(ArCH), 129.3 (ArCH), 131.2 (ArC), 129.9 (ArC), 133.9 (ArCH),
General procedure B for the Pummerer-type cyclisation to
give benzazepinones
134.4 (ArCH), 144.2 (ArC) and 174.6 (C O). nmax/(cm-1) 3054,
=
+
=
2916, 1697 (C O), 1465, 1350, 1085 and 725. m/z (EI mode) 255
1-(Ethoxycarbonylmethoxysulfanyl)-3,4-methylenedioxy-3-propyl-
1,3,4,5-tetrahydro-benzo[d]azepin-2-one 30
(M+, 24%), 218 (14%), 146 (100%), 118 (10%) and 91 (6%). m/z
(M + H) 256.0783, C15H14NOS requires 256.0791.
To a stirred solution of glyoxamide 29 (69 mg, 0.26 mmol, 1 eq)
in CH2Cl2 (3 ml) was added ethylthioglycolate (29 ml, 0.26 mmol,
1 eq) and the reaction mixture stirred at room temperature for 18 h.
TFAA (335 ml, 2.37 mmol, 9 eq) was added followed by BF3·OEt2
(162 ml, 1.32 mmol, 5 eq) after a further 1 h. After 1 h, the reaction
was quenched with aqueous saturated NaHCO3 (5 ml), and the
organic layer washed with aqueous saturated NaHCO3 (2 ¥ 5 ml).
The organic layer was dried (Na2SO4), filtered and concentrated in
vacuo. Purification by column chromatography using 15% EtOAc
in petroleum ether as eluant gave 30 (61 mg, 0.17 mmol, 65% from
hydroxyamide, 2 steps) as a yellow oil. dH (500 MHz, CDCl3) 0.84
(3H, t, J = 7.6 Hz, CH3), 1.24 (3H, t, J = 7.1 Hz, CH3), 1.50–1.57
(2H, m, CH2CH2N), 2.90–2.99 (2H, m, CH2), 3.19–3.27 (2H, m,
1H of CH3CH2CH2N and 1H of NCH2CH2ArC), 3.27 (1H, d, J =
16.0 Hz, 1H of CH2S), 3.41–3.47 (1H, m, 1H of CH3CH2CH2N),
3.55 (1H, d, J = 16.0 Hz, 1H of CH2S), 4.16 (2H, q, J = 7.1 Hz,
CH2CH3), 4.45–4.51 (1H, m, 1H of NCH2CH2ArC), 4.86 (1H, s,
CHS), 5.84 (1H, d, J = 1.25 Hz, 1H of OCH2O), 5.86 (1H, d,
J = 1.25 Hz, 1H of OCH2O), 6.44 (1H, s, ArCH) and 6.73 (1H, s,
ArCH). dC (125 MHz, CDCl3) 11.3 (CH3), 14.2 (CH3), 21.2 (CH2),
33.8 (CH2), 34.5 (CH2S), 45.7 (CH2N), 50.3 (CH2N), 55.5 (CHS),
61.6 (CH2CH3), 101.3 (CH2), 109.7 (ArCH), 111.6 (ArCH), 124.7
Pummerer-type cyclisation with Fmoc-protected cysteine derivative
using Sc(OTf)3-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
3-(5-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-3-ylsulfanyl)-
propionic acid methyl ester 22b
To a solution of glyoxamide 11 (70 mg, 0.33 mmol, 1 eq) in CH2Cl2
(3 ml) was added 2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-
mercaptopropionic acid methyl ester (116 mg, 0.33 mmol, 1 eq)
at room temperature. After 18 h, TFAA (284 ml, 2.00 mmol,
6 eq) was added and, after a further 1 h, Sc(OTf)3 (329 mg,
0.67 mmol, 2 eq) was added. After 1 h, the reaction was quenched
with NaHCO3 (15 ml) and CH2Cl2 (15 ml) added, the organic
layer was washed with NaHCO3(aq) (2 ¥ 15 ml), dried (Na2SO4),
filtered and concentrated in vacuo to give a clear oil. Purification
by column chromatography using 30% EtOAc in petroleum ether
as eluant to give 22b (93 mg, 0.17 mmol, 53% from hydroxyamide,
2 steps) as a clear oil (1 : 1 mixture of diastereoisomers). [a]D
=
8.0 (c = 1.75, CH2Cl2). dH (500 MHz, CDCl3) 0.84 (3H, t, J =
7.3 Hz, CH3), 0.88 (3H, t, J = 7.3 Hz, CH3), 1.56–1.63 (4H, m,
2 ¥ CH2), 2.89 (1H, d, J = 7.3 and 13.9 Hz, 1H of CH2CHS
one isomer), 2.97 (1H, d, J = 4.1 and 14.2 Hz, 1H of CH2CHS
one isomer), 3.34 (1H, d, J = 4.1 and 14.2 Hz, 1H of CH2CHS one
isomer), 3.39 (1H, d, J = 6 and 14.2 Hz, 1H of CH2CHS one
=
(ArC), 131.2 (ArC), 146.6 (ArC), 147.7 (ArC), 169.1 (C O amide)
and 169.8 (C O ester). nmax/(cm-1) 2864, 2920, 1733, 1643, 1504,
=
=
isomer), 3.54–3.60 (4H, m, 2 ¥ CH2N), 3.69 (3H, s, CH3OC O
1486, 1386, 1268, 1226, 1153, 1036 and 867. m/z (ES+ mode)
388 ((M + Na)+ 100%) and 366 ((M + H)+ 23%). m/z (M + Na)
388.1184, C18H23NNaO5S requires 388.1189.
=
one isomer), 3.69 (3H, s, CH3OC O one isomer), 4.12–4.19 (2H,
=
m, 2 ¥ CHCH2OC O), 4.22 (1H, s, CHS one isomer), 4.25–4.35
=
(5H, m, 2 ¥ C OOCH2CH and CHS one isomer), 4.57–4.64 (2H,
m, 2 ¥ CHCH2S), 6.00 (1H, d, J = 7.9 Hz, 1 ¥ NH one isomer),
6.64–6.68, (2H, m, 2 ¥ ArH both isomers), 6.72 (1H, d, J = 8.5 Hz,
1 ¥ NH one isomer), 6.89–6.93 (2H, m, 2 ¥ ArH both isomers),
6.98–7.06 (2H, m, 2 ¥ ArH both isomers), 7.16–7.23 (4H, m, 4 ¥
ArH both isomers), 7.27–7.32 (4H, m, 4 ¥ ArH both isomers),
7.54–7.58 (4H, m, 4 ¥ ArH both isomers) and 7.63–7.67 (4H,
m, 4 ¥ ArH both isomers). dC (125 MHz, CDCl3) 11.3 (CH3),
11.4 (CH3), 20.7 (CH2 one isomer), 20.7 (CH2), 32.5 (CH2S), 32.9
(CH2S), 42.0 (CH2N), 42.1 (CH2N), 44.1 (CHS), 45.4 (CHS),
General procedure C for the two-directional Pummerer-type
cyclisations of bis-glyoxamides
3,5-Bis-benzylsulfanyl-1,7-dipropyl-5,7-dihydro-1H,
3H-pyrrolo[3,2-f ] indole-2,6-dione 42
To a stirred solution of bis-glyoxamide 39 (90 mg, 0.30 mmol,
1 eq) in CH2Cl2 (4 ml) was added benzyl thiol (70 ml, 0.60 mmol,
2.0 eq) and the reaction stirred at room temperature for 18 h.
TFAA (761 ml, 5.27 mmol, 18 eq) was added and after a further
1 h, BF3·Et2O (410 ml, 2.93 mmol, 10 eq) was also added.
After stirring for 1 h, the reaction was quenched with NaHCO3
(20 ml), the organic layer was washed with NaHCO3 (2 ¥ 30 ml),
dried (MgSO4), filtered and concentrated in vacuo. Purification by
column chromatography using 30% EtOAc in petroleum ether as
eluant gave 42 (769 mg, 0.15 mmol, 51% from bis-hydroxyamide,
2 steps) as a dark oil (1 : 1 mixture of diastereoisomers). dH
(500 MHz, CDCl3) 0.92 (6H, t, J = 7.4 Hz, 2 ¥ CH3), 1.60–1.66
(4H, m, 2 ¥ CH2), 3.53–3.58 (4H, m, 2 ¥ NCH2), 3.65 (1H, d, J =
13.2 Hz, 1H of CH2S), 3.69 (1H, d, J = 13.1 Hz, 1H of CH2S),
4.01 (1H, s, CHS), 4.03 (1H, s, CHS), 4.13 (1H, d, J = 13.2 Hz,
1H of CH2S), 4.14 (1H, d, J = 13.1 Hz, 1H of CH2S), 6.14 (1H, s,
ArH) and 7.14–7.31 (11H, m, 1H of ArH and 10H of benzyl
groups). dC (75 MHz, CDCl3) 11.7 (2 ¥ CH3), 21.2 (2 ¥ CH2),
34.6 (2 ¥ CH2S), 42.1 (2 ¥ CH2N), 43.0 (2 ¥ CHS), 91.0 (ArCH),
118.9 (2 ¥ ArC), 122.5 (2 ¥ ArCH), 127.5 (ArCH), 127.6 (ArCH),
=
=
47.1 (CHCH2OC O), 47.2 (CHCH2OC O), 52.8 (CH3O), 52.9
=
(CH3O), 53.4 (CHCH2S), 54.5 (CHCH2S), 67.1 (C OOCH2CH),
=
67.3 (C OOCH2CH), 109.2 (ArCH, d, J = 8.8 Hz), 109.3 (ArCH,
d, J = 8.8 Hz), 113.4 (ArCH, d, J = 25 Hz), 113.6 (ArCH,
d, J = 25 Hz), 115.7 (ArCH, d, J = 23.75 Hz), 115.8 (ArCH,
d, J = 23.75 Hz), 119.9 (2 ¥ ArCH), 120.0 (2 ¥ ArCH), 125.2
(2 ¥ ArCH), 125.3 (2 ¥ ArCH), 127.0 (ArCH), 127.1 (ArCH),
127.1 (ArCH), 127.2 (ArCH), 127.3 (ArCH), 127.4 (ArCH), 127.7
(ArCH), 127.7 (ArCH), 139.0 (ArC), 139.5 (ArC), 141.3 (ArC),
141.3 (ArC), 143.7 (ArC), 143.9 (ArC), 144.0 (2 ¥ ArC), 156.1
(2 ¥ ArC), 159.2 (ArCF, d, J = 240 Hz), 159.2 (ArCF, d, J =
=
=
=
=
240 Hz), 170.9 (C O amide), 171.0 (C O amide), 175.4 (C O
ester) and 175.4 (C O ester). nmax/(cm-1) 3337, 3064, 2962, 1717
=
(C O), 1612, 1489, 1452, 1342, 1266, 1135, 1051 and 815. m/z
(ES+ mode) 607 (22%), 571 ((M + Na)+ 100%), 566 (40%) and
+
549 (14%). m/z (M + NH4 ) 566.2121, C30H33FN3O5S requires
566.2119.
594 | Org. Biomol. Chem., 2009, 7, 589–597
This journal is
The Royal Society of Chemistry 2009
©