Y. Li et al. / Journal of Fluorine Chemistry 130 (2009) 377–382
381
5. A quantity of 0.63 g (46%) in pure crystalline form of orange color
144.32; 11B NMR (d6-DMSO, 128.4 MHz, room temperature):
d
(ppm) 3.12.
was obtained via sublimation. 13C NMR (CDCl3, 75.5 MHz, room
temperature): 168.24. ESCI:[M+H]+: 149.8 (100%), 151.8 (67%).
5.1.9. 2,6-dichloropyridine-4-boronic acid (AA-1):
5.1.6. 2-(1-Hexyn-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6)
[14]
2,6-Dichloro-4-iodo-pyridine was prepared according to lit-
erature protocol [16] and then lithiated with n-butyl lithium
followed by quenching with trimethoxyborate. Briefly, 2,6-
dichloro-4-iodo-pyridine (1.4 g, 10 mmol) at ꢁ75 8C was added
to a solution of butyllithium (15 mmol) in dry ether (30 mL) and
hexanes (8 mL). After 30 min at ꢁ75 8C, the mixture was treated
with trimethoxyborate (1.25 mL, 11 mmol) and was allowed to stir
for 1 h. The temperature was allowed to rise slowly over a period of
2 h to room temperature at which point first pinacol (1.6 g,
13 mmol, 1.1 equiv.) and then 10 min later AcOH (0.6 mL,
10 mmol) was added. The resulting mixture was filtered through
celite, which was then washed with ether, and the combined
filtrates were evaporated under reduced pressure. The desired
product was crystallized from cyclohexane (1.4 g, 74%). 1H NMR
Two grams (24 mmol) of n-hexyne in 24 mL of dry diethyl ether
was cooled to ꢁ78 8C and then 15.2 mL (24.32 mmol) of 1.6 M n-
butyl lithium was added. The resulting slurry was stirred for 0.5 h
at ꢁ78 8C and then 4.58 g (24.6 mmol) of 2-isopropyloxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane in 24 mL of dry diethyl ether was
added quickly to the mixture via syringe and the mixture was
stirred at the same temperature for another 2 h. The reaction
mixture was then warmed to room temperature and stirred at
room temperature for an additional hour, whereupon the mixture
was cooled to ꢁ78 8C and 5.4 mL of 4.5 M hydrochloric acid in dry
diethyl ether was added. The slurry was then stirred for an addition
20 min and then warmed to room temperature. After filtration,
solvent was removed under vacuum and 1.86 g (37%) of colorless
product 6 was obtained via distillation at 75–80 8C over 1–
(CDCl3, 300 MHz, room temperature):
d (ppm) 1.34 (s, 12 H), 8.06
(s, 2H). 13C NMR (CDCl3, 75.5 MHz, room temperature):
24.8, 84.4, 111.9, 128, 149.
d (ppm)
1.5 mmHg. 1H NMR (CDCl3, 300 MHz, room temperature):
0.86(t, J = 7.2 Hz, 1CH3), 1.23(s, 4CH3), 1.28–1.50 (m, 2CH2), 2.22 (t,
J = 7.0 Hz, CH2); 13C NMR (CDCl3, 75.5 MHz, room temperature):
(ppm) 13.61, 19.30, 21.99, 24.75, 30.23, 82.51, 83.16, 84.08. 11B
d (ppm)
d
5.2. Preparation of heteroaryltrifluoroborates
NMR (CDCl3, 128.4 MHz, room temperature):
J = 95 Hz).
d
(ppm) 21.47 (d,
General protocol: boronic acid/ester, potassium hydrogen
difluoride (KHF2) and acetic acid were mixed in either aqueous
acetonitrile, methanol, or DMSO (depending on the solubility of the
compounds) to make a final cocktail containing 5 mM of boronic
acid/ester and 200 mM of KHF2 and 1.8 M acetic acid. The reaction
mixture was stored at room temperature and the reaction could be
monitored by TLC using 10% (v/v) ammonium hydroxide in ethanol
as the mobile phase. Generally, the reactions were left for 2 days to
ensure 100% conversion to the heteroaryltrifluoroborate in
solution. Just prior to use, the heteroaryltrifluoroborates were
purified either by column with 5% (v/v) ammonium hydroxide in
ethanol or by extraction of the organic portion (pinacol,
protiodeboronylated material, or other organic contaminants)
with suitable organic solvents after removal of the reaction
solvent. Products corresponding to unknown heteroaryltrifluor-
oborates were characterized by high-resolution mass spectro-
metry and the solvolytic defluoridation was monitored by 19F NMR
spectroscopy. Products previously obtained in this manner from
literature preparations were used without further characteriza-
tion.
5.1.7. 4-Butyl-3,6-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridazine (YL2P008B) [13]
0.32 g (1.9 mmol) of 6 and 0.152 g (1.28 mmol) of tetrazine 5
was mixed in 7 mL of xylenes. The mixture was then heated to
reflux under nitrogen flow for a period of 24 h. Solvent was
removed under vacuum. The residue was eluted purified by
standard flash column chromatography using ethyl acetate in
hexanes (1:30, v/v). A lightly red colored oil was obtained: 69 mg
(14%). 1H NMR (CDCl3, 300 MHz, room temperature):
d (ppm) 0.95
(t, J = 7.2 Hz, CH3), 1.40 (s, 4CH3), 1.43 (m, CH2), 1.55 (m, CH2), 2.69
(t, J = 8.1 Hz, CH2); 13C NMR (CDCl3, 75.5 MHz, room temperature):
d
(ppm) 13.83, 23.09, 24.85, 31.63, 33.59, 85.99, 147.88, 157.65,
147.88; 11B NMR (CDCl3, 128.4 MHz, room temperature):
d (ppm)
29.78; HRMS [M+H]+,: calcd. for C14H22BCl2N2O2: 331.1151, found:
331.1146.
5.1.8. N-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)pyridinium iodide (YL-3-112) [15]
Briefly, 0.5 g (4 mmol) of 4-pyridinylboronic acid and 0.4 g
(4 mmol) of 2,2-dimethyl-1,3-propanediol were dissolved in 1,4-
TFB-35 HRMS (ESI) [M]ꢁ: Calculated for C5H4BNF3ꢁ: 146.0389,
Found. 146.0385.
TFB-95 HRMS (ESI) [M]ꢁ: Calculated for C5H2BNF5ꢁ, 182.0200,
Found. 182.0196.
˚
dioxane and a few chips of 4 A molecular sieves were added to the
solution. The mixture was heated to reflux for 18 h. The reaction
was then cooled to room temperature and filtered to remove the
molecular sieves. The solution was condensed under vacuum and
the residue was dried over high vacuum to give 0.85 g
(quantitatively) of a white solid which that was used without
further purification. The white solid representing the dimethyl-
propanediolboronate was dissolved in 25 mL of acetonitrile and
2.4 mL (40.2 mmol) of methyl iodide was added. The mixture was
then refluxed overnight. Solvent was removed under vacuum after
cooling the reaction slurry to room temperature. To the yellowish
residue, 30 mL of 1:1 (v/v) water/acetone was added and the slurry
was stirred at room temperature for 1 d. The mixture was then
clarified by filtration and the filtrate was concentrated. The
product was precipitated from methanol/diethyl ether to give
1.02 g (overall 74%) of yellowish solid. 1H NMR (d6-DMSO,
TFB-YL3-112 HRMS (ESI) [M+K]+: Calculated for C6H7BNF3K+,
200.0261, Found. 200.0257.
TFB-66 HRMS (ESI) [M]ꢁ: Calculated for C5H3BNF4ꢁ, 164.0295,
Found. 164.0292.
Acknowledgements
D.M.P. was the recipient of a Michael Smith Career Scholar
Award. The authors thank Dr. Curtis Harwig and Dr. Richard Ting
for useful advice. This work was supported by Canadian Institutes
for Health Research.
References
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J = 6.0 Hz, Ar-H), 8.55 (d, J = 6.0 Hz, Ar-H); 13C NMR (d6-DMSO,
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d
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