10.1002/ejoc.201701033
European Journal of Organic Chemistry
FULL PAPER
multiplet (m). Low resolution mass spectra were measured on Micromass
Trio 200 spectrometer. High resolution mass spectra were measured on
Kratos Concept IS spectrometer. A Carlo Erba EA 1108 Elemental
Analyzer was used for determination of % levels of carbon, hydrogen and
nitrogen. A Metrohm 686 Titroprocessor +665 Dosimat Autotitor was
used to measure chlorine.
m), 2.65-2.81 (4H, m), 4.14 (4H, s), 7.42 (2H, d, J = 8 Hz), 7.87 (1H, t, J
= 8 Hz). 13C NMR: (125 MHz, DMSO-d6) 30.1, 31.3, 37.2, 124.4, 138.7,
156.1 ppm. 19F NMR: (470.5 MHz, DMSO-d6) δ ppm -73.5 ppm. MS:
(ES+) m/z [M+H]+ 479.3. ṽmax (ATR): 2923, 1681, 1583, 1570, 1452, 1401,
1193, 1151, 1114 cm-1. Microanalysis: C13H15AgF3NS3O2.H2O requires C,
31.5; H, 3.5; N, 2.8; S, 19.4 %; found: C, 31.5; H, 3.3; N, 2.8; S, 18.9 %.
ʎmax = 274 nm (ε = 3.4 x 104). A sample suitable for X-ray diffraction was
obtained by slow recrystallisation from CH2Cl2-MeOH.
4-Bromo-2,6-bis(bromomethyl)pyridine15a was prepared from chelidamic
acid17a
.
Chelidamic acid was first converted into dimethyl 4-
hydroxypyridine-2,6-dicarboxylate17b as described previously. Reaction of
this ester with PBr5 at 90 °C for hours afforded dimethyl 4-
Synthesis of silver(I) complex (3a):
To
a
solution of 14-bromo-3,6,9-trithia-1(2,6)-pyridinacyclodecaphane
3
(0.052 g, 0.15 mmol) in DCM (10 mL) was slowly added a solution of
silver trifluoroacetate (0.034g, 0.15 mmol) in methanol (10 mL) over a
period of 20-25 minutes at room temperature. Slow concentration of the
reaction mixture at ambient temperature afforded the title compound as a
colourless powder (0.074 g, 90%). M.p. 195-196 °C. 1H NMR: (400 MHz,
DMSO-d6) δ ppm 2.40 - 2.49 (4H, m) 2.75-2.77 (4H, m) 4.16 (4H, s) 7.74
(2H s). 13C NMR: (125 MHz, DMSO-d6) δ ppm 29.9, 31.0, 36.3, 126.7,
127.7, 157.5. 19F NMR: (376.4 MHz, DMSO-d6) δ ppm -73.3 ppm. ṽmax
(ATR): 3043, 2960, 1560, 1481, 1356, 1319, 1303 cm-1. MS: (ES-) m/z
[M+H]- 555.3. ʎmax = 278 nm (ε = 3.2 x 104). A sample suitable for X-ray
diffraction was obtained by slow recrystallisation from CH2Cl2-MeOH.
Synthesis of Ni(II) complex (4c): To a solution of 3,6,9-trithia-1(2,6)-
pyridinacyclodecaphane (0.252g, 1.0 mmol) in methanol (25 mL) was
added anhydrous nickel(II) chloride (0.130g, 1.0mmol). The reaction
mixture was then brought to a gentle reflux, under an atmosphere of
nitrogen, for 1.5 hours, under an atosphere of nitrogen, and then allowed
to cool to ambient temperature. On doing so the title compound
precipated from solution as a blue-coloured powder which was collected
at the pump (0.200 g, 52%). ṽmax (ATR): 2943, 2919, 2890, 1645, 1620,
1457, 1413, 1389, 1165, 1013 cm-1. Microanalysis: C11H15Cl2NNiS3
requires C, 34.1; H, 3.9; N, 3.6 Cl, 18.3, S 24.8 %; found: C, 33.8; H, 3.9;
N, 3.5, Cl, 18.2, S 24.6 %. ʎmax = 274 nm (ε = 2.9 x 104).
bromopyridine-2,6-dicarboxylate which on reduction with NaBH4 afforded
4-bromo-2,6-pyridinedimethanol.17d
Synthesis of 4-bromo-2,6-bis(bromomethyl)pyridine: A mixture of 4-
bromo-2,6-pyridinedimethanol17d (2.8 g, 13.1 mmol) and 33% HBr in
acetic acid (50 mL) was heated at 125 °C for 5 hours. The reaction
mixture was then poured onto crushed ice and neutralised with 1 M
NaOH to pH 4~5. The precipitated title compound was collected at the
pump as a colourless powder (3.9 g, 89 %). M.p. 127-129 ºC (lit15a 125-
126 ºC). 1H NMR: (400 MHz, DMSO-d6) 4.66 (4H, s) 7.81 (2 H, s) ppm.
13C NMR(125 MHz, DMSO-d6) 33.5, 125, 133.4, 158.6 ppm. MS
(ES+): m/z [M+H]+ 341.8. Accurate Mass: [C7H7N79Br3]+, [M+H]+ requires
341.8128; found 341.8129. ṽmax (ATR): 2971, 1563, 1452, 1355, 1283
cm-1.
Synthesis
of
2,6-bis(bromomethylpyridine)15b
:
Pyridine-2,6-
diyldimethanol (1.82 g, 13.1 mmol) was added to 33% HBr in acetic acid
(26 mL) and the reaction mixture heated to 100 °C for 90 minutes. The
reaction mixture was poured onto crushed ice and neutralised with 1 M
NaOH to pH 9. The precipitated title compound was collected at the
pump as an off-white solid (3.00 g, 88%). M.p. 79-80 °C (lit.15b 80-82 °C).
1H NMR: (300 MHz, CDCl3) 4.55 (4H, s, CH2), 7.38 (2H, d, J = 7 Hz),
7.72 (1H, t, J = 7 Hz) ppm. 13C NMR: (75 MHz, CDCl3) 33.8, 123.1,
138.4, 157.1 ppm. ṽmax (ATR): 1168, 1205, 1451, 1581, 2981, 3029 cm-1.
Accurate Mass: (ES+) [C7H8NO479Br2]+, [M+H] requires 263.9007; found
263.9011.
Synthesis of Cu(II) complex (4b): To a solution of 3,6,9-trithia-1(2,6)-
pyridinacyclodecaphane (0.013 g, 0.05 mmol) in DCM (4 mL) was added,
dropwise, a solution of copper nitrate pentahydrate (0.012 g, 0.05 mmol)
in methanol (4 mL) over a period of 20-25 minutes at room temperature.
Slow concentration of the reaction mixture at ambient temperaure,
Synthesis of Ligands:
Synthesis of 14-bromo-3,6,9-trithia-1(2,6)-pyridinacyclodecaphane
(3): 2,2-Thiodiethanethiol (0.28 mL, 2.11 mmol) was added to 4-bromo-
2,6-bis(bromomethyl)pyridine (0.791 g, 2.11 mmol) and KOH (0.24 g,
4.22 mmol) in toluene (25 mL) - ethanol/H2O (50:1 v/v; 25 mL) at room
temperature. The reaction mixture was stirred vigorously for 24 hours,
under an atmosphere of nitrogen, and the solvent was then removed in
vacuo. The residue was triturated with DCM (50 mL) and the organic
extracts washed with water (6 x 20 mL). The organic phase was dried
(MgSO4) and solvent removed in vacuo. Recrystallisation of the residue
(DCM:Pet) afforded the title compound as a colourless, crystalline, solid
(0.462 g, 66%). M.p. 122-123 °C. 1H NMR: (CDCl3, 400 MHz) 2.52 (8H,
s), 3.79 (4H, s), 7.49 (2H, s) ppm. 13C NMR: (CDCl3, 100 MHz) 30.1,
31.0, 35.4, 125.7, 134.6, 158.7 ppm. ṽmax (ATR): 1187, 1348, 1478, 1558,
1724, 3106, 3307 cm-1. MS: (ES+): m/z [M+H]+ 336. Accurate Mass: (ES+)
[C11H1479BrNS3]+,[M]+ requires 335.9547; found 335.9545. Microanalysis:
C11H14BrNS3 requires C, 39.28; H, 4.2; N, 4.16 %; found: C, 39.16; H,
4.17; N, 3.82 %. ʎmax = 275 nm (ε = 3.2 x 104).
overnight, afforded the title compound as
a dark green-coloured
crystalline solid (0.021 g, 91%). M.p. 225-226 °C. ṽmax (ATR): 3028, 2995,
1434, 1418, 1353, 1262 cm-1. Microanalysis: C11H15CuN3O6S3 requires C,
29.6.; H, 3.4; N, 9.4, S 21.6; found: C, 29.5; H, 3.4; N, 9.3, S 21.5%. ʎmax
280 nm (ε = 3.3 x 104). A sample suitable for X-ray diffraction was
obtained by slow recrystallisation from CH2Cl2-MeOH.
Synthesis of Cu(II) complex (3b): To a solution of 14-bromo-3,6,9-
trithia-1(2,6)-pyridinacyclodecaphane, 3 (0.017 g, 0.05 mmol) in DCM (4
mL) was slowly added a solution of copper nitrate pentahydrate (0.012 g,
0.05 mmol) in methanol (4 mL) over a period of 20-25 minutes at room
temperature. Slow concentration of the reaction mixture at ambient
temperature afforded the title compound as a dark green-coloured
crystalline solid. Yield 0.025 g (92%); m.p. 252-254 °C. ṽmax (ATR): 2977,
2951, 2932, 2163, 1585, 1286, 1228 cm-1. MS: (ES+) m/z [M+H]+ 540.86.
Microanalysis: C11H14BrCuN3O6S3.2H2O requires C, 23.6.; H, 3.2; Br
14.3; N, 7.5%; found: C, 23.7; H, 3.4; Br 13.1; N, 7.3, Br 13.1. ʎmax = 282
nm (ε = 3.5 x 104).
Synthesis of 3,6,9-trithia-1(2,6)-pyridinacyclodecaphane (4)14a: 2,2-
Thiodiethanethiol (0.28 mL, 2.11 mmol) was added to 2,6-
bis(bromomethyl)pyridine (0.56 g, 2.11 mmol) and KOH (0.24 g, 4.22
mmol) in toluene (25 mL)-ethanol/H2O (50:1 v/v; 25 mL) at room
temperature. The reaction mixture was stirred vigorously for 24 hours,
under an atmosphere of nitrogen, and the solvent was then removed in
vacuo. The residue was triturated with DCM (50 mL) and the organic
extracts washed with water (6 x 20 mL). The organic phase was dried
(MgSO4) and solvent removed in vacuo. Purification of the crude product
General procedure for the catalysis of the A3-coupling reaction of
aldehyde, amine and alkyne under conventional heating:
A mixture of the complex 3a,3b,4a,4b or 4c (for precise ratios of
reagents see Table 1 and Table 2) in toluene (3 mL) or water (3 mL) in a
sealed microwave reaction vial equipped with a stirring bar was heated to
90 °C for 10 min under an atmosphere of nitrogen. Phenylacetylene (for
quantities see Table 1 and Table 2) was then introduced into the
reaction mixture via a syringe and the reaction mixture was heated (see
Table 1 and Table 2 for conditions). The reaction mixture was cooled to
room temperature, poured into water and extracted with DCM. The
organic extracts were dried over MgSO4 and concentrated in vacuo to
afford the crude product. Purification of the residue by column
by recrystallization (DCM:petrol) afforded the title compound as
a
colourless, crystalline, solid (0.406 g, 75%). M.p. 164-165 ºC (lit14a 162-
163 ºC). 1H NMR: (400 MHz, DMSO-d6) 2.50 (s, 8H), 3.85 (s, 4H), 7.38
(d, J = 7.5 Hz, 2H,), 7.84 (t, J = 7.5 Hz, 1H) ppm. 13C NMR: (125 MHz,
DMSO-d6) 29.6, 30.5, 35.3, 122.5, 138.8, 157.5. MS: (ES+) m/z [M+H]+
258.2. Accurate Mass: (ES+) [C11H15NS3]+, [M]+ requires 257.0361; found
257.0362. ṽmax (ATR): 2921, 1588, 1569, 1451, 1428, 1280, 1208, 1154
cm-1. ʎmax = 276 nm (ε = 3.6 x 104).
chromatography (SiO2; hexane:DCM
= 9:1 v/v) aforded the title
compound.
General procedure for the catalysis of the A3-coupling reaction of
aldehyde, amine and alkyne in a microwave reactor:
A mixture of the complex 3a,3b,4a,4b or 4c, aldehyde, amine and
phenylacetylene (for precise ratios of reagents see Table 3) in toluene (1
mL) or water (1 mL) in a sealed microwave reaction vial equipped with a
stirring bar was heated, under nitrogen, at 150 °C, in a focused
microwave reactor for 30 minutes.‡ The reaction mixture was cooled to
ambient temperature, poured into water and extrated with DCM. The
organic extracts were dried over MgSO4 and concentrated in vacuo to
Synthesis of metal complexes:
Synthesis of silver(I) complex (4a): A modified version of Vögtle’s14a
original procedure was adopted for these preparations. To a solution of
3,6,9-trithia-1(2,6)-pyridinacyclodecaphane (0.260 g, 1.0 mmol) in DCM
(40 mL) was slowly added, over 20-25 minutes at room temperature, a
solution of silver trifluoroacetate (0.120 g, 1.0 mmol) in methanol (40 mL).
Slow cencentration of the reaction mixture at ambient temperature,
overnight, afforded the title compound as a colourless powder (0.421 g,
88%). M.p. 211-212 ºC. 1H NMR: (400 MHz, DMSO-d6) 2.28-2.45 (4H,
‡ A Biotage InitiatorTM microwave reactor (maximum power output of 300 W;
operating frequency 2450 MHz) was used in these experiments.
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