Angewandte
Chemie
conditions do not have to be optimized for different batch
sizes. We have obtained gram quantities by flowing reaction
mixtures through a single capillary for about 90 min; bundling
capillaries together will produce much larger quantities in the
same time period. Unlike expension chip-type reactors (e.g.,
US$3280 per chip from Microlyne Inc.), several capillaries
can be purchased for US$0.01. Further, owing to simple,
straight design of the capillary system developed in this
3 equiv) in DMF (2 mL) was prepared. Condition B: In reactions
with pyridineboronic acid, the stock solution contained aryl halide
(
0.6 mmol, 1 equiv), pyridine boronic acid (1.2 equiv), base (K CO ,
2 3
120 mg, 1.5 equiv), and CsF (217 mg, 2.4 equiv) all dissolved in DMA/
H O (2:1; 3 mL). The plumbing of the MACOS microreactor system
2
was primed with the same solvent as the stock solution. A 1-mL
aliquot from the homogenous stock solution was taken up in a
Hamilton gas-tight syringe and connected to the microreactor by
PEEK tubing with the aid of microtight fittings. The syringe was
[
6]
placed in a Harvard22 syringe pump that was set to deliver
report, and other systems from our group, particulate matter
cannot accumulate and block the reactor as is the case with
À1
1
0 mLmin , and the single-mode microwave was programmed to
heat constantly at the temperatures indicated in Table 1. The output
from the reactor was fed into a collection tube and then analyzed by
[
11]
[4c]
more elaborate chip designs and even large-bore spiral
reactors designed specifically for microwave applications.
1
H NMR spectroscopy immediately after the reaction. All products
0
In summary, the Pd films prepared in this report are
highly porous and composed of nanometer-size grains
are known and their spectra were identical to those reported in the
literature (see Table 1 for references).
General procedure for the Heck coupling: A stock solution
containing the aryl halide (1.2 mmol, 1.2 equiv), acrylate (1 mmol,
(
94.0 wt% Pd and 5.5 wt% carbon). The film thickness is
approximately 6 mm and the film porosity is of the order of
5%. The films are robust and stand up well to the physical
1
equiv), and base (triethylamine, 3 mmol, 3 equiv) in 1.5 mL DMA
7
was prepared. The MACOS reaction was performed using the same
technique as that described above for the Suzuki–Miyama reaction.
All products are known and their spectra were identical to that
reported in the literature (see Table 2 for references).
wear and tear of flow conditions and the high temperatures
associated with microwave irradiation. The Pd film serves as
an excellent catalyst for Suzuki–Miyama and Heck reactions,
given the very short durations that the reaction mixture
actually spends in the capillary, which is far less than one
minute. In further investigations we are examining Pd and
other metal films for metal-catalyzed reactions, as well as
other reactions that are not specifically metal catalyzed.
Received: October 12, 2005
Revised: November 24, 2005
Published online: March 20, 2006
Keywords: cross-coupling · microwaves · palladium ·
.
synthetic methods · thin films
Experimental Section
Pd film coating of capillaries: Borosilicate capillaries (1150 mm i.d.)
were filled with a 0.1 mmolmL solution of palladium acetate in
[1]a) J. P. Tierney, P. Lidstrom, Microwave Assisted Organic Syn-
thesis, Blackwell, Oxford, 2005; b) C. O. Kappe, Angew. Chem.
2004, 116, 6408; Angew. Chem. Int. Ed. 2004, 43, 6250; c) M.
Nüchter, B. Ondruschka, W. Bonrath, A. Gum, Green Chem.
2004, 6, 128; d) K. M. K. Swamy, W.-B. Yeh, M.-J. Lin, C.-M.
Sun, Curr. Med. Chem. 2003, 10, 2403; e) B. Wathey, J. Tierney, P.
Lidstrom, J. Westman, Drug Discovery Today 2002, 7, 373; f) P.
Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron 2001,
57, 9225.
À1
DMF. The capillaries were then capped at both ends with septa and
placed in a muffle furnace at room temperature, and the temperature
was gradually increased up to 1508C. After 10 min, metallic
palladium was gradually released from the solution and deposited
on the inner wall of the capillary. The capillaries were rotated a few
times during deposition to encourage uniform film thickness, and
heating was continued at 1508C for a total of 30 min. Capillaries were
calcinated by removing the plugs, pouring out the remaining solution,
rinsing with fresh DMF, and heating (3 1 min each time) at 4008C
before use.
[2]For discussion of flow synthesis on a microscale, see: a) G. N.
Doku, W. Verboom, D. N. Reinhoudt, A. van den Berg, Tetra-
hedron 2005, 61, 2733; b) H. R. Luckarift, L. J. Nadeau, J. C.
Spain, Chem. Commun. 2005, 383; c) G. Jas, A. Kirschning,
Chem. Eur. J. 2003, 9, 5708; d) N. G. Anderson, Org. Process Res.
Dev. 2001, 5, 613; e) M. Sands, S. J. Haswell, S. M. Kelly, V.
Skelton, D. O. Morgan, P. Styring B. Warrington, Lab Chip 2001,
1, 64; f) W. Ehrfeld, V. Hessel, H. Lꢀwe, Microreactors: New
Technology for Modern Chemistry, Wiley-VCH, Weinheim,
2000; g) A. M. Hafez, A. E. Taggi, H. Wack, W. J. Drury III, T.
Lectka, Org. Lett. 2000, 2, 3963.
[3]For discussion of flow synthesis on a nonmicroscale, see: a) R. A.
Kautz, W. K. Goetzinger, B. L. Karger, J. Comb. Chem. 2005, 7,
14; b) D. M. Ratner, E. R. Murphy, M. Jhunjhunwala, D. A.
Snyder, K. F. Jensen, P. H. Seeberger, Chem. Commun. 2005,
578; c) S. Saaby, K. R. Knudsen, M. Ladlow, S. V. Ley, Chem.
Commun. 2005, 2909.
[4]For reports dealing with the use of flow microwave approaches
for preparative- or semipreparative-scale organic synthesis, see:
a) M. C. Bagley, R. L. Jenkins, M. C. Lubinu, C. Mason, R.
Wood, J. Org. Chem. 2005, 70, 7003; b) S. Saaby, I. R. Baxendale,
S. V. Ley, Org. Biomol. Chem. 2005, 3, 3365; c) N. S. Wilson,
C. R. Sarko, G. P. Roth, Org. Process Res. Dev. 2004, 8, 535;
d) M. Fagrell PCT Int. Appl. (2003), 20 pp. CODEN:
Continuous flow system with microwave heating for organic
synthesis reactions: PIXXD2 WO 2003041856A1 20030522
Preparation and analysis of Pd thin films: Capillaries were
cleaved open and pieces of the films were fixed on carbon tape for
analysis. Films were also prepared on 1-cm flat borosilicate glass
2
slides by dipping them in the same Pd(OAc) solution described
A
H
R
U
G
2
above. Sample imaging was carried out with a Hitachi S-4500 field
emission scanning electron microscope (SEM) equipped with an
EDAX Phoenix model energy-dispersive X-ray (EDX) analyzer.
EDX analysis can detect all elements above atomic number 5 and has
a minimum detection limit of 0.5 wt% for most elements. A 5-kV
electron beam was used to obtain SEM images and EDX spectra.
Both the lower and upper SE detectors were used for imaging
purposes.
Microwave irradiation experiments: All microwave experiments
were performed in a MACOS reactor designed and constructed in our
laboratory (see Figure 2), operating at a frequency of 2.45 GHz with
irradiation power from 0 to 300 W. The reactions were carried out in
Pd-film-coated glass capillaries (1150 mm i.d.) that were placed in the
cavity of the Biotage Smith Creator Synthesizer. The recorded
temperature was measured by an IR sensor that was focused on the
outer surface of the reaction capillaries.
General procedure for the Suzuki–Miyara coupling: Condi-
tion A: A stock solution containing the aryl halide (0.6 mmol,
1
equiv), arylboronic acid (1.2 equiv), base (2m KOH, 0.9 mL,
Angew. Chem. Int. Ed. 2006, 45, 2761 –2766
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2765