Conclusion
The control strategy for a Suzuki coupling performed as
slowly added over 24 min with cooling to permit a controlled
release of hydrogen while maintaining 21-28 °C. After the
addition was complete, the reactor headspace was flushed
with nitrogen for 45 min to remove hydrogen. The reaction
mixture was filtered through Celite (750 g) to remove the
catalyst, and the reaction flask and filter cake were rinsed
with acetonitrile (4.0 L). The filtrate was concentrated to a
weight of 3038 g by distillation under reduced pressure, and
the concentrate was diluted with ethyl acetate (2.9 L). The
mixture was cooled to 2 °C over 2 h and was filtered to
remove precipitated triethylammonium iodide. The filter cake
was rinsed with ethyl acetate (2 L) which had been prechilled
to 0 °C. The filtrate was extracted twice with water (3 L)
and once with brine (4.0 L). Sodium sulfate (803 g) was
added to the organic phase, and the suspension was stirred
at 25 °C for 40 min. The suspension was filtered, and the
filtrate was concentrated under reduced pressure to 2.44 kg.
Heptane (5 L) was added to the concentrate, and the solution
was slowly cooled to 2 °C over 30 min. The resulting
precipitate was recovered by filtration, and the filter cake
was rinsed with heptane (3.5 L) which was precooled to 2
a final step is described. Suppression of the homocoupling
of an aryl boronic acid leading to a persistent dimer (6) was
achieved by the combination of two key process modifica-
tions. Thus, it was shown that rigorous exclusion of dissolved
oxygen from the reaction mixture could be easily and
efficiently achieved by subsurface sparge with nitrogen.
Furthermore, dimer 6 suppression was additionally promoted
by the introduction of potassium formate to the Suzuki
reaction, which may have played the role of a mild reducing
agent that did not block the catalytic cycle. These modifica-
tions apparently minimized the concentration of free Pd(II)
in the reaction medium without causing significant reduction
of the oxidative addition product. And finally, use of a
heterogeneous catalyst, palladium black, enabled the es-
sentially quantitative separation of palladium from the desired
cross-coupling product by filtration of the reaction mixtures
through a 0.8 µm glass fiber filter. These conditions were
successfully executed in three campaigns using 3-, 5-, 12-,
and 22-L glassware.
°
C. The collected solids were vacuum dried at 40 °C,
Experimental Section
affording aryl boronate 2 (656 g, 67.2% yield) from aryl
iodide 1. H NMR (CDCl , 500.0 MHz): δ 7.78 (d, 2H, J
1
Generalized Procedure for Deoxygenation of Aqueous
3
1-Propanol Using Subsurface Nitrogen Sparging. An
) 8), 7.23 (d, 2H, J ) 8), 4.15 (t, 1H, J ) 6.5), 3.42 (doublet
of triplets, 2H), 2. 90 (t 2H), 2.83 (s, 3H), 2.83 (s, 3H).1.35
(s, 12H).
[4-[2-[(Methylsulfonyl)amino]ethyl]phenyl]boronic Acid
(3). Aryl boronate 2 (0.655 kg, 2.01 mol) was added to a
mixture of water (3.7 L) and concentrated (48%) HBr (0.865
L, 7.64 mol). The reaction mixture was warmed to 85 °C
and stirred for 11 h under nitrogen and then was cooled to
apparatus was assembled consisting of a 1-L round-bottom
flask equipped with a mechanical stirrer, 1/4 in. Teflon dip
tube, dissolved oxygen probe, and a reflux condenser
supplied with -5 °C cooling fluid. A mixture of 441 mL of
deionized water and 559 mL of 1-propanol was charged to
the flask. The mixture was held at 25 °C and stirred while
compressed air was added subsurface. Nitrogen gas was then
introduced into the rapidly stirred solution through the 1/4
in. Teflon dip tube at 0.5 SCFH until the oxygen meter
indicated less than 0.5 ppm dissolved oxygen.
N-[2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]ethyl]methanesulfonamide (2). Aryl iodide 1 (977
g, 3.00 mol) and triethylamine (914 g, 9.03 mol) were added
to acetonitrile (5.9 L). The resulting mixture was stirred under
nitrogen and cooled to 14 °C. 4,4,5,5-Tetramethyl-1,3,2-
dioxaborolane (pinacol borane), (929 g, 7.26 mol) was added
slowly via cannula to the mixture over 75 min, allowing a
controlled evolution of hydrogen and warming to 25 °C.
Upon completion of the addition, acetonitrile (0.20 L) was
used to rinse the transfer line. The reaction mixture was
stirred at 25-30 °C for about 3 h, after which time the reactor
headspace was flushed with nitrogen in order to remove
hydrogen from the flask and reaction mixture. Agitation was
stopped, and a Teflon transfer tube was inserted below the
2
0 °C. The pH of the reaction mixture was adjusted to 10.8
by addition of 2.0 N sodium hydroxide (4.9 L, 9.8 mol),
and the resulting solution was extracted three times with tert-
butyl methyl ether (1.8 L). The aqueous phase was stirred
with activated carbon (87.7 g) at 25 °C for 1 h under nitrogen.
The suspension was filtered, and the filter cake was rinsed
with water (1 L). The filtrate was acidified slowly with 24%
HBr (0.435 L) to a pH of 2.7. The resulting suspension was
cooled to 0-5 °C, and the precipitate was recovered by
filtration. The product filter cake was rinsed with cold water
(2.0 L) and vacuum dried at 40 °C, affording boronic acid
1
3
D
8
(0.412 kg, 1.69 mol) in 84% yield. H NMR (acetone-d
6
/
2
O, 300.0 MHz): δ 7.81 (d, 2H, J ) 8), 7.26 (d, 2H, J )
), 3.268 (t, 2H, J ) 7) 2. 827 (s 3H), 2.814 (t, 4H, J ) 7).
Independent Synthesis of N,N′-([1,1′-Biphenyl]-4,4′-
diyldi-2,1-ethanediyl)-bis-methanesulfonamide (6). A mix-
ture of 1-propanol (134 mL), water (104 mL), arylboronic
acid 3 (12.2 g, 0.0500 mol, 1.0 equiv), Boc-protected aryl
iodide 10 (22.3 g, 0.0525 mol, 1.05 equiv), K
0
mmol, 0.010 equiv) was heated to reflux at 89 °C for 2.5 h.
The mixture was cooled to 50 °C, and the resulting
suspension was filtered. The filter cake was dissolved in
DMSO (150 mL), and the suspension was filtered to remove
palladium black. The filtrate was poured slowly into water
(750 mL) and stirred for 15 min. The precipitate was
13
liquid surface. A suspension of palladium black (9.6 g, 0.09
mol) in acetonitrile (0.10 L) was added to the reaction
mixture though the transfer line. Additional acetonitrile (0.4
L) was used to rinse the palladium from the flask and transfer
line. Agitation was resumed, and the mixture was warmed
to 75 °C under nitrogen for 24 h. The reaction mixture was
cooled to 21 °C, and deionized water (115 g, 6.40 mol) was
2 3
CO (11.3 g,
.0820 mol, 1.64 equiv), and palladium black (53 mg, 0.5
(13) Alternatively, palladium dichloride or palladium diacetate may be used, since
these are immediately reduced to palladium (0) by excess pinacol borane.
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