Pasumansky et al.
of n-BuLi) (25 mL, 1 M solution in THF 25 mmol, 1 equiv).
Trimethylsilylchloride (3.20 mL, 25 mmol, 1 equiv) was added
dropwise over 5 min via syringe while stirring at 25 °C. After 1 h
of stirring at 25 °C, a 0.5 mL aliquot was taken and analyzed via
11B NMR, which showed the solution to be monomeric diisopro-
pylaminoborane (δ +35.2, t, J ) 125 Hz). For other aminoboranes
prepared by this method see Table 2.
4.5. General Synthesis of Aminoborane from the Direct
Reaction of Heterocyclic Amines with BH3:THF. To a 50-mL
flask was added BH3:THF (30 mL, 10 M solution in THF, 30 mmol,
1 equiv). To this flask was added pyrrole (2.1 mL, 30 mmol, 1
equiv) dropwise over 3 min. After the mixture stirred at 25 °C for
1 h, an aliquot was withdrawn for 11B NMR analysis, and the spectra
showed significant amounts of unreacted BH3:THF (δ -1.5, t, J
) 104 Hz). After 4 h, 11B NMR spectroscopy analysis showed the
completion of the reaction and exclusive formation of pyrrolylbo-
rane (δ +4.0, t, J ) 113 Hz). For other heterocyclic aminoboranes
prepared by this method see Table 3.
2H), 3.83 (s, 2H), 7.18-7.25 (mult, 3H); 13C NMR (125 MHz,
CDCl3) δ 40.1, 119.2, 120.8, 127.5, 129.3, 130.4, 160.8; FTIR (neat,
cm-1) 876, 1223, 1365, 1439, 1662, 1704, 2975, 2947, 2954, 3292,
3360; HRMS (70 eV) m/z (M+ + 1) calcd 202.97459, found
202.97558.
4.7.2. 2-Chloro-5-fluorobenzylamine (Table 4, entry 2); yel-
lowish oil; 70% yield; 1H NMR (500 MHz, CDCl3) δ 1.80 (brd s,
2H), 3.99 (s, 2H), 6.99 (m, 1H), 7.17 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 30.5, 37.7, 114.4, 114.5, 125.6, 128.9, 128.9, 160.4, 162.4,
163.5; FTIR (neat, cm-1) 782, 1055, 1244, 1361, 1454, 1579, 1606,
2873, 2931, 3085, 3365; HRMS (70 eV) m/z (M+ + 1) calcd
159.02511, found 159.02601.
4.7.3. 4-Methoxybenzylamine (Table 4, entry 3): yellowish oil;
1
80% yield; H NMR (500 MHz, CDCl3) δ 2.42 (s, 2H), 3.87 (s,
2H), 6.92 (t, 1H, J ) 9 Hz), 7.33 (m, 1H), 7.49 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 158.8, 132.5, 129.7, 129.6, 128.4, 114.1, 55.4,
52.5; FTIR (neat, cm-1) 812, 1033, 1513, 1611, 2869, 2929, 2954,
3294, 3366; HRMS (70 eV) m/z (M+ + 1) calcd 137.08406, found
137.08511.
4.6. Synthesis of Aryl Boronic Acids. A Representative
Procedure. A 100-mL, round-bottom flask with side arm was
charged with triethylamine (3.47 mL, 25 mmol, 5 equiv), 4-bro-
moanisole (0.61 mL, 5 mmol, 1 equiv), and THF (3 mL). The
septum was replaced with a reflux condenser while adding
palladium (0.175 g, 0.5 mmol, 5 mol %). Finally, diisopropylami-
noborane (15 mL, 1 M solution in THF, 15 mmol, 3 equiv) was
added to the reaction mixture via syringe. The reaction mixture
was subsequently heated to reflux at 65 °C. After 19 h of refluxing
the solution was cooled to 25 °C, and methanol (8 mL) was added
slowly (CAUTION: exothermic reaction). The solvent was evapo-
rated in vacuo (25 Torr), and the residue was dissolved with sodium
hydroxide (3 M, 8 mL). The aqueous layer was washed with
hexanes (3 × 10 mL) and then acidified with 3 M HCl (pH ) 1).
In most cases, the boronic acid precipitated out of the solution.
The slurry was extracted with diethyl ether (4 × 15 mL). The
organic portions were combined, dried with anhydrous MgSO4, and
filtered. Solvents were evaporated in vacuo to produce 4-methoxy-
phenylboronic acid as a white solid.
4.8. General Procedure for Competitive Reduction of Alde-
hyde in the Presence of Nitrile. A 50-mL, round-bottom flask,
equipped with a magnetic stir bar and fitted with a rubber septum,
was charged with 4-bromo-2-fluorobenzonitrile (0.20 g, 1 mmol,
1 equiv), mesitylene (0.08 g, 1 mmol, 1 equiv), benzaldehyde (0.106
g, 1 mmol, 1 equiv), and THF (10 mL). An aliquot (0.1 mL) was
withdrawn from the reaction mixture before the addition of
diisopropyl aminoborane to serve as a reference (t0). Diisopropyl-
aminoborane (2.4 mL, 1.2 mmol, 1.2 equiv) was then added to the
flask via syringe. Finally, LiBH4 (0.05 mL, 2 M solution in THF,
0.1 mmol, 10 mol %) was added to the flask via syringe. The
reaction was monitored by analyzing aliquots via GC. Aliquots (0.1
mL) were diluted with pentane (1 mL) to precipitate diisopropy-
laminoborane to avoid contamination of the GC column by boron
compounds. The percentage of unreacted 4-bromo-2-fluoroben-
zonitrile and benzaldehyde was determined from the peak areas
using mesitylene as the internal standard.
4.9. General Procedure for the Reduction of Esters. A 50-
mL, round-bottom flask with a side arm, condenser, and stir bar
was charged with diisopropylaminoborane (10 mL, 1 M solution
in THF, 10 mmol, 2 equiv) and lithium borohydride (0.5 mL, 2 M
solution in THF, 1 mmol, 10 mol %). Methyl octanoate (0.90 mL,
5 mmol, 1 equiv) was added to this solution via syringe. The
reaction mixture was subsequently heated to 65 °C. The reaction
went to completion after 2 h of heating as evidenced by the
disappearance of methyl octanoate on TLC (Hex/EtOAc, 2:1)
analysis. The reaction mixture was cooled to 0 °C (ice bath), and
unreacted BH2-N(iPr)2 was quenched with 1 M HCl (5 mL).
(CAUTION: hydrogen evolution!) The reaction mixture was than
extracted with pentane (3 × 15 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered, and evaporated in vacuo
(25 °C, 1 Torr) to afford octanol as colorless oil.
4.6.1. Phenylboronic acid (3): white solid; 82% yield (0.501
1
g); mp ) 215-218 °C [lit.26 mp 216 °C]. H NMR (500 MHz,
MeOH-d4) δ 7.31 (m, 3H), 7.56 (d, J ) 6.5 Hz, 1H), 7.71 (d,
J ) 7 Hz, 1H); 13C NMR (125 MHz, MeOH-d4) δ 128.6, 128.7,
130.8, 131.3, 134.6, 135.0; 11B NMR (80.25 MHz, MeOH-d4) δ
+18 (s).
4.6.2. 4-Methoxyphenylboronic acid (4): white solid; 78% yield
1
(0.598 g); mp ) 203-207 °C [lit.26 mp 209-210 °C]; H NMR
(500 MHz, MeOH-d4) δ 3.74 (s, 3H), 6.85 (d, J ) 8 Hz, 2H), 7.55
(s, 2H), 7.7 (d, J ) 8 Hz, 2H; 13C NMR (125 MHz, MeOH-d4) δ
55.5, 114.1, 136.7, 163.9; 11B NMR (80.25 MHz, MeOH-d4) δ
+30.0 (s).
4.7. General Procedure for Nitrile Reduction. To a 50-mL
round-bottom flask equipped with a magnetic stir bar and fitted
with a rubber septum was added 4-bromo-2-fluorobenzonitrile (1.0
g, 5 mmol, 1 equiv). The round-bottom flask was charged with
diisopropylaminoborane (20.0 mL, 0.5 M in THF, 10 mmol, 2
equiv). Lithium borohydride (0.25 mL, 2 M in THF, 0.5 mmol, 10
mol %) was then added, and the solution turned deep red in color.
The reaction went to completion in 3 h at 25 °C, as evidenced by
TLC (Hex/EtOAc, 2:1) analysis. The reaction mixture was cooled
to 0 °C (ice bath), and unreacted BH2-N(iPr)2 was quenched with
3 M HCl (7 mL). (CAUTION: hydrogen eVolution!) The acidic
solution was stirred for 30 min and then washed with Et2O (3 ×
10 mL). The acidic solution was than made basic with NaOH pellets
to pH ≈ 10. 4-Bromo-2-fluorobenzyl amine was extracted with
1:1 Et2O/THF (3 × 10 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered, and evaporated in vacuo
(25 °C, 1 Torr) to afford 4-bromo-2-fluorobenzylamine as a light-
yellow oil.
4.9.1. Benzyl alcohol (9): colorless oil; 96% yield (0.518 g).
4.9.2. Octanol (11): colorless oil; 98% yield (0.637 g).
4.10. General Procedure for Hydroboration and Boronic Acid
Synthesis. To a 50-mL, round-bottom flask equipped with a
magnetic stir bar and fitted with a rubber septum was added
pyrrolylborane (5.3 mL, 1 M solution in THF, 5 mmol, 1 equiv).
The reaction flask was cooled to 0 °C (ice bath), and styrene (0.573
mL, 5 mmol, 1 equiv) was added. The reaction was then allowed
to warm to 25 °C. After 19 h the reaction mixture was mixed with
pentane (25 mL) and NaOH (10 mL, 3 M). (CAUTION: hydrogen
eVolution!) After 1 h of stirring the reaction mixture the aqueous
layer was removed. The pentane layer was then extracted with
NaOH (2 × 5 mL, 3 M) collecting all the aqueous layers together.
The aqueous layers were then acidified with HCl (8 mL, 12 M
solution in H2O, 96 mmol) while at 0 °C, forming a white
precipitate. Sodium chloride (2 g) was added to aid precipitation.
4.7.1. 4-Bromo-2-fluorobenzylamine (Table 4, entry 1): yel-
lowish oil; 90% yield; 1H NMR (500 MHz, CDCl3) δ 1.80 (brd s,
(26) Lappert, M. F. Chem. ReV. 1956, 56, 959.
1904 J. Org. Chem., Vol. 73, No. 5, 2008