Jul-Aug 2008
New Results of the THORPE-ZIEGLER Cyclization
1075
d6): ꢀ 3.55 -3.75 (br, 8H, NCH2,CH2O), 6.71 (br, 2H, NH2), 7.55
(m, 5H, CHar),. 13C nmr (DMSO-d6): ꢀ 47.43 (C-11, NCH2),
68.09 (C-12, OCH2), 81.93 (t, C-6), 112.32 (s, C-4), 117.28 (s,
CN-9), 129.23 (t, o-C-14), 129.38 (d, m-C-15), 131.26 (t, p-C-
16), 135.03 (t, i-C-13), 146.32 (t, C-5), 165.74 (s, C-3) 160.71
(s, C-7), 172.43 (m, C-1). Anal. Calcd. for C17H15N5OS (337.40):
C, 60.52; H, 4.48; N, 20.76; S, 9.50. Found: C, 60.53; H, 4.53;
N, 20.81; S, 9.38.
3H, CH3), 2.69 (s, 3H, SCH3), 7.50 (br, 2H, NH2). 13C nmr
(DMSO-d6): ꢀ 16.85 (C-11, SCH3), 28.17 (C-6, CH3), 97.32 (t,
C-2), 107.91 (t, C-4), 112.96 (s, CN-10), 154.18 (s, C-3), 159.81
(q, C-1), 187.92 (q, C-5, C=O). Anal. Calcd. for C8H8N2OS2
(212.28) : C, 45.23; H, 3.80; N, 13.20; S, 30.21. Found: C,
45.19; H, 3.84; N, 13.22; S, 30.56.
5-Acetyl-4-amino-2-(4-morpholinyl)-thiophen-3-carboni-
trile (22c). 1.27 g (0.006 mole) 21c was heated with 5 mL
morpholine to reflux for 30 min. The surplus morpholine was
evaporated and the residue poured in ice-cold saturated solution
of NaCl in water was purified by filtration. Yield: 0.67 g (45%),
green crystals, mp 275-277° (CH3NO2/CH3CN 1:1), ir: 3413,
3383 (NH2), 2950, 2900, 2850 (CH2), 2201 (CN), 1600 (C=O),
4-Amino-5-benzoyl-2-methylthio-thiophen-3-carbonitrile (21a).
1.94 g (0.01 mole) 1 dissolved in 15 mL DMSO was dropped
under stirring at 60°C to 1.99 g (0.01 mole) phenacyl bromide
dissolved in 3 mL glacial acetic acid. After stirring for 30 min
the mixture was poured in 50 mL water and after 1-2 h the
precipitate was collected by filtration and crystallized in ethanol.
Furthermore the product can be washed with CS2. Yield: 1.73 g
(63%), mp 149-151° (ethanol), ir: 3400, 3312, 3288 (NH2), 2220
1
1501 (C=C), 1245, 1116 (CH2), cm-1, H nmr (DMSO-d6): ꢀ
2.22 (s, 3H, CH3), 3.62, 3.75 (t, each 4H, NCH2CH2O), 7.51 (br,
2H, NH2). 13C nmr (DMSO-d6): ꢀ 27.80 (C-6, CH3), 49.76 (C-
11, NCH2), 65.04 (C-12, OCH2), 79.33 (t, C-2), 104.81 (t, C-4),
115.08 (s, CN-10), 162.10 (s, C-3), 166.20 (m, C-1), 183.52 (q,
C-5, C=O). Anal. Calcd. for C11H13N3O2S (251.31) : C, 52.57; H,
5.21; N, 16.72; S, 12.75. Found: C, 52.48; H, 5.17; N, 16.60; S,
12.38.
1
(CN), 1594 (C=O), cm-1, H nmr (DMSO-d6): ꢀ 2.65 (s, 3H,
SCH3), 7.45-7.70 (m, 5H , CHar) 7.90 (br, 2H, NH2). 13C nmr
(DMSO-d6): ꢀ 16.66 (C-11, SCH3), 96.99 (t, C-2), 106.21 (t, C-
4), 112.36 (s, CN-10), 127.07 (t, o-C-7), 128.57 (d, m-C-8),
131.23 (t, p-C-9), 140.05 (t, i-C-6), 156.45 (s, C-3), 162.39 (q,
C-1), 185.40 (t, C-5, C=O). Anal. Calcd. for C13H10N2OS2
(274.36) : C, 56.91; H, 3.67; N, 10.21; S, 23.37. Found: C,
56.93; H, 3.70; N, 10.19; S, 23.44.
4-Amino-5-benzoyl-2-methylthio-thiazole (23a). To
a
solution of 3.40 g (0.02 mole) 6 in 30 mL ethanol was dropped a
solution of 3.98 g (0.02 mole) phenacyl bromide in 10 mL
ethanol. The mixture was heated to reflux for 10 min and after
cooling the product was taken and purified by an evaporator.
Yield: 3.96 g (81%), mp 149-151° (ethanol), ir: 3374, 3275
4-Amino-5-benzoyl-2-(4-morpholinyl)-thiophen-3-carbo-
nitrile (22a). 4.12 g (0.015 mole) 21a was heated with 35 mL
morpholine to reflux for 45 min. After cooling the product was
poured in 350 mL water and the yellow crystals were collected
by filtration. Yield: 2.78 g (61%), mp 240-241° (CH3CN), ir:
3407, 3338 (NH2), 3150, (CHar). 2950, 2900 (CH2), 2200, 2198
(CN), 1607 (C=O), 1557 (C=C), 1474, 1113 (CH2), 750, 700
(Car) cm-1, 1H nmr (DMSO-d6): ꢀ 3.60, 3.75 (t, each 4H,
NCH2CH2O), 7.40-7.70 (m, 5H , CHar) 7.91 (br, 2H, NH2). 13C
nmr (DMSO-d6): ꢀ 50.02 (C-11, NCH2), 65.74 (C-12, OCH2),
79.02 (t, C-2), 95.81 (t, C-4), 115.13 (s, CN-10), 127.22 (t, o-C-
7), 128.40 (d, m-C-8), 130.80 (t, p-C-9), ), 140.75 (t, i-C-6),
157.79 (s, C-3), 167.66 (q, C-1), 185.92 (t, C-5, C=O). Anal.
Calcd. for C16H15N3O2S (313.37) : C, 61.13; H, 4.82; N, 13.41;
S, 10.23. Found: C, 61.23; H, 4.75; N, 13.61; S, 10.34.
1
(NH2), 1598 (C=O), 1470, 1376 (CH3), 737, 695 (Car) cm-1, H
nmr (DMSO-d6): ꢀ 2.66 (s, 3H, SCH3), 7.46-7.71 (m, 5H, CHar)
8.10 (br, 2H, NH2). 13C nmr (DMSO-d6) (in accordance with
[11]): ꢀ 15.46 (C-11, SCH3), 99.95 (t, C-4), 126.87 (t, o-C-7),
128.55 (d, m-C-8), 131.07 (t, p-C-9), 141.07 (t, i-C-6), 165.12 (s,
C-3), 175.58 (q, C-1), 184.25 (t, C-5, C=O). Anal. Calcd. for
C11H10N2OS2 (250.33) : C, 52.78; H, 4.03; N, 11.19; S, 25.67.
Found: C, 52.78; H, 4.03; N, 11.12; S, 25.35.
4-Amino-5-benzoyl-2-(4-morpholinyl)-thiazole (24a). 0.37
g (0.0015 mole) 23a was heated with 5 mL morpholine to reflux
for 30 min. The morpholine was evaporated and the residue was
poured in 50 mL water and purificated by filtration. Yield: 0.34
g (78%), mp 182-184° (n-propanol), ir: 3375, 3250 (NH2), 2950,
2900, 2850 (CH2), 1603 (C=O), 1540 (C=C), 1486, 1468, 1431
(CH2), 737, 702 (Car) cm-1. 13C nmr (DMSO-d6) (in accordance
with [12]): ꢀ 47.46 (C-11, NCH2), 65.27 (C-12, OCH2), 93.02 (t,
C-4), 126.63 (t, o-C-7), 128.30 (d, m-C-8), 130.16 (t, p-C-9),
141.90 (t, i-C-6), 166.08 (s, C-3), 171.81 (m, C-1), 182.19 (t, C-
5, C=O). Anal. Calcd. for C14H15N3O2S (289.35) : C, 58.11; H,
5.23; N, 14.52; S, 11.08. Found: C, 58.23; H, 5.25; N, 14.54; S,
11.02.
4-Amino-5-benzoyl-2-(1-piperidinyl)-thiophen-3-carboni-
trile (22b). 2.28 g (0.008 mole) 21a was dissolved in 20 mL
piperidine and heated to reflux for 30 min. After cooling the
mixture was poured in 200 mL water and concentrated by
evaporation. Yield: 1.48 g (59%), mp 161° (CH3CN), ir: 3395
(NH2),. 2900, 2850 (CH2), 2199 (CN), 1599 (C=O), 1549, 1482,
1
1461 (C=C), 730, 700 (Car) cm-1, H nmr (DMSO-d6): ꢀ 1.5 (s,
6H, CH2), 3.50, (m, 4H, NCH2), 7.40-7.70 (m, 5H , CHar) 7.95
(br, 2H, NH2). 13C nmr (DMSO-d6): ꢀ 22.87 (C-13, CH2), 24.86
(C-12, CH2), 51.45 (C-11, NCH2), 76.31 (t, C-2), 93.18 (t, C-4),
115.31 (s, CN-10), 126.77 (t, o-C-7), 128.42 (d, m-C-8), 130.42
(t, p-C-9), ), 140.98 (t, i-C-6), 159.22 (s, C-3), 166.67 (q, C-1),
183.77 (t, C-5, C=O). Anal. Calcd. for C16H15N3O2S (301.40) :
C, 65.57; H, 5.50; N, 13.49; S, 10.30. Found: C, 65.63; H, 5.55;
N, 13.61; S, 10.34.
4-Amino-5-acetyl-2-methylthio-thiazole (23b). To a slowly
stirred solution of 8.52 g (0.05 mole) 6 in 50 mL ethanol was
dropped 4.63 g (4 mL, 0.05 mole) chloroacetone dissolved in 25
mL ethanol. After heating for 15 min to reflux 1 mL trietylamine
was added. The residue was poured in 50 mL water and the
precipitate was collected after filtration. Yield: 1.89 g (10%), mp
155-156° (ethanol), ir: 3396, 3290 (NH2), 1616 (C=O), 1487
5-Acetyl-4-amino-2-methylthio-thiophen-3-carbonitrile
(21c). To a stirred solution of 5.83 g (0.03 mole) 1 in 60 mL
DMSO was dropped over 15 min 2.78 g (0.031 mole) chloro-
acetone. After further stirring for 30 min at 60°C the reaction
mixture was poured in 200 mL water and the precipitate was
collected after evaporation. Yield: 1.20 g (18%), mp 205-207°
(CH3NO2), ir: 3366 (NH2), 2207 (CN), 1604 (C=O), 1505
1
(C=C), 1388 (CH3), cm-1, H nmr (DMSO-d6): ꢀ 2.21 (s, 3H,
CH3), 2.67 (s, 3H, SCH3), 7.62 (br, 2H, NH2). 13C nmr (DMSO-
d6) (in accordance with [11]): ꢀ 15.54 (C-11, SCH3), 29.24 (C-6,
CH3), 101.75 (m, C-4), 162.75 (s, C-3), 172.78 (q, C-1), 186.95
(q, C-5, C=O). Anal. Calcd. for C6H8N2OS2 (188.26) : C, 38.28;
H, 4.28; N, 14.88; S, 43.06. Found: C, 38.24; H, 4.28; N, 14.89;
S, 34.01.
1
(C=C), 1405, 1380 (CH3), cm-1, H nmr (DMSO-d6): ꢀ 2.22 (s,