, 1059 (1976).
7. Borisevich A.N., Shulezhko S.A. and Pelkis P., Khim. Geterotsikl. Soedin., 368 (1966).
8. Curcumelli-Rodostamo M. and Harrison W.A., Can. J. Chem., 48, 2632 (1970).
9. Pocar D., Rossi L.M. and Trimarco P., J. Heterocycl. Chem., 12, 401 (1975).
10. Bogdanowicz-Szwed K., Kozicka M. and Lipowska M., J. Prakt. Chem., 331, 231 (1989).
11. Bogdanowicz-Szwed K., Nowak I. and Tyrka M., J. Prakt. Chem/Chem.-Ztg., 337, 71 (1975).
12. Roth M., Dubs P., Goetschi E. and Eschenmoser A., Helv. Chim. Acta, 54, 510 (1971), and references
therein.
13. Rudorf W.D. and Augustin M., Z. Chem., 21, 69 (1981).
14. Boldwin J.E., J. Chem. Soc., Chem. Comm., 734 (1976).
15. Soœnicki J.G. and Wichert-Tur Z., Mag. Res. Chem., 37, 605 (1999).
16. Anulewicz R., Krygowski T.M. and Jagodziñski T., Polish J. Chem., 72, 439 (1998).
17. Hansen P.E., Duus F., Bolvig S. and Jagodziñski T.S., J. Mol. Struct., 378, 45 (1996).
18. Satzinger G., Ann. Chem., 665, 150 (1963).
19. Harvieu G., Rioulet Ph. and Vialle J., Bull. Soc. Chim. France, 12, 4380 (1971).