added to a flask containing THF (20 mL). The stirred solution
was cooled to 0 ◦C and n-butyllithium (1.5 mL, 1.6 M in hexane,
3.78 mmol) was added dropwise via syringe. After 20 min,
diethyl malonate (0.6 mL, 3.6 mmol) was added and the reaction
mixture was stirred for a further 20 min. A solution of 1a (1.00 g,
3.3 mmol) in THF (20 mL) was then added dropwise. A bright
yellow colour appeared instantly. After 1 h the reaction was
complete (by TLC analysis) and was quenched with saturated
aqueous ammonium chloride (20 mL). CH2Cl2 (20 mL) was
added and the phases were separated. The aqueous phase was
extracted with CH2Cl2 (2 ¥ 10 mL) and the combined organic
layers were washed with aqueous sodium bicarbonate (2 ¥ 10 mL),
brine (2 ¥ 10 mL), dried and evaporated to give 2a as a yellow,
low-melting solid. Purification by chromatography using ethyl
acetate–hexane (20 : 80) as eluent gave 2a (1.23 g, 80%) as a
yellow, crystalline solid. The product contained a minor isomer
which could not be separated by chromatography. The ratio was
estimated to be (27 : 1) by 1H NMR spectroscopic integration; mp
68–70 ◦C; (Found C, 64.56; H, 5.77; N, 2.95; S, 7.13. C23H25NO5S
requires C, 64.62; H, 5.89; N, 3.28; S, 7.50%); nmax/cm-1 (KBr)
3354 (br NH), 1749, 1736 (CO ester), 1664 (CO a,b-unsaturated
amide); dH (270 MHz, CDCl3) 1.29 (6H, t, J 7, 2 ¥ CH3CH2O),
2.31 (3H, s, ArCH3), 4.22 (4H, q, J 7, 2 ¥ CH2O), 4.94 [1H, d, J
10, C(4)H], 7.06–7.57 (9H, m, ArH), 7.75 (1H, d, J 10, CH(3) =),
8.62 (1H, br s, NH); dC (67.8 MHz, CDCl3) 13.9 (CH3CH2O),
20.8 (ArCH3), 54.4 [C(4)H], 62.1 (CH2O), 120.1, 127.2, 127.8,
129.0, 129.2 (aromatic CH), 132.3, 133.1, 134.5, 134.7 (C and
SC =), 141.2 (CH =), 160.9 (CO amide), 166.3 (CO ester); MS
m/z 427 (M+, 25%), 381 (25%), 267 [30%, M+-CH2(CO2Et)2],
Addition of the enolate of ethyl acetoacetate.
N-(4-Methylphenyl)-4-ethoxycarbonyl-2-(phenylthio)-5-oxo-
2-hexenamide 4a. Ethyl acetoacetate (0.17 g, 1.32 mmol) was
added to a freshly prepared solution of sodium ethoxide [using
sodium (30 mg, 1.32 mmol) and ethanol (10 mL) at 0 ◦C] and
stirred for 30 min. A solution of b-chloroacrylamide 1a (0.2 g,
0.66 mol) in ethanol (3 mL) was added. After stirring for 3 h
(while slowly returning to room temperature), the reaction mixture
was quenched with water (10 mL). CH2Cl2 (20 mL) was added
and the phases were separated. The organic layer was washed
with brine (2 ¥ 10 mL), dried and evaporated. Excess ethyl
acetoacetate was removed under vacuum at 1 mmHg. Purification
by recrystallisation from ether-CH2Cl2–hexane (10 : 5 : 75) gave
what is tentatively assigned as 4a (29 mg, 11%) as white crystals in
enol tautomeric form; mp 184–185 ◦C; nmax/cm-1 (KBr) 3480 (br
NH), 1711 (CO conjugated ester), 1654, 1592 (CO a,b-unsaturated
amide); dH (270 MHz, CDCl3) 1.22 (3H, t, J 7, CH3CH2O), 2.34
(3H, s, ArCH3), 2.42 [3H, s, C(6)H3], 4.19 (2H, q, J 7, OCH2),
7.01–7.57 (11H, m, ArH and C(5)H = and NH); dC (67.8 MHz,
CDCl3) 14.1 (CH3, CH3CH2O), 19.4 [CH3, C(6)H3], 21.2 (CH3,
ArCH3), 60.9 (CH2, CH2O), 109.6 [C, C(4)], 127.5, 128.6, 129.5,
130.6, 134.0 (CH, ArCH), 128.2, 131.8, 139.2 (3 ¥ C, aromatic C
and PhSC =), 135.8 [CH, C(3)H], 150.6 (C, = COH), 160.8, 165.4
(2 ¥ C, CO amide, CO ester).
Addition of n-Bu2CuLi.
N-(4-Methylphenyl)-2-(phenylthio)-Z-2-heptenamide
7a.
Ether (25 mL) was added to a flask containing CuI (250 mg,
1.32 mmol) which had been freshly purified. The suspension was
cooled to -30 ◦C, n-butyllithium (1.65 mL, 1.6 M in hexane,
2.64 mmol) was added and stirring was continued for 30 min,
after which time the solution was brown and opaque. The reaction
mixture was cooled to -78 ◦C and b-chloroacrylamide 1a (0.20 g,
0.66 mmol) in ether (10 mL) was added quickly. The react◦ion
was complete after 30 min at a reaction temperature of -50 C.
Saturated aqueous ammonium chloride (10 mL) was added and
stirred for 15 min while the reaction mixture was warmed to room
temperature. Saturated aqueous ammonium chloride (10 mL) and
ether (10 mL) were added and the solution was filtered through
a layer of celite. Separation of the phases followed by washing of
the organic phase with brine (2 ¥ 20 mL), drying and evaporation
gave a yellow oil. Purification by chromatography using ethyl
acetate–hexane (5 : 95) as eluent gave 7a-Z (85 mg, 40%) as a light
yellow solid; mp 43–45 ◦C; (Found C, 73.40; H, 7.00; N, 4.21; S,
9.84. C20H23NOS requires C, 73.81; H, 7.21; N, 4.30; S, 9.85%);
1
109 (91%). Signals for the minor isomer were seen in H NMR
spectrum at 5.42 [1H, d, J 10, C(4)H], 6.82 (1H, d, J 10, CH =);
all other signals were identical to the major isomer.
Alkylation of 2c.
N-Phenylmethyl-4,4-di(ethoxycarbonyl)-2-phenylthiohept-2,6-
dienamide 3a. Potassium carbonate (0.19 g, 1.41 mmol) was added
to a solution of 2c (0.30 g, 0.70 mmol) in acetonitrile (6 mL).
A solution of allyl bromide (0.12 mL, 1.41 mmol) in acetone
(3 mL) was added and the reaction mixture was stirred overnight
under nitrogen. Ether (10 mL) was added to precipitate the salts,
and the mixture was filtered through a celite plug. The filtrate
was then dried and the solvent evaporated to give the crude
product as a brown oil. Following chromatography on silica gel
using 15 : 85 ethyl acetate–hex◦ane, 3a was isolated as a white
solid (0.09 g, 27%); mp 66–68 C; (Found C, 66.99; H, 6.15; N,
3.07; S, 7.10; C26H29NO5S requires C, 66.79; H, 6.25; N, 2.90; S,
6.86%); nmax/cm-1 (KBr) 3374 (NH), 1738 (CO saturated ester),
1666 (CO amide); dH (300 MHz, CDCl3) 1.19 (6H, t, J 7.1, 2 ¥
OCH2CH3), 2.93 [2H, d, J 7.4, C(5)H2], 3.96–4.21 (4H, 2 ¥ sym
m, 2 ¥ OCH2CH3), 4.36 (2H, d, J 5.8, NCH2Ph), 5.07–5.17 [2H,
m, C(7)H2 =], 5.71–5.88 [1H, m, C(6)H =], 6.73–6.80 (2H, m,
ArH), 6.94–7.27 (9H, m, ArH, br s at 7.00 for NH), 7.97 [1H,
s, C(3)H =]; dC (75.5 MHz, CDCl3) 14.3 (CH3, OCH2CH3), 41.7
[CH2, C(5)H2], 44.5 (CH2, NCH2Ph), 60.7 [C, C(4)], 62.4 (CH2,
OCH2CH3), 120.1 [CH2, C(7)H2 =], 127.0, 127.6, 127.8, 128.9,
129.0 [CH, aromatic CH, C(6)H =], 129.6 (C, = CSPh), 129.7,
132.5 [CH, aromatic CH, C(6)H =], 134.3, 138.0 (C, aromatic C),
146.2 [CH, C(3)H =], 164.1 (C, amide CO), 169.3 (C, ester CO);
MS m/z 467 (6%, M+), 394 [3%, (M-CO2Et)+], 84 (100%).
n
max/cm-1 (film) 3354 (br NH), 1674, 1594 (CO a,b-unsaturated
amide); dH (270 MHz, CDCl3) 0.92 [3H, t, J 7, C(7)H3], 1.29–1.37
[2H, m, C(6)H2], 1.40–1.54 [2H, m, C(5)H2], 2.28 (3H, s, ArCH3),
2.49–2.58 [2H, dt, J 7, 7, C(4)H2], 7.06–7.38 (9H, m, ArH), 7.75
[1H, t, J 7, C(3)H =], 8.79 (1H, br s, NH); dC (67.8 MHz, CDCl3)
13.4 [CH3, C(7)H3], 20.3 (CH3, ArCH3), 22.0 [CH2, C(6)H2], 28.9
[CH2, C(5)H2], 30.0 [CH2, C(4)H2], 119.6, 125.9, 126.7, 128.9
(CH, aromatic CH), 125.7, 133.6, 134.2, 134.7 (4 ¥ C, aromatic C
and SC =), 153.5 [CH, C(3)H =], 161.8 (C, CO); MS m/z 325 (M+,
17%), 149 (15%), 107 [22%, (NHTol)+], 96 (100%). A compound
which was detected in a mixture of side-products was tentatively
assigned as 21-E (total wt = 5 mg, 2%). dH (270 MHz, CDCl3)
0.93 [3H, t, J 7, C(7)H3], 1.36–1.57 [4H, m, C(6)H2, C(5)H2], 2.27
2468 | Org. Biomol. Chem., 2011, 9, 2452–2472
This journal is
The Royal Society of Chemistry 2011
©