Thioacetic acid S-[3-(3-formyl-phenoxymethyl)-benzyl] ester (5).
4 (1.81 g, 5.93 mmol, 1.0 equiv.) was dissolved in DMF (20 mL)
and a solution of KSAc (1.36 g, 11.91 mmol, 2.0 equiv.) in DMF
(20 mL) was added dropwise. The mixture was stirred over night
at room temperature. The reaction was quenched by addition of
a saturated aqueous solution of NH4Cl (20 mL). The mixture
was extracted with EtOAc (3 ¥ 30 mL) and the combined organic
layers were washed with 1 M HCl (20 mL), H2O (20 mL), and
brine (20 mL) and dried (MgSO4). Concentration under reduced
pressure yielded 5 (1.70 g, 95%) as a brownish oil that did not
was stirred for another 15 min. The mixture was extracted with
EtOAc (3 ¥ 25 mL) and the combined organic layers were washed
with H2O (2 ¥ 50 mL) and brine (25 mL) and dried (MgSO4).
The solvent was removed under reduced pressure to yield a 15 : 1
mixture of 8 and 11 (1.07 g, 78%) as a thick transparent oil. The
dithiol 8 was found in an E/Z ratio of about 9 : 1. Major E-isomer.
1H NMR (400 MHz, CDCl3): d = 9.23 (s, 1H, Hn), 7.72 (s, 1H,
Ha), 7.43 (s, 1H, HAr), 7.38–7.30 (m, 5H, HAr), 7.22 (d, J = 7.7 Hz,
1H, HAr), 7.02 (ddd, J = 8.2, 2.6, 0.8 Hz, 1H, HAr), 5.10 (s, 2H, Hf ),
3.77 (d, J = 7.6 Hz, 2H, Hk), 3.12 (t, J = 6.9 Hz, 2H, Ho), 2.91 (dt,
J = 8.2, 6.9 Hz, 2H, Hn), 1.79 (t, J = 7.6 Hz, 1H, Hl), 1.74 (t, J =
8.2 Hz, 1Hm); characteristic signals of the minor Z-isomer: 8.71
(s, 1H, Hn), 8.12 (s, 1H, Ha), 5.08 (s, 2H, Hf ), 2.64 (t, J = 6.5 Hz,
2H, Hm); 13C NMR (100 MHz, CDCl3): d = 174.10 (s), 159.01 (s),
144.08 (d), 141.61 (s), 137.14 (s), 135.10 (s), 129.90 (d), 129.04 (d),
127.86 (d), 127.20 (d), 126.27 (d), 120.64 (d), 116.99 (d), 112.60
(d), 69.94 (t), 36.94 (t), 28.89 (t), 19.52 (t); HRMS (ESI): m/z =
378.1300 [M+NH4]+ (calcd. 378.1304 for C18H24N3O2S2).
1
require further purification. H NMR (400 MHz, CDCl3): d =
9.98 (s, 1H, Ha), 7.50–7.44 (m, 3H, HAr), 7.37 (s, 1H, HAr), 7.34–
7.31 (m, 2H, HAr), 7.29–7.24 (m, 2H, HAr), 5.09 (s, 2H, Hf ), 4.14
(s, 2H, Hk), 2.36 (s, 3H, Hl); 13C NMR (100 MHz, CDCl3): d =
195.02 (s), 192.09 (d), 159.22 (s), 138.22 (s), 137.81 (s), 136.75 (s),
130.16 (d), 129.01 (d), 128.70 (d), 127.97 (d), 126.50 (d), 123.73 (d),
122.15 (d), 113.27 (d), 69.95 (t), 33.27 (t), 30.36 (q); HRMS (ESI):
m/z = 318.1157 [M+NH4]+ (calcd. 318.1158 for C17H20NO3S).
3-Mercaptopropanehydrazide (6). Synthesized according to a
modified literature procedure.15 Methyl 3-mercaptopropionate
(10 g, 83 mmol, 1.0 equiv.) was added dropwise to a solution
of hydrazine monohydrate (10 g, 200 mmol, 2.4 equiv.) in MeOH
(30 mL). The reaction mixture was stirred over night at room
temperature. Evaporation of the solvent, followed by flash column
chromatography (SiO2, Et2O–MeOH 8 : 2) gave 6 (4.99 g, 50%) as
a colourless oil. H NMR (400 MHz, CDCl3): d = 6.81 (bs, 1H,
Hd ), 3.93 (bs, 2H, He), 2.84 (dt, J = 8.4 Hz, 6.4 Hz, 2H, Hb), 2.50
(t, J = 6.7 Hz, 2H, Hc), 1.61 (t, J = 8.4 Hz, 1H, Ha).
2-Oxa-10,11-dithia-15,16-diazatricyclo[16.3.1.14,8
1(22),4,6,8(23),16,18,20-heptaen-14-one (11). Under N2,
]
tricosa-
a
mixture of dithiol 8 and disulfide 11 (15 : 1, 360 mg, 1.00 mmol,
1.0 equiv.) was dissolved in MeOH (100 mL) and CH2Cl2
(100 mL). A solution of KI (51 mg, 0.303 mmol, 0.3 equiv.) in
MeOH (~5 mL) was added and subsequently, at 0 ◦C, a solution
of I2 (267 mg, 1.05 mmol, 1.05 equiv.) in MeOH (~ 25 mL) was
added dropwise until the brown colour persisted. Na2SO3 was
added and, when decolourisation was complete, stirring was
continued for 15 min. H2O (100 mL) and CH2Cl2 (100 mL) were
added and the H2O layer was extracted another time with CH2Cl2
(100 mL). The combined organic layers were washed with H2O
(100 mL) and with brine (100 mL) and dried (MgSO4). Removal
of the solvents under reduced pressure and purification by flash
column chromatography (SiO2, CHCl3–EtOAc 3 : 1◦) yielded pure
1
Thioacetic acid S-(3-{3-[(3-mercapto-propionyl)-hydrazono-
methyl]-phenoxymethyl}-benzyl) ester (7). 5 (1.33 g, 4.38 mmol,
1.0 equiv.) was dissolved in MeOH (25 mL) and 5 drops of
acetic acid were added. A solution of 6 (673 mg, 5.60 mmol,
1.3 equiv.) in MeOH (15 mL) was added dropwise after which the
mixture was stirred for 3 h at room temperature. The reaction was
monitored by TLC (SiO2, cyclohexane/EtOAc 5 : 2). The solvent
was removed in vacuo and the residue was purified by flash column
chromatography (SiO2, cyclohexane/EtOAc 5 : 2 → 3 : 2) to yield
a mixture of thioester 7 and dithiol 8 in a ratio of 85 : 15 (1.52 g,
88%). E/Z ratio of the hydrazone was approximately 9 : 1. Major
E-isomer: 1H NMR (400 MHz, CDCl3): d = 9.13 (s, 1H, Hp), 7.72
(s, 1H, Ha), 7.34 (s, 1H, HAr), 7.34–7.27 (m, 5H, HAr), 7.21 (d, J =
7.6 Hz, 1H, HAr), 7.02 (ddd, J = 8.2, 2.7, 0.8 Hz, 1H, HAr), 5.07 (s,
2H, Hf ), 4.14 (s, 2H, Hk), 3.12 (t, J = 6.9 Hz, 2H, Ho), 2.91 (dt, J =
8.3, 6.9 Hz, 2H, Hn), 2.36 (s, 3H, Hl), 1.74 (t, J = 8.3 Hz, 1H, Hm);
some characteristic signals of the minor Z-isomer; 8.70 (s, 1H,
Hp), 8.12 (s, 1H, Ha), 5.06 (s, 2H, Hf ), 2.64 (t, J = 6.6 Hz, 2H, Ho);
13C NMR (100 MHz, CDCl3): d = 195.04 (s), 173.83 (s), 159.02 (s),
143.85 (d), 138.14 (s), 137.10 (s), 135.04 (s), 129.88 (d), 128.99 (d),
128.61 (d), 127.95 (d), 126.50 (d), 120.58 (d), 117.01 (d), 112.66
(d), 69.96 (t), 36.95 (t), 33.32 (t), 30.35 (q), 19.47 (t); HRMS (ESI):
m/z = 403.1144 [M+H]+ (calcd. 403.1145 for C20H23N2O3S2).
1
11 (200 mg, 56%) as a colourless solid. M.p. 188 C. H NMR
(400 MHz, CDCl3): d = 9.48 (s, 1H, Hn), 7.66 (s, 1H, Ha), 7.48 (s,
1H, Hj), 7.39 (dd, J = 2.6, 1.5 Hz, 1H, He), 7.30–7.28 (m, 3H, Hc,
Hg, Hh), 7.19 (ddd, J = 6.7, 1.5, 0.9 Hz, 1H, Hi), 7.06 (ddd, J =
8.4, 2.6, 0.9 Hz, 1H, Hd ), 6.89 (d, J = 7.4 Hz, 1H, Hb), 5.28 (s, 2H,
Hf ), 3.89 (s, 2H, Hk), 3.14 (dd, J = 7.7, 7.1 Hz, 2H, Hm), 2.92 (dd,
J = 7.7, 7.1 Hz, 2H, Hl); 13C NMR (100 MHz, DMSO-d6): d =
172.37 (s), 157.95 (s), 142.07 (d), 137.35 (s), 137.05 (s), 135.36 (s),
129.91 (d), 129.68 (d), 129.00 (d), 128.19 (d), 126.10 (d), 122.24
(d), 119.69 (d), 107.31 (d), 68.81 (t), 41.08 (t), 31.14 (t), 30.37 (t); e
(260 nm, CH2Cl2) = 7872.5 dm3 mol-1 cm-1; HRMS (ESI): m/z =
359.0882 [M+H]+ (calcd. 359.0882 for C18H19N2O2S2).
Benzoic acid [1-phenyl-meth-(E)-ylidene]-hydrazide (10). Syn-
thesized according to a modified literature procedure.16 A mixture
of p-anisaldehyde (2.0 g, 14.7 mmol, 1.0 equiv.) and acethydrazide
(1.21 g, 14.7 mmol, 1.0 equiv.) in EtOH (100 mL) was stirred
at room temperature for 3 h. Filtration of the precipitate and
recrystallisation from EtOH gave 10 (1.84 g, 65%) as a colourless,
1
crystalline solid. H NMR (400 MHz, CDCl3): d = 9.58 (bs, 1H,
3-Mercapto-propionic acid [1-[3-(3-mercaptomethyl-benzyloxy)-
phenyl]-meth-(E)-ylidene]-hydrazide (8). Under N2, a mixture of
starting material 7 and the product 8 (85 : 15, 1.50 g, 3.80 mmol,
1.0 equiv.) was dissolved in MeOH (25 mL). A solution of NaOMe
(246 mg, 4.55 mmol, 1.2 equiv.) in MeOH (15 mL) was added.
After 2 h NH4Cl, (satd., 20 mL) was added and the mixture
He), 7.75 (sb, 1H, Hd ), 7.61 (d, J = 8.8 Hz, 2H, Hc), 6.92 (d, J =
8.8 Hz, 2H, Hb), 3.85 (s, 3H, Ha), 2.37 (s, 3H, Hf ); e (260 nm,
CH2Cl2) = 6353.5 dm3 mol-1 cm-1.
3-Benzyldisulfanyl-propionic acid [1-[3-(3-benzyl disulfanyl-
methyl-benzyloxy)-phenyl]-meth-(E)-ylidene]-hydrazide
(11).
4622 | Org. Biomol. Chem., 2010, 8, 4617–4624
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