Homocoupling of aryl halides in flow: Space integration of lithiation and FeCl3 promoted homocoupling

Article abstract of DOI:10.3762/bjoc.7.122

The use of FeCl₃ resulted in a fast homocoupling of aryllithiums, and this enabled its integration with the halogen-lithium exchange reaction of aryl halides in a flow microreactor. This system allows the homocoupling of two aryl halides bearing electrophilic functional groups, such as CN and NO₂, in under a minute.

Full text of DOI:10.3762/bjoc.7.122

Homocoupling of aryl halides in flow:
Space integration of lithiation and
FeCl3 promoted homocoupling
Aiichiro Nagaki, Yuki Uesugi, Yutaka Tomida and Jun-ichi Yoshida*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1064–1069.
Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University,
doi:10.3762/bjoc.7.122
Kyotodaigakukatsura, Nishikyo-ku, Kyoto, 615-8510, Japan
Received: 15 April 2011
Accepted: 29 June 2011
Published: 02 August 2011
Email:
Aiichiro Nagaki - anagaki@sbchem.kyoto-u.ac.jp; Jun-ichi Yoshida* -
yoshida@sbchem.kyoto-u.ac.jp
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
*
Corresponding author
Keywords:
© 2011 Nagaki et al; licensee Beilstein-Institut.
License and terms: see end of document.
homocoupling; iron salts; microreactor; organolithiums
Abstract
The use of FeCl3 resulted in a fast homocoupling of aryllithiums, and this enabled its integration with the halogen–lithium
exchange reaction of aryl halides in a flow microreactor. This system allows the homocoupling of two aryl halides bearing electro-
philic functional groups, such as CN and NO2, in under a minute.
Introduction
Biaryl structures often occur in various organic compounds pling reaction of Grignard reagents bearing functional groups,
including natural products, bioactive compounds, functional using atmospheric oxygen [20]. The use of aryllithium com-
polymers, ligands in catalysts and theoretically interesting pounds instead of Grignard reagents is very interesting, because
molecules, and the oxidative homocoupling of arylmetals is one they are easily generated by halogen–lithium exchange under
of the most useful methods for the construction of biaryl frame- homogeneous conditions, thus enabling the generation in a
works [1]. Stoichiometric amounts of transition metal salts such flow. However, to the best of our knowledge, oxidative homo-
as TiCl4 [2], TlCl [3], VO(OEt)Cl2 [4], CoCl2 [5], CuCl2 [6] coupling of aryllithiums using iron salts has not been reported
and Pd(OAc)2 [7] have been used for homocoupling of aryl- so far. One of the major reasons for this seems to be the insta-
metals. In some cases catalytic processes in the presence of a bility of aryllithiums, especially of those bearing electrophilic
reoxidant, such as oxygen or other organic oxidants, are effec- functional groups such as cyano and nitro groups [21], making
tive. Recently, iron salts have been also used because of their the subsequent homocoupling difficult or impossible.
low costs and lack of toxicity [8-18]. For example, Hayashi et
al. reported the iron-catalyzed oxidative homocoupling of Grig- Recently, we have reported that flow microreactor systems [22-
nard reagents, using 1,2-dihalogenoethanes as an oxidant [19]. 85] are quite effective for the generation and reaction of highly
Cahiez et al. have also reported the FeCl3-catalyzed homocou- reactive organolithiums such as functionalized aryllithiums,
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Beilstein J. Org. Chem. 2011, 7, 1064–1069.
oxiranyllithums, aziridinyllithiums, and allenyllithiums [86-98].
Herein we report that integration [99,100] of the generation of
aryllithiums, especially those bearing electrophilic functional
groups, by halogen–lithium exchange and FeCl3 promoted
homocoupling has been effectively accomplished in an inte-
grated flow microreactor system.
Results and Discussion
First, we focused on the generation of p-methoxyphenyllithium
from p-bromoanisole (Scheme 1). A flow microreactor system,
consisting of two T-shaped micromixers (M1 and M2) and two
microtube reactors (R1 and R2) shown in Figure 1, was used. A
solution of p-bromoanisole (Ar–X) (0.10 M in THF, flow rate:
Figure 1: Flow microreactor system for halogen–lithium exchange of
aryl halide followed by reaction with methanol. T-shaped micromixer:
M1 (inner diameter: 250 μm), and M2 (inner diameter: 500 μm), micro-
tube reactor: R1 and R2 (
aryl halides: 0.10 M in THF (6.0 mL/min), a solution of lithium reagent:
.40 M or 0.42 M in hexane (n-BuLi) or Et2O (PhLi) (1.5 mL/min), a
= 1000 μm, length = 50 cm), a solution of
6
.0 mL/min) and a solution of n-butyllithium (0.40 M in
hexane, flow rate: 1.5 mL/min) were introduced to M1 (
50 μm) by syringe pumps. The resulting mixture was passed
through R1 to conduct the bromine–lithium exchange reaction.
Methanol (neat, flow rate: 3.0 mL/min) was added in M2 (
00 μm) and the mixture was passed through R2 ( = 1000
0
=
solution of methanol: Neat (3.0 mL/min).
2
=
5
μm, L = 50 cm) to protonate p-methoxyphenyllithium. The
reactions were carried out with varying residence time in R1
(
tR1: 0.2–6.3 s) and varying temperature (T: −78 to 24 °C). The
temperature (T) was controlled by adjusting the bath tempera-
ture. The residence time (tR1) was adjusted by changing the
inner diameter and the length in the microtube reactor R1 with a
fixed flow rate. After a steady state was reached, the product
solution was collected for 30 s. As shown in Figure 2, the yield
of the protonated product, anisole, depends on both T and tR1.
The reaction at low temperatures (T < −48 °C) with short resi-
dence times (tR1 < 0.79 s) resulted in very low yields, because
the Br–Li exchange reaction was not complete. The increase in
T and tR1 caused an increase in the yield, and high yields
(
>85%) were obtained through the appropriate choice of T and
tR1.
Figure 2: Effects of the temperature (T) and the residence time in R1
Next, we examined the integration of the halogen–lithium
exchange reaction with FeCl3 promoted homocoupling
(tR1) on the yield of anisole in the Br–Li exchange reaction of
p-bromoanisole followed by reaction with methanol in the flow microre-
actor system. The contour plot with scatter overlay shows the yields of
anisole (%), which are indicated by small circles.
(
Scheme 2). Integrated flow microreactor systems consisting of
three micromixers (M1, M2, and M3) and three microtube reac-
Scheme 1: Halogen–lithium exchange of p-bromoanisole followed by reaction with methanol.
Scheme 2: Halogen-lithium exchange of p-bromoanisole followed by oxidative homocoupling with FeCl3.
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Beilstein J. Org. Chem. 2011, 7, 1064–1069.
tors (R1, R2, and R3) were used, as shown in Figure 3. A solu-
tion of p-bromoanisole (Ar–X) (0.10 M in THF, flow rate: 6.0
mL/min) and a solution of n-butyllithium (0.42 M in hexane,
flow rate: 1.5 mL/min) were introduced to M1 ( = 250 μm)
by syringe pumps. The resulting mixture was passed through
R1 (tR1 = 13 s (−78 °C), tR1 = 13 s (−48 °C), tR1 = 3.1 s (−28
°
C), tR1 = 3.1 s (0 °C), tR1 = 3.1 s (24 °C)) at the corresponding
temperatures and was mixed with a solution of FeCl3 (0.10 M in
THF, flow rate: 6.0 mL/min) in M2 ( = 500 μm). The
resulting mixture was passed through R2 and was then mixed
with methanol (neat, flow rate: 1.5 mL/min) in M3 ( = 500
μm) to protonate the unchanged p-methoxyphenyllithium. The
resulting solution was passed through R3 ( = 1000 μm, L =
5
0 cm). The temperature (T) was controlled by adjusting the
bath temperature, and the residence time in R2 (tR2) by
changing the inner diameter and the length in R2 with the fixed
flow rate. After a steady state was reached, the product solution
was collected for 30 s. The results obtained from varying tR2
and T are summarized in Figure 4, in which the yield of 4,4'-
dimethoxybiphenyl is plotted against T and tR2 as a contour
map with scattered overlay (see Supporting Information File 1
for details). The yield depends on both T and tR2. At −78 °C, the
yield increased with tR2 because of the progress of the homo-
Figure 4: Effects of the temperature (T) and the residence time in R2
(tR2) on the yield of 4,4'-dimethoxybiphenyl in the oxidative homocou-
pling of p-methoxyphenyllithium with FeCl3 in the integrated flow
microreactor system. Contour plot with scatter overlay of the yields of
4,4'-dimethoxybiphenyl (%), which are indicated by small circles.
coupling. At 0 °C, the homocoupling product was obtained in mediates can be rapidly generated and transferred to another
reasonable yields for a wide range of tR2. The productivity of location to be used in a subsequent reaction before they decom-
the present system is acceptable for large scale laboratory syn- pose. We have already reported the generation and reactions of
thesis (6.2 g/h). It is noteworthy that the integrated reactions unstable aryllithium species such as o-bromophenyllithiums,
were complete within the overall residence time of 14.7 s, even and aryllithiums bearing alkoxycarbonyl, cyano, nitro, and
at low temperatures such as −48 °C. Thus, we envisaged that ketone carbonyl groups [86,87,93,95,96,98], which are difficult
the reaction could also be applied to less stable aryllithium com- to use in conventional macro batch reactors. As shown in
pounds that decompose very quickly.
Table 1, reactions of aryllithiums bearing cyano and nitro
groups proceeded successfully to give the corresponding homo-
One of the major benefits of flow microreactor synthesis is the coupling products, where in contrast it is very difficult to
ability to use highly unstable reactive intermediates. Such inter- achieve such reactions using conventional batch reactors. A
mechanism involving transmetalation of the aryl group from
lithium to iron followed by reductive elimination of the homo-
coupling product seems to be plausible, while a similar mecha-
nism is proposed for homo-coupling of organomagnesium com-
pounds with FeCl3 [19,20]. The regiospecificity of the coupling
is consistent with this mechanism. Radical coupling seems to be
less likely.
Conclusion
In conclusion, we found that the use of FeCl3 results in fast
oxidative homocoupling of aryllithiums, which enables its inte-
Figure 3: Integrated flow microreactor system for oxidative homocou-
pling reaction of aryllithium with FeCl3. T-shaped micromixer: M1
gration with the halogen–lithium exchange of aryl halides.
Various aryl halides, including those bearing electrophilic func-
tional groups, can be used for this transformation in the inte-
grated flow microreactor system. Hence, the method greatly
enhances the synthetic utility of aryllithium compounds and
adds a new dimension to the chemistry of coupling reactions.
(
inner diameter: 250 μm), M2 (inner diameter: 500 μm), and M3 (inner
diameter: 500 μm), microtube reactor: R1, R2 and R3 ( = 1000 μm,
length = 50 cm), a solution of aryl halides: 0.10 M in THF (6.0 mL/min),
a solution of lithium reagent: 0.42 M in hexane (n-BuLi) or Et2O (PhLi)
(1.5 mL/min), a solution of FeCl3: 0.10 M in THF (6 mL/min), a solu-
tion of methanol: Neat (1.5 mL/min).
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Beilstein J. Org. Chem. 2011, 7, 1064–1069.
Table 1: Homocoupling of aryl halides using the integrated flow microreactor system.
Ar–X
T (°C)
tR1 (s)
Ar–Ar
Yield (%)
72
2
4
4
3.100
2
3.100
3.100
69
76
0
−
28
0.055
0.055
75
66
0
2
4
0.055
0.014
0.014
76
−
48
48
53a
63a
−
aPhLi instead of n-BuLi was used as lithiating reagent.
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