Angewandte
Chemie
a subsidiary of Thermo Fisher. Microfluidic connections were made
with standard Upchurch fittings (IDEX Health and Science), either
10–32 coned fittings, or 1/4–28 flat-bottomed fittings for 1/16 inch OD
tubing.
8442; h) K. F. Jensen, MRS Bull. 2006, 31, 101 – 107; i) A. J.
J. L. Steinbacher, A. R. Bogdan, D. T. McQuade, Chem. Rev.
H. Lowe, Microreactors: New Technology for Modern Chemistry,
Wiley-VCH: Weinheim, 2000; p) K. F. Jensen, in New Avenues
to Effcient Chemical Synthesis: Emerging Technologies (Eds.:
P. H. Seeberger, T. Blume), Springer, Heidelberg, 2007, pp 57 –
76; q) V. hessel, J. C. Schouten, A. Renken, J.-I. Yoshida,
Handbook of Micro Reactors, Wiley-VCH, Weinheim, 2009.
[5] For a selection of recent papers that use palladium-catalyzed
aminations to make biologically active compounds, see: a) F. W.
Goldberg, R. A. Ward, S. J. Powell, J. E. Debreczeni, R. A.
Norman, N. J. Roberts, A. P. Dishington, H. J. Gingell, K. F.
b) S. Guo, Y. Song, Q. Huang, H. Yuan, B. Wan, Y. Wang, R. He,
J. Winger, M. Krohn, L.-M. Zhou, M. Keyvan, L. Enache, D.
Sullins, E. Onau, J. Zhang, G. Halldorsdottir, H. Sigthorsdottir,
A. Thorlaksdottir, G. Sigthorsson, M. Thorsteinnsdottir, D. R.
Davies, L. J. Stewart, D. E. Zembower, T. Andresson, A. S.
585; d) M. Decker, Y.-G. Si, B. I. Knapp, J. M. Bidlack, J. L.
Neumeyer , J. Med. Chem. 2010, 53, 402 – 418.
Procedure for the reaction reported in Figure 1: An oven-dried
screw-top volumetric flask (5.00 mL), equipped with a stir bar and a
teflon screw-cap septum, was charged with 2 (32.2 mg, 0.06 mmol)
and 5 (9.2 mg, 0.025 mmol). The vessel was evacuated and back-filled
with argon (this process was repeated a total of 3 times) and toluene
(ca. 5 mL) was added to make the solution up to volume. Solution 1
was stirred for 5 min to allow complete dissolution of the solid
reagents. A second flask (5.00 mL), equipped in the same manner,
was charged with biphenyl (308 mg, 2.0 mmol) and TBAB (161 mg,
0.5 mmol). The vessel was evacuated and back-filled with argon (this
process was repeated a total of 3 times), and then 2-chloroanisole
(1.21 mL, 10.0 mmol) and ethyl 2-aminobenzoate (1.77 mL,
12.0 mmol) were added, with toluene used to make the solution up
to volume. Solution 2 was stirred to allow the dissolution of the solid
reagents. Solutions 1 and 2 were loaded into plastic syringes and fitted
to syringe pumps as described in the Supporting Information (448 mL
packed bed). Three other syringes were filled separately with KOH
(2m), ethyl acetate and water, and were fitted to the remaining
syringe pumps. The reagents were flowed through the packed-bed
reactor at the appropriate flow rates to give residence times of 2–
10 min. Samples were collected, diluted with ethyl acetate and water,
mixed vigorously, and an aliquot of the organic layer was filtered
through a plug of silica, eluting with ethyl acetate, and the sample was
analyzed by GC.
Received: July 20, 2010
Published online: October 29, 2010
[6] For references pertaining to palladium-catalyzed amination
reactions in microflow, see: a) C. Mauger, O. Buisine, S.
3627 – 3629; b) D. Popa, R. Marcos, S. Sayalero, A. Vidal-
enko, S. L. Buchwald, K. F. Jensen, Org. Proc. Res. Dev. early
view; e) P. Bazinet, J. P. McMullen, J. R. Naber, A. Musacchio,
K. F. Jensen, S. L. Buchwald, Org. Proc. Res. Dev. (submitted).
[7] For recent reviews of palladium-catalyzed aminations, see:
Buchwald, L. Jiang, in Metal-Catalyzed Cross-Coupling Reac-
tions (Eds.: A. deMeijere, F. Diederich), Wiley-VCH, Weinheim,
[8] a) R. E. Tundel, K. W. Anderson, S. L. Buchwald, J. Org. Chem.
[9] For a reviews of metal-catalyzed reactions in water, see: a) M.
Keywords: amination · continuous flow · cross-coupling ·
packed-bed reactors · palladium
.
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