Crystal Growth & Design
Article
vacuum. The resulting solid was further purified by column
chromatography on silica gel using hexanes/ethyl acetate (4:1 to
3:2) mixture, affording 4-(pyridin-4-yl)benzaldehyde as a yellow-
colored solid. Yield: 386 mg (2.11 mmol, 78%). 1H NMR (400 MHz,
CDCl3) δ (ppm): 10.10 (s, 1H), 8.73 (dd, 2H), 8.01 (d, 2H), 7.81 (d,
2H), 7.55 (dd, 2H).
equiv) and triphenylphosphine (260 mg, 0.98 mmol, 8 mol %) were
suspended in 75 mL of triethylamine. It was degassed by bubbling
nitrogen for 30 min, and bis(triphenylphosphine)palladium(II)
dichloride (340 mg, 0.49 mmol, 4 mol %), copper(I) iodide (93
mg, 0.49 mmol, 4 mol %) and trimethylsilylacetylene (2.57 mL, 18.3
mmol, 1.5 equiv) were added. The reaction flask was fitted to a water-
jacketed condenser, cooled to −78 °C, subjected to a brief vacuum/
backfill cycle, and stirred at 80 °C for 20 h under nitrogen
atmosphere. After volatile materials were removed in vacuo, the
residue was redissolved in 100 mL of chloroform and filtered through
a pad of Celite, using an extra 25 mL portion of chloroform to wash
the filter pad. The combined filtrate was then washed with distilled
water (2 × 25 mL) and brine (25 mL), dried over anhydrous
magnesium sulfate, and evaporated to dryness under a vacuum. The
resulting dark color product was purified by column chromatography
(silica gel, hexanes/ethyl acetate = 1:1) which afforded 4-
((trimethylsilyl)ethynyl)pyridine as a yellow/orange oil. Yield: 1.82
g (10.4 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.55 (d,
2H), 7.29 (d, 2H), 0.26 (s, 9H).
Synthesis of 2,2,2-Trimethoxy-4,5-dimethyl-1,3,2λ5-dioxa-
phosphole (2). A 50 mL round-bottom flask was evacuated and
refilled with nitrogen gas. After repeating this process twice more to
ensure an inert atmosphere, butane-2,3-dione (1.00 mL, 11.4 mmol, 1
equiv) was transferred into the flask. It was then cooled in an ice bath
to 0 °C, and trimethyl phosphite (1.48 mL, 12.5 mmol, 1.1 equiv) was
added slowly while the content was stirred. The resulting yellow-
colored mixture was stirred at room temperature for 12 h under
nitrogen to obtain the biacetyl/trimethyl phosphite adduct as a
colorless liquid. This as-prepared dioxaphospholene derivative was
kept under nitrogen in a freezer at −10 °C and used for subsequent
reactions without further purification. 1H NMR (400 MHz, CDCl3) δ
(ppm): 3.40 (d, 3H), 1.64 (s, 2H).
Synthesis of 1-(2,2,2-Trimethoxy-4-methyl-5-(4-(pyridin-4-
yl)phenyl)-1,3,2λ5-dioxaphospholan-4-yl)ethan-1-one (3). A
100 mL round-bottom flask containing 4-(pyridin-4-yl)benzaldehyde
(350 mg, 1.91 mmol, 1 equiv) was brought to an inert atmosphere by
three cycles of evacuation and nitrogen backfilling. It was placed in an
ice bath and, using a cannula, anhydrous methylene chloride (2 mL)
followed by freshly prepared biacetyl/trimethyl phosphite adduct
(602 mg, 2.87 mmol, 1.5 equiv) were vacuum-transferred with
continuous stirring. The reaction mixture was then stirred at room
temperature for 12 h under nitrogen to yield the dioxaphospholane
intermediate, 3, as a clear yellow, viscous liquid. 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.66 (dd, 2H), 7.62 (d, 2H), 7.49 (dd, 2H), 7.41
(d, 2H), 4.75 (d, 1H), 3.74 (d, 9H), 1.86 (s, 3H), 1.64 (s, 3H).
Synthesis of 4-Hydroxy-3-(4-(pyridin-4-yl)phenyl)pent-3-
en-2-one (L1). The dioxaphospholane derivative, 3, was immediately
used in the methanolysis step. Methanol (50 mL) was added, and the
resultant clear solution was heated under reflux for 5 h under nitrogen
atmosphere. The clear yellow solution was then concentrated via
rotary evaporation and cooled to −78 °C, during which time a yellow-
colored sticky solid was formed. This solid seemed to contain
phosphorus-based impurities. Despite numerous attempts at further
purification (recrystallization from methanol, ethanol, etc. and column
chromatography with different solvent systems), we were unfortu-
nately unable to obtain a pure product. Precipitation in diethyl ether
by adding cold methanol slightly improved the purity, and, after this
procedure, the ligand was used for the metal binding studies. 1H
NMR (400 MHz, CDCl3) δ (ppm): 16.73 (s, 1H), 8.68 (dd, 2H),
7.67 (d, 2H), 7.54 (dd, 2H), 7.30 (d, 2H), 1.93 (s, 6H).
Synthesis of 4-Ethynylpyridine (7). In a nitrogen-flushed, 100
mL round-bottom flask, 4-((trimethylsilyl)ethynyl)pyridine (1.04 g,
5.93 mmol, 1 equiv) and potassium carbonate (1.64 g, 11.9 mmol, 2
equiv) were suspended in 25 mL of methanol. After being stirred
vigorously at room temperature for 2 h, the reaction mixture was
diluted with 75 mL of diethyl ether and filtered through a pad of
Celite, using an extra 25 mL portion of diethyl ether to wash the filter
pad. Solvents were removed under reduced pressure to yield 4-
ethynylpyridine as a pale-yellow solid, which was used directly in the
next step without further purification. Yield: 0.57 g (5.5 mmol, 93%).
1H NMR (400 MHz, CDCl3) δ (ppm): 8.60 (d, 2H), 7.35 (d, 2H),
3.29 (s, 1H).
Synthesis of 4-Hydroxy-3-(4-(pyridin-4-ylethynyl)phenyl)-
pent-3-en-2-one (L2). 4-Hydroxy-3-(4-iodophenyl)pent-3-en-2-one
(1.00 g, 3.31 mmol, 1 equiv) and triphenylphosphine (70 mg, 0.26
mmol, 8 mol %) were placed in a 100 mL round-bottomed flask.
Triethylamine (50 mL) was added, and the resulting solution was
purged with nitrogen gas for 30 min. Then, bis(triphenylphosphine)-
palladium(II) dichloride (93 mg, 0.13 mmol, 4 mol %), copper(I)
iodide (25 mg, 0.13 mmol, 4 mol %), and 4-ethynylpyridine (0.51 g,
5.0 mmol, 1.5 equiv) were added. The reaction mixture was cooled to
−78 °C, subjected to a brief vacuum/backfill cycle, and stirred at 75
°C under nitrogen atmosphere. The progress of the reaction was
monitored by TLC for disappearance of 4-hydroxy-3-(4-iodophenyl)-
pent-3-en-2-one and, upon completion (after 24 h), volatile materials
were removed in vacuo. The residue was redissolved in 100 mL of
methylene chloride and filtered through a pad of Celite, using an extra
25 mL portion of solvent to wash the filter pad. The combined filtrate
was washed with saturated ammonium chloride (25 mL), distilled
water (25 mL), and brine (25 mL), dried over anhydrous magnesium
sulfate, and evaporated to dryness under a vacuum. The crude
product was chromatographed on silica gel using pure hexanes
followed by hexanes/ethyl acetate (1:3) mixture to obtain the title
compound, L2, as a pale-yellow solid. Single crystals were grown by
slow evaporation of a diethyl ether solution. Yield: 0.63 g (2.3 mmol,
Synthesis of 1-(5-(4-Iodophenyl)-2,2,2-trimethoxy-4-meth-
yl-1,3,2λ5-dioxaphospholan-4-yl)ethan-1-one (4). A 250 mL
round-bottom flask containing 4-iodobenzaldehyde (1.20 g, 5.17
mmol, 1 equiv) was made oxygen-free by three cycles of alternating
evacuation and replacement with nitrogen. Then, it was placed in an
ice bath and freshly prepared biacetyl/trimethyl phosphite adduct
(1.63 g, 7.76 mmol, 1.5 equiv) was introduced via vacuum-
transferring. The resulting neat slurry was stirred at room temperature
for 12 h under nitrogen atmosphere to afford the dioxaphospholane
1
69%). H NMR (400 MHz, CDCl3) δ (ppm): 16.69 (s, 1H), 8.62
1
(dd, 2H), 7.58 (d, 2H), 7.39 (dd, 2H), 7.21 (d, 2H), 1.91 (s, 6H).
13C NMR (100 MHz, CDCl3) δ (ppm): 190.91, 149.87, 138.21,
132.65, 132.32, 131.76, 131.32, 121.55, 114.77, 93.60, 87.59, 24.42.
Synthesis of [Cu(L1)2(MeOH)2]n. In a glass vial, L1 (6.0 mg, ca. 2
equiv) was dissolved in 5 mL of methanol. Then, copper(II)
perchlorate hexahydrate (4.1 mg, 11 μmol, 1 equiv) dissolved in 1 mL
of methanol was added and mixed well. After careful addition of two
drops of triethylamine/methanol (1:5 v/v) solution with minimal
agitation, the vial was sealed and left undisturbed at ambient
conditions to allow triethylamine to diffuse into the solution slowly.
Dark green crystals suitable for single-crystal X-ray diffraction were
observed after 24 h. ATR-FTIR (cm−1): 3019.70, 1571.52, 1484.91,
1419.24, 1372.14, 1313.84, 1219.60, 1109.67, 1005.42, 975.38,
920.54, 858.38, 812.74, 765.02, 736.84.
intermediate, 4, as a colorless, viscous liquid. H NMR (400 MHz,
CDCl3) δ (ppm): 7.65 (d, 2H), 7.03 (d, 2H), 4.62 (d, 1H), 3.70 (d,
9H), 1.82 (s, 3H), 1.58 (s, 3H).
Synthesis of 4-Hydroxy-3-(4-iodophenyl)pent-3-en-2-one
(5). The dioxaphospholane derivative, 4, was directly subjected to
methanolysis by adding methanol (100 mL) and refluxing under
nitrogen for 12 h. The clear solution was then concentrated via rotary
evaporation and cooled to −78 °C. The white crystalline solid formed
upon cooling was collected by filtration, washed with cold methanol,
and air-dried. Yield: 1.14 g (3.78 mmol, 73% with respect to 4-
iodobenzaldehyde). 1H NMR (400 MHz, CDCl3) δ (ppm): 16.66 (s,
1H), 7.73 (d, 2H), 6.93 (d, 2H), 1.88 (s, 6H).
Synthesis of 4-((Trimethylsilyl)ethynyl)pyridine (6). In a 250
mL round-bottomed flask, 4-iodopyridine (2.50 g, 12.2 mmol, 1
G
Cryst. Growth Des. XXXX, XXX, XXX−XXX