Synthesis of the thioamide derivatives of methyl vinyl ketone and their cyclization to 2,3-dihydro-4H-thiopyran-4-ones

Article abstract of DOI:10.1007/s10593-006-0067-5

A novel synthesis of thioamide derivatives of methyl vinyl ketone and their cyclization to 2,3-dihydro-4H-thiopyran-4-ones were developed. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0067-5

Chemistry of Heterocyclic Compounds, Vol. 42, No. 2, 2006
SYNTHESIS OF THE THIOAMIDE DERIVATIVES
OF METHYL VINYL KETONE AND THEIR CYCLIZATION
TO 2,3-DIHYDRO-4H-THIOPYRAN-4-ONES
L. Gros, S. Westerlich, A. Wesolowska, and T. S. Jagodzinski
A novel synthesis of thioamide derivatives of methyl vinyl ketone and their cyclization to 2,3-dihydro-
4H-thiopyran-4-ones were developed.
Keywords: benzylideneacetone, 2,3-dihydro-4H-thiopyran-4-ones, α-ionone, pseudoionone phenyl
isothiocyanate, thioamides.
The structure of many organic compounds of type 1, including natural products, incorporates the methyl
vinyl ketone fragment. We have developed a simple method which makes it possible to build a thioamide
function on the methyl group of such compounds. It consists in the reaction of the anion generated in situ from
arylidene- or alkylideneacetone 1, in particular, benzylidene- acetone, α-ionone, and pseudoionone, with an
isothiocyanate. Both aromatic and aliphatic isothiocyanates are reactive under the applied reaction conditions
(from 0°C to room temperature). In contrast to the earlier report [1], the reaction yields linear thioamides which
proved to be versatile synthons to give heterocyclic compounds in intra- and intermolecular reactions [2].
1. R2N=C=S / NaH
monoglyme, 0°C – r.t.
O
O
S
OH
S
R1
NHR2
NHR2
R1
R1
2. H3O+
2a–c
1a–c
+
O
O
H
OH
+
+
H
R
S
NHPh
+
R
O
HS
NHPh
R
HS
NHPh
2a–c
H+
6-exo-trig
–
B
–
O
O
H+
+
–
R
S
NHPh
R
R
S
NHPh
S
NHPh
6-endo-trig
3a–c
2,3 a R = Ph, b R = 2,6,6-trimethylcyclohex-2-enyl, c CH2=CMe(CH2)3MeC=CH−
__________________________________________________________________________________________
Szczecin University of Technology, Institute of Chemistry and Environmental Protection, 71-065
Szczecin, Poland; e-mail: jagszcz@ps.pl. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 2,
pp. 201-204, February, 2006. Original article submitted October 18, 2005.
176
0009-3122/06/4202-0176©2006 Springer Science+Business Media, Inc.

Now we present the cyclization reactions converting the prepared thioamides 2a-c into the derivatives of
2,3-dihydro-4H-thiopyran-4-one 3a-c. With reference to the Baldwin rules [3] they can proceed in an alkaline
medium as a 6-endo-trig, and in an acidic medium as a 6-exo-trig process, although the former seems to be
disfavored. In the presence of triethylamine, prolonged heating of the thioamides in ethanol secures only a
moderate yield of 3. When thioamides 2 are heated in toluene or benzene with TsOH acid, thiopyranones 3 are
formed along with some difficultly identifiable and removable by-products. However, if the BF3–AcOH
complex is used as the reaction catalyst, a quantitative yield (crude product) of thiopyranones 3 is reached in
10 min.
Both thioamides 2 and their cyclic counterparts turned out to be highly reactive substrates in other
reactions, the results of which will be published separately.
EXPERIMENTAL
1H and 13C NMR spectra were registered on a Bruker DPX 400 spectrometer (400 and 100 MHz for
1H and 13C respectively). For 2D-spectra a standard Bruker software was used. IR spectra were taken with a
Specord M-80 instrument.
Thioamides 2a-c (General Procedure). A solution of the appropriate benzylidene- or alkylideneacetone
(10 mmol) and phenyl isothiocyanate 1.65 g (12 mmol) in 10 ml of monoglyme was added dropwise under
nitrogen to a stirred cold (0°C) suspension of NaH (25 mmol, 80% in mineral oil) in 25 ml of monoglyme. The
reaction mixture was allowed to reach room temperature and stirred for 2.5 h or left standing overnight. The
yellow-brown mixture was poured into a 10% HCl solution with crushed ice and the organic product was
extracted with ethyl acetate. After a routine work-up, the crude products were chromatographed on silica gel
using n-hexane–ethyl acetate (1:1) as the eluent. Recrystallization from appropriate solvent gave the final
products.
3,4-Dihydrothiopyran-4-ones 3a-c (General Procedure). Two ml of BF3–2AcOH (36% BF3, Fluka)
were added to a stirred solution of the thioamide 2 (0.33 mmol) in 2 ml of dry THF and the reaction was
monitored by TLC until the substrates disappeared. Upon dilution with water, the organic product was extracted
with ethyl acetate and the extract was washed with water and passed under reduced pressure through a 10-cm
column packed with Al2O3. Concentration of the eluate gave crude products which were purified by
recrystallization from toluene. In the case of 3c, the crude product was chromatographed on silica gel using
n-hexane–ethyl acetate (1:1) as the eluent.
3-Hydroxy-5-phenylpenta-2,4-dienethioic acid phenylamide (2a). Yield 86%. Yellow solid;
mp 140-143°C (methanol). IR spectrum (KBr), νmax, cm-1: 3292 (NH), 1630 (C=C, CH), 1522 (NH, CN), 1400
1
(OH, CO), 1318 (CN), 1208 (NCS). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz), enol form: 6.00 (1H, s,
CH=COH); 6.75 (1H, d, J = 15.8, PhCH=CH); 7.32-7.77 (10H, m, 2C6H5); 7.61 (1H, d, J = 7.6, PhCH=CH);
11.40 (1H, s, NH), 14.26 (1H, s, OH). 13C NMR spectrum (DMSO-d6), δ, ppm: 103.90 (CHCOH), 124.68,
128.26, 129.10, 129.35, 135.71, 138.82 (C6H5), 129.83 (PhCH=CH), 135.88 (PhCH=CH), 167.04 (C−OH),
1
189.72 (C=S). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz), ketone form: 4.30 (2H, s, COCH2CS); 6.99 (1H,
d, J = 16.2, PhCH=CH); 7.32-7.77 (10H, m, 2 C6H5); 7.86 (1H, d, J = 7.7, PhCH=CH); 11.80 (1H, s, NH).
Found, %: C 72.11; H 5.23; N 4.95; S 11.72. C17H15NOS. Calculated, %: C 72.57; H 5.37; N 4.98; S 11.40.
3-Hydroxy-5-(2,6,6-trimethylcyclohex-2-enyl)penta-2,4-dienethioic Acid Phenylamide (2b).
Yield 61%. Yellow solid; mp 125-127°C (hexane–benzene). IR spectrum, νmax, cm-1: 3304 (NH), 2970-2880
(OH···S=C, C−H), 1642 (C=C, C−H), 1586 (C=C), 1526 (NH, C−N), 1400 (OH, C−O), 1322 (C−N), 1208
1
(NCS). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz), enol form: 0.80 (3H, s, CH3); 0.88 (3H, s, CH3);
1.10-1.23 (1H, m, =CHCH2CHH); 1.30-1.43 (1H, m, =CHCH2CHH); 1.5 (3H, s, CH3); 1.94-2.03 (2H, m,
=CHCH2CHH); 2.3 (1H, d, J = 9.6, CHCH=CH); 5.46 (1H, s, C=CHCH2); 5.81 (1H, s, CH=COH); 5.90 (1H, d,
177

J = 15.2, C=CHCOH); 6.37 (1H, dd, J = 15.2, J = 9.9, CHCH=CH); 7.30-7.52 (3H, m, C6H5); 7.58 (2H, d,
J = 7.8, C6H5); 11.25 (1H, s, NH), 14.11 (1H, s, OH). 13C NMR spectrum (DMSO-d6), δ, ppm: 22.87 (CH3),
23.00 (=CCH2), 26.95 (CH3), 27.04 (CH3), 31.33 (CHCH2CH2), 32.58 (CH2CH2C), 53.98 (CHCH=CH), 102.29
(CH=COH), 122.11 (CH=CHCH2), 128.36 (CH=CHCOH), 131.17 (CH=CHCOH), 132.93 (CH3C=CH), 124.54,
1
126.55, 129.01, 138.79 (C6H5), 166.73 (COH), 189.97 (C=S). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz),
ketone form: 0.84 (3H, s, CH3); 0.87 (3H, s, CH3); 1.10-1.23 (1H, m, =CHCH2CHH); 1.30-1.43 (1H, m,
=CHCH2CHH); 1.49 (3H, s, CH3); 1.94-2.03 (2H, m, =CHCH2CHH); 2.34 (1H, d, J = 9.6, CHCH=CH); 4.20
(2H, s, CSCH2CO); 5.46 (1H, s, C=CHCH2); 6.13 (1H, d, J = 15.8, C=CHCO); 6.71 (1H, dd, J = 15.8, J = 9.9,
CHCH=CH); 7.30-7.52 (3H, m, C6H5); 7.81 (2H, d, J = 7.8, C6H5); 11.76 (1H, s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 22.87 (CH3), 23.08 (=CCH2), 26.77 (CH3), 27.94 (CH3), 31.14 (=CHCH2CH2), 32.86
(CH2CH2C), 53.89 (CHCH=CH), 58.72 (CH2CS), 122.70 (C=CHCH2), 132.19 (CH3C=CH), 139.83
(CH=CHCO), 123.27, 126.55, 129.08, 140.48 (C6H5), 149.34 (CH=CHCO), 193.63 (C=O), 195.14 (C=S).
Found, %: C 73.03; H 7.45; N 4.15; S 10.16. C20H25NOS. Calculated, %: C 73.35; H 7.96; N 4.28; S 9.79.
3-Hydroxy-7,11-dimethyldodeca-2,4,6,10-tetraenethioic Acid Phenylamide (2c). Yield 65%. Dark
oil. IR spectrum (thin layer), νmax, cm-1: 3276-3164 (NH, OH), 1738 (C=O), 1612-1556 (C=C−OH, C=C), 1060
1
(C=S). H NMR spectrum (CDCl3), δ, ppm (J, Hz), enol form: 1.86 (6H, s, CH3); 2.02 (3H, s, CH3); 2.08-2.25
(4H, m, 2CH2); 4.94-5.04 (1H, m, =CHCH2); 5.60 (1H, s, CHCOH); 5.73 (1H, d, J =14.6, =CHCOH); 5.94 (1H,
d, J = 11.3, =CHCH=); 7.14-7.36 (8H, m, C6H5, =CHCH=CH); 7.39-7.49 (4H, m, C6H5); 8.12 (1H, br. s, NH),
14.57 (1H, s, OH). 13C NMR spectrum (CDCl3), δ, ppm: 17.47 (CH3), 17.71 (CH3), 25.70 (CH3), 26.39
(CHCH2CH2), 40.42 (CH2CH2C), 103.80 (C=COH), 120.48 (=CHCH=), 123.02 (CHCOH), 123.74 (C=CHCH2),
132.58 (C=CHCH2), 123.38, 125.33, 126.81, 137.89 (C6H5), 141.03 (CH3CCH2), 142.90 (C=CHCOH), 171.20
(C−OH), 197.13 (C=S). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz), ketone form: 1.88 (6H, s, CH3); 2.02 (3H, s,
CH3); 2.08-2.25 (4H, m, 2CH2); 4.24 (2H, s, CH2CS); 5.04-5.16 (1H, m, =CHCH2); 6.07 (1H, d, J = 11.3,
=CHCH=); 6.15 (1H, d, J =14.9, =CHCOH); 7.14-7.36 (8H, m, C6H5, =CHCH=CH); 7.39-7.49 (4H, m, C6H5);
11.21 (1H, br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm: 17.71 (CH3), 21.06 (CH3), 25.70 (CH3), 26.95
(CHCH2CH2), 40.66 (CH2CH2C), 60.42 (CH2CS), 121.86 (=CHCH=), 124.25 (CHCO), 132.17 (C=CHCH2),
123.48, 125.11, 126.50, 138.73 (C6H5), 155.26 (C=CHCOH), 190.54 (C=S), 193.55 (C=O). Found, %: C 73.23;
H 7.65; N 4.13; S 10.08. C20H25NOS. Calculated, %: C 73.35; H 7.69; N 4.28; S 9.79.
2-Phenyl-6-phenylamino-2,3-dihydrothiopyran-4-one (3a). Yield 54%. Pale yellow solid;
mp 195-197°C (toluene). IR spectrum (KBr), νmax, cm-1: 3212 (NH), 1590 (C=O, C=C), 1550-1500 (NH, C−N,
C=C), 1444 (C−H), 1262 (NH). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.65 (1H, dd, J = 16.2, J = 2.8,
CHH); 3.02 (1H, dd, J = 16.1, J = 3.0, CHH); 4.77 (1H, dd, J = 12.7, J = 2.5, Ph−CH); 5.67 (1H, s, =CH); 7.10
(1H, t, J = 7.3, N−Ph); 7.19 (2H, d, J = 8.0, N−C6H5); 7.26-7.40 (5H, m, C−C6H5, N−C6H5); 7.45 (2H, d, J = 7.5,
C−C6H5); 9.41 (1H, s, NH). 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 44.38 (CH2), 45.03 (CH), 98.55
(=CH), 123.53, 125.13, 128.12, 128.58, 129.18, 129.53, 138.76, 139.33 (2 C6H5), 160.92 (=C), 192.20 (C=O).
Found, %: C 72.49; H 5.29; N 4.89; S 11.20. C17H15NOS. Calculated, %: C 72.57; H 5.37; N 4.98; S 11.40.
6-Phenylamino-2-(2,6,6-trimethylcyclohex-2-enyl)-2,3-dihydrothiopyran-4-one (3b). Yield 90%.
Pale yellow solid; mp 193-197°C (heptane–toluene). IR spectrum (CHCl3), νmax, cm-1: 3400 (NH), 1608 (C=O,
C=C), 1550-1500 (NH, C−N, C=C), 1252 (NH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.84 (3H, s, CH3);
0.95 (3H, s, CH3); 1.12-1.17 (1H, m, CCHHCH2); 1.56 (1H, dd, J = 22.4, J = 9.3, CCHHCH2); 1.69 (1H, s,
CCHC); 1.81 (3H, s, CH3); 1.97 (2H, s, =CCH2); 2.53 (1H, t, J = 15.8, COCHH); 2.87 (1H, t, J = 15.6,
COCHH); 3.80 (1H, d, J = 14.1, SCH); 5.48 (1H, s, C=CHCH2); 5.72 (1H, s, C=CHCO); 7.05-7.10 (3H, m,
C6H5); 7.11-7.27 (2H, m, C6H5). 13C NMR spectrum (CDCl3), δ, ppm: 22.27 (=CCH2), 26.37 (CH3), 27.08
(CH3), 28.41 (CH3), 30.38 (=CCH2CH2), 33.27 (CH2C), 43.53 (SCH), 47.89 (CH2CO), 53.46 (=CCH), 99.62
(CCHCO), 123.34, 125.51, 129.45, 138.30 (C6H5), 124.76 (=CCH2), 132.29 (C=CCH2), 162.35 (SC=CH),
195.33 (C=O). Found, %: C 73.33; H 7.48; N 4.20; S 9.65. C20H25NOS. Calculated, %: C 73.35; H 7.69; N 4.28;
S 9.79.
178

2-(2,6-Dimethylhepta-1,5-dienyl)-6-phenylamino-2,3-dihydrothiopyran-4-one (3c). Yield 52%. Dark
1
oil. IR spectrum (thin layer), νmax, cm-1: 3188 (NH), 1738 (C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
1.52 (3H, s, CH3); 1.61 (3H, s, CH3); 1.97 (3H, s, CH3); 1.88-2.06 (4H, m, 2CH2); 2.58 (2H, t, J = 7.2, CH2CO);
4.01-4.08 (1H, m, CHS); 4.95-5.06 (1H, m, CHCH2); 5.46-5.53 (1H, m, =CHCH); 5.75 (1H, s, CHCO); 7.05-
13
7.13 (3H, m, C6H5); 7.23-7.28 (2H, m, C6H5). C NMR spectrum (CDCl3), δ, ppm: 14.2 (CH3), 17.77 (CH3),
21.08 (CH3), 25.70 (SCH), 25.73 (=CCH2), 39.38 (CH2C=), 46.80 (CH2CO), 99.57 (=CHCO), 120.80
(=CHCHS), 123.22 (=CCH2CH2), 123.37, 125.50, 129.45, 138.02 (C6H5), 132.54 (CH3C=CH), 142.35
(CH2CH2C=C), 161.90 (C−NH), 194.18 (C=O). Found, %: C 73.29; H 7.55; N 4.22; S 10.01. C20H25NOS.
Calculated, %: C 73.35; H 7.69; N 4.28; S 9.79.
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J. Becher, H. Nissen, and K. S. Varma, Liebigs Ann. Chem., 1109 (1986).
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