Cross-coupling in a flow microreactor: Space integration of lithiation and murahashi coupling

Article abstract of DOI:10.1002/anie.201002763

Going with the flow: The use of palladium catalysts bearing a carbene ligand resulted in a faster Murahashi coupling, and enabled its integration with the Br-Li exchange of ArBr with Bu-Li in a microreactor (see picture). This system allows the cross-coupling of two different arylbromides within a minute without necessitating low temperatures (-78°C).

Full text of DOI:10.1002/anie.201002763

Angewandte
Chemie
DOI: 10.1002/anie.201002763
Microreactors
Cross-Coupling in a Flow Microreactor: Space Integration of Lithiation
and Murahashi Coupling**
Aiichiro Nagaki, Akira Kenmoku, Yuya Moriwaki, Atsushi Hayashi, and Jun-ichi Yoshida*
[
11]
Cross-coupling reactions of aryl metals with organic halides
serve as a powerful method for carbon–carbon bond forma-
tion in the synthesis of a variety of functional materials and
prompted us to then study the integration of the Br–Li
exchange and Murahashi coupling in a flow microreactor
[12]
system. Herein we report that the Murahashi coupling can
be much faster than the competing reaction with alkyl halides
if an appropriate catalyst is used, and that the space
of Br–Li exchange and Murahashi coupling
using an integrated flow microreactor system enables the
[1]
biologically active compounds. Aryl–boron, aryl–silane,
aryl–tin, aryl–zinc, and aryl–magnesium compounds are
often used for these cross-coupling reactions because these
organometallic compounds are relatively stable. In contrast,
the use of less stable but more reactive aryllithium com-
[13]
integration
1
cross-coupling of two different aryl bromides (Ar Br and
Ar Br). In addition, H–Li exchange is also effective for the
[
2,3]
2
pounds in cross-coupling has been rather limited,
although
many aryl metals including arylboron compounds are often
prepared from aryllithium compounds. In 1979 Murahashi
et al. reported pioneering work on the palladium-catalyzed
cross-coupling of organolithium compounds with organic
generation of ArLi in some cases, especially for heteroaryl
substrates, and therefore, we also report that the space
integration of H–Li exchange with Murahashi coupling
1
2
enables the cross-coupling of Ar H and Ar Br [Eq. (2)].
[
4]
halides. Since then, to the best of our knowledge, additional
studies have not been reported, one of the major reasons
being that X–Li exchange of ArX with BuLi, which is one of
the most powerful methods for generating ArLi, leads to the
formation of BuX. However, ArLi reacts with BuX if the
subsequent coupling is slow. This is indeed the case. Usually,
cross-coupling reactions take hours to reach completion at
room temperature or higher temperatures, whereas reactions
of ArLi with alkyl halides such as BuX are complete within
minutes at 08C. If this problem is solved, the combination of
X–Li exchange and Murahashi coupling will then enable the
cross-coupling of two aryl halides, hence providing a powerful
First, we focused on the coupling of p-methoxyphenyl-
lithium, which was generated by the Br–Li exchange reaction
of p-bromoanisole, in a macrobatch system. p-Methoxyphe-
nyllithium reacted with BuBr, which was inevitably generated
1
in the Br–Li exchange of Ar Br with BuLi, within 30 minutes
at 308C to give p-butylmethoxybenzene (2, 86% yield).
Having this information in hand, we examined the reaction
with bromobenzene as a coupling partner to give p-methoxy-
biphenyl (1; Scheme 1). The use of [Pd(PPh ) ] as a catalyst
3
4
[
5,6]
method in organic synthesis [Eq. (1)].
Though tBuLi does
resulted in the formation of the coupling product 1 in very low
yield (Table 1, entry 1), and a significant amount of 2 was
produced as a by-product. Butylbenzene (3) was also
produced, presumably from Br–Li exchange between p-
not suffer from this problem, the use of two equivalents of
highly reactive tBuLi is not suitable for large-scale laboratory
synthesis and industrial production.
[
14]
methoxyphenyllithium and bromobenzene
followed by
the reaction of the resulting phenyllithium with BuBr to
give 3. For this process to work we had to improve the rate of
the palladium-catalyzed cross-coupling to minimize this side
reaction. Thus, we searched for a catalyst that makes the
Recently we reported that Br–Li exchange reactions of
ArBr and the subsequent reactions with electrophiles could
[
7–10]
1
2
be conducted in flow microreactor systems.
This finding
coupling reaction of Ar Li and Ar Br much faster. The use of
[
Pd(PtBu ) ], [Pd (dba) ] and L1, [Pd (dba) ] and L2, [Pd -
3 2 2 3 2 3 2
(
dba) ] and L3, [Pd (dba) ] and L4, [Pd(acac) ], Pd(OAc) ,
[
*] Dr. A. Nagaki, Y. Moriwaki, A. Hayashi, Prof. J. Yoshida
Department of Synthetic and Biologycal Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
3 2 3 2 2
Fax: (+81)75-383-2727
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/yoshida-lab/index_
e.html
A. Kenmoku
The Research Association of Micro Chemical Process Technology
(
MCPT), Nishikyo-ku, Kyoto 615-8510 (Japan)
[**] This work was partially supported by the Grant-in-Aid for Scientific
Research and NEDO projects.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002763.
Scheme 1. Integration of Br–Li exchange and Murahashi coupling in a
conventional macrobatch reactor.
Angew. Chem. Int. Ed. 2010, 49, 7543 –7547
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7543

Communications
Table 1: Cross-coupling of p-methoxyphenyllithium with bromobenzene
[
a]
in a conventional macrobatch reactor.
[
b]
Entry Pd catalyst
Yield [%]
1
2
3
1
[Pd(PPh ) ]
[Pd(PtBu ) ]
3 2
4
2
3
14
8
18
4
18
5
38
44
38
34
34
31
28
20
35
30
11
10
37
45
39
34
35
30
40
22
33
35
3
3
4
2
3
4
5
6
7
8
9
1
1
1
[Pd (dba) ] and L1
2
3
[Pd (dba) ] and L2
2
3
[Pd (dba) ] and L3
2
3
[Pd (dba) ] and L4
2
3
Figure 1. Integrated flow microreactor system for the cross-coupling
micromixers: M1, M2, and M3, microtube reactors: R1, R2, and R3).
[Pd(acac)2]
Pd(OAc)2
(
PdCl /PPh /CH Li
2
3
3
0
1
2
PdCl (CH CN)
2
2
53
73
2
3
PEPPSI-IPr
PEPPSI-SIPr
1
[a] A solution of BuLi (2.36 mmol) in n-hexane was added dropwise
(
1 min) to a solution of p-bromoanisole (2.20 mmol) in THF contained in
a 25 mL round-bottomed flask at À788C. After the mixture had been
stirred for 10 min, a solution of the Pd catalyst (0.0760 mmol) and
bromobenzene (1.52 mmol) in THF was added. The mixture was stirred
for 30 min at 308C. [b] Reported yields, based on bromobenzene, were
determined by GC analysis using an internal standard (pentadecane).
The yield of 2 was based on p-bromoanisole. L1: 2-(dicyclohexylphos-
phino)biphenyl. L2: 2-(di-tert-butylphosphino)biphenyl (JohnPhos). L3:
2
,6-(dimethoxy)-2’-dicyclohexylphosphinobiphenyl (SPhos). L4: 2-(dime-
thylamino)-2’-dicyclohexylphosphinobiphenyl (DavePhos). acac=acetyl-
acetonate, dba=dibenzylideneacetone, PEPPSI-IPr=[1,3-bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichlor-
ide,
PEPPSI-SIPr=[1,3-bis(2,6-diisopropylphenyl)imidazolidene](3-
chloropyridyl)palladium(II) dichloride).
2
R2
Figure 2. Effects of the temperature (T ) and the residence time (t )
in R2 upon the yield of 1 in the PEPPSI-SIPr-catalyzed cross-coupling
of p-bromoanisole with bromobenzene using the integrated flow
microreactor system. Counter plot with scatter overlay of the yields of
1 (%), which are indicated by small circles.
PdCl /PPh /CH Li, and [PdCl (CH CN) ] did not improve the
2
3
3
2
3
2
[15]
yield of the coupling product 1 (Table 1, entries 2—10).
However, we found that the use of a palladium catalyst
bearing a carbene ligand developed by Organ and co-work-
[16]
R2
ers led to a faster cross-coupling relative to the occurrence
of the side reactions, and the yield of 1 increased significantly
at the expense of the undesired by-products 2 and 3. Because
PEPPSI-SIPr was superior to PEPPSI-IPr, hereafter we used
PEPPSI-SIPr as the catalyst (Table 1, entries 11 and 12).
Next, we examined the reaction using a flow microreactor
system comprising three micromixers (M1, M2, and M3) and
three microtube reactors (R1, R2, and R3; Figure 1). We have
already reported that ArLi can be generated by Br–Li
exchange of ArBr at 08C and 208C in a flow microreactor
reaction at 508C gave a slightly better yield of 1 (t > 16 s, ca.
[
19]
90%), and hereafter we carried out the coupling reactions
at 508C. Notably, the cross-coupling reactions were complete
within the overall residence time of one minute, and the
productivity of the present system is reasonable for laboratory
À1
scale synthesis (15.6 gh of 1).
The present flow microreactor method could be applied to
the cross-coupling of various aryl bromides (Table 2). In the
1
first step, Ar Br was reacted with BuLi at 08C. In the second
1
2
step, the resulting Ar Li was reacted with Ar Br in the
presence of PEPPSI-SIPr to give the cross-coupling product
[10]
system,
though much lower temperatures (for example
1
2
À788C) are required for a conventional macrobatch reaction.
Ar –Ar . The overall transformation was complete within a
minute or so. The reactions could be successfully carried out
with para-, meta-, and ortho-bromoanisoles, and para-, meta-,
and ortho-bromotoluenes (Ar Br; Table 2, entries 1–11).
Though the reaction with aryl bromides (Ar Br) as coupling
partners gave the products in good yields, the use of aryl
chloride resulted in much lower yields (Table 2, entry 2),
because the coupling reaction was much slower. The use of
aryl iodide also gave rise to lower yields (Table 2, entry 3),
because an I–Li exchange reaction between Ar Li and Ar I
took place. The introduction of a methyl group and a fluorine
Therefore, p-methoxyphenyllithium was generated using M1
[
17]
1
R1
(f= 500 mm)
and R1 (T = 08C, t = 2.6 s), and was
1
allowed to react with bromobenzene in the presence of
[
17]
2
PEPPSI-SIPr using M2 (f= 250 mm) and R2. The reaction
was quenched by adding methanol, which protonated the
unchanged p-methoxyphenyllithium very quickly (M3 and
[
18]
R3). As profiled in Figure 2, the yield significantly depends
2
R2
upon both the temperature (T ) and the residence time (t )
in R2 (see the Supporting Information for details). At 308C,
1
2
R2
the yield of 1 increased with t because of the progress of the
2
cross-coupling reaction. The coupling product 1 was obtained
atom in Ar did not affect the reaction, although the yields
were somewhat lower (Table 2, entries 4 and 5). The reaction
of Ar Br having an electron-withdrawing group such as CF
R2
in good yield (t > 16 s, > 80%), and the amounts of the
1
undesired by-products were very small (2: 7%, 3: 2%). The
3
7544
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7543 –7547

Angewandte
Chemie
1
2
[a]
Table 2: Cross-coupling of Ar Br and Ar X using the integrated flow microreactor system.
The palladium-catalyzed cross-
coupling with 2-bromopyridine at
1
2
1
2
[b]
Entry
Ar Br
Ar X
Ar –Ar
Yield [%]
R2
5
08C (t = 94 s) gave the desired
9
90)
3
1
2
3
4
5
product in 80% yield.
[
c]
(
In conclusion, we found that
the use of palladium catalysts bear-
ing a carbene ligand results in the
Murahashi coupling being much
faster, enabling its integration
[
d]
20
[
e]
32
71
54
1
with the Br–Li exchange of Ar Br
with BuLi in a flow reactor. The
undesired side reactions such as the
1
reaction of Ar Li with BuBr and
[c,f]
6
7
76
the Br–Li exchange reaction of
1
2
Ar Li with Ar Br could be avoided.
Eventually cross-coupling of two
71
82
1
2
aryl bromides Ar Br and Ar Br to
1
2
give Ar –Ar was successfully ac-
complished in a continuous flow
reactor with the residence time of a
minute or so without using low
temperatures. In the case of
heteroaromatic compounds, the
use of H–Li exchange enabled
cross-coupling of ArH and ArBr.
Hence the method greatly enhan-
ces the synthetic utility of organo-
lithium compounds and adds a new
dimension to the chemistry of
cross-coupling. Additional work is
in progress to explore the wider
scope and limitations of this useful
transformation.
8
9
75
71
1
1
0
1
59
[
[
[
c,f]
c,f]
g]
12
13
14
64
58
78
[
g]
1
1
5
6
87
80
[
f,g]
Experimental Section
2
1
1
[
0
a] Ar X was reacted with Ar Li, which was generated from Ar Br (1.50 equiv) and BuLi (1.50 equiv) at
General procedure: A flow microreac-
tor consisting of three T-shaped micro-
mixers (M1, M2, and M3), three micro-
tube reactors (R1, R2, and R3) and four
tube precooling units [P1 (inner diam-
eter f= 1000 mm, length L = 100 cm),
P2 (f= 1000 mm, L = 100 cm), P3 (f=
R1
R2
8C (t =2.6 s), in the presence of PEPPSI-SIPr (0.05 equiv) in THF at 508C (t =94 s) using the flow
microreactor system. [b] Determined by GC analysis using an internal standard (pentadecane). [c] Yield
of the isolated product. [d] Chlorobenzene was recovered in 60% yield [e] Significant amounts of by-
product such as 2 and 3 (2: 57%, 3: 23%) were produced. [f] Ar Br (1.80 equiv) and BuLi (1.80 equiv)
were used. [g] CPME was used as solvent in the presence of TMEDA (3.00 equiv) for the coupling.
1
CPME=cyclopentyl methyl ether, TMEDA=N,N,N’,N’-tetramethylethylenediamine.
1
1
000 mm, L = 100 cm), and P4 (f=
000 mm, L = 100 cm)] was used. A
1
also took place to give the coupling products in good yields
Table 2, entries 12 and 13). The method could also be applied
to heteroaryl bromides (Table 2, entries 14–16). For example,
the coupling of 2-bromothiophene with 2- and 3-bromopyr-
idines gave the coupling products in good yields.
solution of aryl bromide (Ar Br; 0.314m in THF; flow rate:
7.5 mLmin ) and a solution of n-butyllithium (1.57m in n-hexane;
flow rate: 1.5 mLmin ) were introduced to M1 (f= 500 mm) by
plunger pumps. The resulting solution was passed through R1 (f=
00 mm, L = 200 cm) and was mixed with a solution of aryl bromide
Ar Br; 0.523m in THF) and PEPPSI-SIPr (26.2 mm in THF; flow
rate: 3.0 mLmin ) in M2 (f= 250 mm). The resulting solution was
passed through R2 was mixed with methanol (flow rate:
À1
(
À1
5
(
2
Notably, the H–Li exchange could be used to generate
À1
1
Ar Li in the case of heteroaromatic compounds such as
2
À1
thiophene. Reaction with Ar Br led to the cross-coupling of
5.0 mLmin ) in M3 (f= 500 mm). The resulting solution was
1
2
Ar H and Ar Br. Thus, thiophene was deprotonated with
passed through R3 (f= 1000 mm, L = 100 cm). The inner pressure
of the system was adjusted to give a continuous steady flow using a
back pressure regulator, which was located at the outlet of the system.
After a steady state was reached, the product solution was collected
for 1.0 min. Then, the reaction mixture was poured into water. The
organic phase was separated and the aqueous phase was extracted
with diethyl ether. The combined organic phase was concentrated,
and the resulting crude product was purified by flash chromatography
R1
sBuLi at 08C using a flow microreactor (t = 11 s) [Eq. (3)].
Angew. Chem. Int. Ed. 2010, 49, 7543 –7547
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7545

Communications
on silica gel with subsequent preparative gel permeation chromatog-
raphy on. GC yields were obtained by analyzing the combined
organic phases using an internal standard.
Angew. Chem. Int. Ed. 2007, 46, 5704; f) C. H. Hornung, M. R.
Mackley, I. R. Baxendale, S. V. Ley, Org. Process Res. Dev. 2007,
11, 399; g) T. Fukuyama, M. Kobayashi, M. T. Rahman, N.
Kamata, I. Ryu, Org. Lett. 2008, 10, 533; h) C. Wiles, P. Watts,
Org. Process Res. Dev. 2008, 12, 1001; i) A. Nagaki, E. Takizawa,
J. Yoshida, J. Am. Chem. Soc. 2009, 131, 1654; j) A. Nagaki, E.
Takizawa, J. Yoshida, Chem. Lett. 2009, 38, 486; k) I. C.
Wienhꢁfer, A. Studer, M. T. Rahman, T. Fukuyama, I. Ryu,
Org. Lett. 2009, 11, 2457; l) A. R. Bogdan, S. L. Poe, D. C. Kubis,
S. J. Broadwater, D. T. McQuade, Angew. Chem. 2009, 121, 8699;
Angew. Chem. Int. Ed. 2009, 48, 8547.
Received: May 7, 2010
Revised: July 21, 2010
Published online: September 3, 2010
Keywords: biaryls · cross-coupling · lithiation · microreactors
.
[
10] a) H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami, J.
Yoshida, J. Am. Chem. Soc. 2007, 129, 3046; b) A. Nagaki, Y.
Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H.
Okamoto, J. Yoshida, Chem. Asian J. 2007, 2, 1513; c) A. Nagaki,
N. Takabayashi, Y. Tomida, J. Yoshida, Org. Lett. 2008, 10, 3937;
d) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. 2008, 120, 7951;
Angew. Chem. Int. Ed. 2008, 47, 7833; e) A. Nagaki, N.
Takabayashi, Y. Tomida, J. Yoshida, Beilstein J. Org. Chem.
[
1] a) Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Dieder-
ich, P. J. Stang), Wiley-VCH, New York, 1998; b) S. P. Stanforth,
Tetrahedron 1998, 54, 263; c) J. Hassan, M. Sꢀvignon, C. Gozzi,
E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359.
[
[
2] Review: S. I. Murahashi, J. Organomet. Chem. 2002, 653, 27.
3] Stoichiometric process: a) S. I. Murahashi, Y. Tanba, M. Yama-
mura, I. Moritani, Tetrahedron Lett. 1974, 15, 3749; b) S. I.
Murahashi, Y. Tanba, M. Yamamura, N. Yoshimura, J. Org.
Chem. 1978, 43, 4099.
2009, 5, 1; f) Y. Tomida, A. Nagaki, J. Yoshida, Org. Lett. 2009,
11, 3614; g) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. 2009,
121, 8207; Angew. Chem. Int. Ed. 2009, 48, 8063; h) A. Nagaki,
[
4] Catalytic process: S. I. Murahashi, M. Yamamura, K. Yanagi-
sawa, N. Mita, K. Kondo, J. Org. Chem. 1979, 44, 2408.
5] One-pot Negishi cross-coupling reactions of in situ generated
H. Kim, C. Matuo, J. Yoshida, Org. Biomol. Chem. 2010, 8, 1212.
[
1
2
zinc compounds (Ar Zn) with Ar X may be suitable for this
[11] Recent examples of integrated synthesis: a) T. A. Cernak, T. H.
Lambert, J. Am. Chem. Soc. 2009, 131, 3124; b) I. R. Baxendale,
S. C. Schou, J. Sedelmeier, S. V. Ley, Chem. Eur. J. 2010, 16, 89;
c) A. Kirschning, S. Wladimir, M. Klaas, Chem. Eur. J. 2006, 12,
5972; d) J. Wang, G. Sui, V. P. Mocharla, R. J. Lin, M. E. Phelps,
H. C. Kolb, H. R. Tseng, Angew. Chem. 2006, 118, 5402; Angew.
Chem. Int. Ed. 2006, 45, 5276.
[12] For examples of catalytic reaction using microreactors: a) C.
de Bellefon, N. Tanchoux, S. Caravieilhes, P. Grenouillet, V.
Hessel, Angew. Chem. 2000, 112, 3584; Angew. Chem. Int. Ed.
2000, 39, 3442; b) G. M. S. Greenway, J. Haswell, D. O. Morgan,
V. Skelton, P. String, Sens. Actuators B 2000, 63, 153; c) S. J.
Haswell, B. OꢃSullivan, P. Styring, Lab Chip 2001, 1, 164; d) S.
Niwa, M. Eswaramoorthy, J. Nair, A. Raj, N. Itoh, H. Shoji, T.
Namba, F. Mizukami, Science 2002, 295, 105; e) T. Fukuyama, M.
Shinmen, S. Nishitani, M. Sato, I. Ryu, Org. Lett. 2002, 4, 1691;
f) G. Jas, A. Kirschning, Chem. Eur. J. 2003, 9, 5708; g) J.
Kobayashi, Y. Mori, K. Okamoto, R. Akiyama, M. Ueno, T.
Kitamori, S. Kobayashi, Science 2004, 304, 1305; h) C. Basheer,
F. S. J. Hussain, H. K. Lee, S. Valiyaveettil, Tetrahedron Lett.
1
purpose, but aryl iodides (Ar I), which are more expensive and
less easily available than aryl bromides, was often used as a
starting material for the generation of zinc compounds; a) P.
Knochel, A. Krasovskiy, I. Sapountzis in Handbook of Func-
tionalized Organometallics (Ed.: P. Knochel), Wiley-VCH,
Weinheim, 2005; b) G. Cahiez, A. Moyeux, J. Buendia, C.
Duplais, J. Am. Chem. Soc. 2007, 129, 13788; c) S. Sase, M. Jaric,
A. Metzger, V. Malakhov, P. Knochel, J. Org. Chem. 2008, 73,
7380; d) G. Cahiez, L. Foulgoc, A. Moyeux, Angew. Chem. 2009,
121, 3013; Angew. Chem. Int. Ed. 2009, 48, 2969; e) G. Cahiez, C.
Chaboche, C. Duplais, A. Moyeux, Org. Lett. 2009, 11, 277.
6] One-pot palladium-catalyzed borylation and Suzuki–Miyaura
coupling reaction may also be used; a) S. P. Maddaford, B. A.
Keay, J. Org. Chem. 1994, 59, 6501; b) N. G. Andersen, S. P.
Maddaford, B. A. Keay, J. Org. Chem. 1996, 61, 9556; c) S. D.
Brown, R. W. Armstrong, J. Am. Chem. Soc. 1996, 118, 6331;
d) A. Carbonnelle, J. Zhu, Org. Lett. 2000, 2, 3477; e) L. Zhu, J.
Duquette, M. Zhang, J. Org. Chem. 2003, 68, 3729. However,
catalyzed borylation may not be suitable for large-scale syn-
thesis; f) W. Li, D. P. Nelson, M. S. Jensen, R. S. Hoerrner, D.
Cai, R. D. Larsen, P. J. Reider, J. Org. Chem. 2002, 67, 5394.
7] Books on microreactor synthesis: a) W. Ehrfeld, V. Hessel, H.
Lꢁwe, Microreactors, Wiley-VCH, Weinheim, 2000; b) V.
Hessel, S. Hardt, H. Lꢁwe, Chemical Micro Process Engineering,
Wiley-VCH, Weinheim, 2004; c) J. Yoshida, Flash Chemistry.
Fast Organic Synthesis in Microsystems, Wiley-Blackwell, Hobo-
ken, 2008; d) V. Hessel, A. Renken, J. C. Schouten, J. Yoshida,
Micro Process Engineering, Wiley-Blackwell, Hoboken, 2009.
8] Reviews on microreactor synthesis: a) K. Jꢂhnisch, V. Hessel, H.
Lꢁwe, M. Baerns, Angew. Chem. 2004, 116, 410; Angew. Chem.
Int. Ed. 2004, 43, 406; b) G. N. Doku, W. Verboom, D. N.
Reinhoudt, A. van den Berg, Tetrahedron 2005, 61, 2733; c) T.
Fukuyama, M. T. Rahman, M. Sato, I. Ryu, Synlett 2008, 151;
d) J. Yoshida, A. Nagaki, T. Yamada, Chem. Eur. J. 2008, 14,
[
2004, 45, 7297; i) S. Liu, T. Fukuyama, M. Sato, I. Ryu, Org.
Process Res. Dev. 2004, 8, 477; j) U. Kunz, H. Schꢁnfeld, W.
Solodenko, G. Jas, A. Kirschning, Ind. Eng. Chem. Res. 2005, 44,
[
[
[
8458; k) E. Comer, M. G. Organ, J. Am. Chem. Soc. 2005, 127,
8160; l) C. K. Y. Lee, A. B. Holmes, S. V. Ley, I. F. McConvey, B.
Al-Duri, G. A. Leeke, R. C. D. Santosd, J. P. K. Sevilled, Chem.
Commun. 2005, 2175; m) C. Mauger, O. Buisine, S. Caravieilhes,
G. Mignani, J. Organomet. Chem. 2005, 690, 3627; n) Y. Uozumi,
Y. M. A. Yamada, T. Beppu, N. Fukuyama, M. Ueno, T.
Kitamori, J. Am. Chem. Soc. 2006, 128, 15994; o) G. Shore, S.
Morin, M. G. Organ, Angew. Chem. 2006, 118, 2827; Angew.
Chem. Int. Ed. 2006, 45, 2761; p) G. Shi, F. Hong, Q. Liang, H.
Fang, S. Nelson, S. G. Weber, Anal. Chem. 2006, 78, 1972;
q) M. T. Rahman, T. Fukuyama, N. Kamata, M. Sato, I. Ryu,
Chem. Commun. 2006, 2236; r) E. R. Murphy, J. R. Martinelli, N.
Zaborenko, S. L. Buchwald, K. F. Jensen, Angew. Chem. 2007,
7450; e) R. L. Hartman, K. F. Jensen, Lab Chip 2009, 9, 2495.
9] Some recent examples: a) A. Nagaki, K. Kawamura, S. Suga, T.
119, 1764; Angew. Chem. Int. Ed. 2007, 46, 1734; s) H.
Ando, M. Sawamoto, J. Yoshida, J. Am. Chem. Soc. 2004, 126,
1
4702; b) A. Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae, J.
Kawanami, K. Matsushima, M. Sato, Y. Ikushima, Angew.
Chem. 2007, 119, 5221; Angew. Chem. Int. Ed. 2007, 46, 5129;
t) Y. M. A. Yamada, T. Watanabe, K. Torii, Y. Uozumi, Chem.
Commun. 2009, 5594; u) J. Jin, M. Cai, J. Li, Synlett 2009, 2534;
v) B. Ahmed-Omer, D. A. Barrow, T. Wirth, Tetrahedron Lett.
2009, 50, 3352.
Yoshida, J. Am. Chem. Soc. 2005, 127, 11666; c) P. He, P. Watts, F.
Marken, S. J. Haswell, Angew. Chem. 2006, 118, 4252; Angew.
Chem. Int. Ed. 2006, 45, 4146; d) K. Tanaka, S. Motomatsu, K.
Koyama, S. Tanaka, K. Fukase, Org. Lett. 2007, 9, 299; e) H. R.
Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem. 2007, 119, 5806;
7546
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7543 –7547

Angewandte
Chemie
[
13] Integration of a sequence of reactions in flow by adding reaction
components at different places. S. Suga, D. Yamada, J. Yoshida,
Chem. Lett. 2010, 39, 404.
14] E. I. Negishi, T. Takahashi, S. Baba, S. B. Van Horn, N. Okukado,
J. Am. Chem. Soc. 1987, 109, 2393.
Angew. Chem. 2009, 121, 2419; Angew. Chem. Int. Ed. 2009, 48,
2383; d) S. C¸ alimsiz, M. Sayah, D. Mallik, M. G. Organ, Angew.
Chem. 2010, 122, 2058; Angew. Chem. Int. Ed. 2010, 49, 2014.
[17] Recent studies (Refs. [10b,d]) revealed that mixing in the
micromixer used in this work was complete in less than 0.014 s
(f= 250 mm) and 0.39 s (f= 500 mm) because an almost quanti-
tative conversion was obtained for Br–Li exchange reactions
within these residence times.
[
[
15] a) J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buchwald, J. Am.
Chem. Soc. 1999, 121, 9550; b) S. D. Walker, T. E. Barder, J. R.
Martinelli, S. L. Buchwald, Angew. Chem. 2004, 116, 1907;
Angew. Chem. Int. Ed. 2004, 43, 1871; c) R. Martin, S. L.
Buchwald, J. Am. Chem. Soc. 2007, 129, 3844.
[18] Figure 2 was produced using Origin 7.5J. The contours were
drawn to aid in visualizing the results.
[
16] a) M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B.
Kantchev, C. J. OꢃBrien, C. Valente, Chem. Eur. J. 2006, 12,
[19] The use of 1 mol% of PEPPSI-SIPr resulted in much lower yield
R2
of the product (18% yield t = 94.2 s), and significant amounts
4
749; b) M. G. Organ, M. Abdel-Hadi, S. Avola, N. Hadei, J.
of by-products were produced (see the Supporting Information),
indicating that competing side reactions were faster than the
coupling.
Nasielski, C. J. OꢃBrien, C. Valente, Chem. Eur. J. 2007, 13, 150;
c) M. G. Organ, S. Calimsiz, M. Sayah, K. H. Hoi, A. J. Lough,
Angew. Chem. Int. Ed. 2010, 49, 7543 –7547
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7547