Synthesis of unsymmetrically substituted biaryls via sequential lithiation of dibromobiaryls using integrated microflow systems

Article abstract of DOI:10.3762/bjoc.5.16

A microflow system consisting of micromixers and microtube reactors provides an effective method for the introduction of two electrophiles onto dibromobiaryls. Selective monolithiation of dibromobiaryls, such as 2,2'-dibromobiphenyl, 4,4'-dibromobiphenyl, 2,7-dibromo-9,9-dioctylfluorene, 2,2'-dibromo-1,1'-binaphthyl, and 2,2'-dibromobibenzyl with 1 equiv of n-butyllithium followed by the reaction with electrophiles was achieved using a microflow system by virtue of fast micromixing and precise temperature control. Sequential introduction of two different electrophiles was achieved using an integrated microflow system composed of four micromixers and four microtube reactors to obtain unsymmetrically substituted biaryl compounds.

Full text of DOI:10.3762/bjoc.5.16

Synthesis of unsymmetrically substituted biaryls via
sequential lithiation of dibromobiaryls using
integrated microflow systems
Aiichiro Nagaki, Naofumi Takabayashi, Yutaka Tomida
and Jun-ichi Yoshida*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University,
Kyotodaigakukatsura, Nishikyo-ku, Kyoto, 615-8510, Japan
doi:10.3762/bjoc.5.16
Received: 22 January 2009
Accepted: 02 April 2009
Published: 29 April 2009
Email:
Jun-ichi Yoshida* - yoshida@sbchem.kyoto-u.ac.jp
Guest Editor: A. Kirschning
* Corresponding author
© 2009 Nagaki et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
dibromobiaryls; fast mixing; integrated microflow system; selective
lithiation; unsymmetrically substituted biaryls
Abstract
A microflow system consisting of micromixers and microtube reactors provides an effective method for the introduction of two
electrophiles onto dibromobiaryls. Selective monolithiation of dibromobiaryls, such as 2,2′-dibromobiphenyl, 4,4′-dibromobi-
phenyl, 2,7-dibromo-9,9-dioctylfluorene, 2,2′-dibromo-1,1′-binaphthyl, and 2,2′-dibromobibenzyl with 1 equiv of n-butyllithium
followed by the reaction with electrophiles was achieved using a microflow system by virtue of fast micromixing and precise
temperature control. Sequential introduction of two different electrophiles was achieved using an integrated microflow system
composed of four micromixers and four microtube reactors to obtain unsymmetrically substituted biaryl compounds.
Introduction
Unsymmetrical biaryls have received significant research further transformations [10-12]. However, halogen-lithium
interest because of the frequent occurrence of such structures in exchange reactions of dihalobiaryls usually give a mixture of
natural products, pharmaceuticals, agrochemicals, and func- mono- and dilithiated compounds in a conventional macrobatch
tional organic materials [1]. Transition metal-catalyzed cross- reactor, even when one equivalent of butyllithium is used.
coupling of arylmetal compounds with aryl halides or triflates
serves as a useful method for preparation of such unsymmet- Recent investigations revealed that microflow systems [13-26]
rical biaryls [2-9]. Selective monolithiation of dihalobiaryls also serve as useful method for improving product selectivity in fast
seems to be useful for synthesis of unsymmetrically substituted competitive consecutive reactions. If a reaction is faster than
biaryls because the remaining halogen atom can be utilized for mixing, the reaction takes place before the homogeneity of the
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
solution is achieved. This often happens in macrobatch reactors successful results prompted us to perform a study on the
such as flasks. In such cases, arguments based on kinetics do synthesis of unsymmetrically substituted biaryls via sequential
not work, and product selectivity is determined by the manner lithiation of dibromobiaryls using an integrated microflow
of mixing (disguised chemical selectivity) [27,28]. To obtain a system. These observations may open a new aspect of the
predictable selectivity close to kinetically based one, extremely synthesis of unsymmetrically substituted biaryls (Scheme 1),
fast mixing is necessary. Micromixing based on short diffusion and herein we report full details of this study.
paths proved to be quite effective for this purpose [29-33]. Fast
Results and Discussion
heat transfer by virtue of high surface-to-volume ratios in
Br-Li Exchange Reaction of 2,2′-Dibromobi-
phenyl
microspaces is also important for conducting fast reactions,
because fast reactions are often highly exothermic. Fast reac-
tions often involve unstable short-lived intermediates. In such
cases residence time control in microflow system is effective
for conducting reactions without decomposing such intermedi-
ates [34-40]. Moreover, microflow systems serve as effective
ways of integrating chemical reactions, in which an initial
product is used for a subsequent transformation [41-51]. For
example, sequential introduction of two electrophiles to p-, m-,
and o-dibromobenzenes based on Br-Li exchange reactions has
been accomplished using an integrated microflow system at
much higher temperatures than those for conventional
macrobatch systems by virtue of residence time control and
temperature control [52,53].
First, we focused on Br-Li exchange reaction of 2,2′-dibromobi-
phenyl (1) to generate (2-bromobiphenyl-2′-yl)lithium. It is
known that Br-Li exchange reaction of 2,2′-dibromobiphenyl
(1) gives a significant amount of dilithiated product in a
conventional macrobatch system [55,56]. In order to confirm
this, we reexamined the Br-Li exchange reaction of 1 with 1
equiv of n-BuLi in a conventional macrobatch reactor (Scheme
2). A hexane solution of n-BuLi was added dropwise (1 min) to
a THF solution of 1 in a 20 mL round-bottomed flask at T °C (T
= −78, −48, −27, 0, and 24) to generate (2-bromobiphenyl-2′-
yl)lithium. After stirring methanol was added, and the mixture
was stirred for 10 min. Then, the solution was analyzed by gas
chromatography (GC) to determine the yields of 2-bromobi-
phenyl (2, product derived from monolithiation) and biphenyl
(3, product derived from dilithiation).
Recently, we reported that selective monolithiation can be
achieved by extremely fast 1:1 micromixing of dibromobiaryls
and n-butyllithium using microflow systems [54]. The
As shown in Table 1, 2 was obtained with high selectivity at
−78 °C, but the yield was not very high. Moreover, the require-
ment of such low temperatures like −78 °C causes severe limita-
Scheme 1: Sequential introduction of two electrophiles onto dibromo-
biaryls using Br-Li exchange reactions.
Scheme 2: Br-Li exchange reaction of 2,2′-dibromobiphenyl (1) with
n-BuLi using a conventional macrobatch reactor.
Table 1: Br-Li exchange reaction of 2,2′-dibromobiphenyl (1) using a conventional macrobatch system.a
temperature (°C)
reaction time (min)
1 conversion (%)b
2 yield (%)b
3 yield (%)b
4 yield (%)b
−78
−48
−27
0
60
10
10
10
10
94
86
81
75
66
76
69
48
36
14
4
0
0
0
2
3
4
18
25
34
24
aA solution of 1 (0.10 M, 6.0 mL) in THF was stirred in a flask (20 mL). A solution of n-BuLi (0.50 M, 1.2 mL) in hexane was added dropwise for 1.0 min.
After stirring, methanol (neat, 3.0 mL) was added dropwise for 1.0 min. After stirring for 10 min, the mixture was analyzed. bDetermined by GC.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Figure 1: Microflow system for Br-Li exchange reaction of 2,2′-dibromobiphenyl (1). T-shaped micromixer: M1 (ø = 250 μm) and M2 (ø = 500 μm),
microtube reactor: R1 and R2 (ø = 1000 μm, l = 50 cm), a solution of 2,2′-dibromobiphenyl (1): 0.10 M in THF, a solution of n-BuLi: 0.50 M in hexane,
a solution of electrophile: 0.30 M in THF.
tions in the industrial application. The selectivity decreased exchange reaction can be inherently conducted at 0 °C and 24
with an increase in the temperature, and a significant amount of °C, while the reaction in macrobatch reactors suffers from
3 was produced at higher temperatures. The major side product insufficient heat removal, and therefore, over-cooling is neces-
was 2-bromo-2′-butylbiphenyl (4), which seemed to be sary. At −48 °C and −78 °C, the Br-Li exchange reaction was
produced by the reaction of (2-bromobiphenyl-2′-yl)lithium not complete within 0.1 s. At higher temperatures, however, the
with 1-bromobutane that was produced by Br-Li exchange reac- Br-Li exchange reaction was complete within 0.1 s.
tion.
In the next step, the same reaction was examined using a micro-
flow system composed of two T-shaped micromixers (M1 and
M2) and two microtube reactors (R1 and R2) shown in Figure
1. A solution of 2,2′-dibromobiphenyl (1) (0.10 M) in THF
(flow rate: 6.00 ml·min−1, 0.60 mmol min−1) and a solution of
n-BuLi (0.50 M) in hexane (flow rate: 1.20 ml·min−1, 0.60
mmol min−1) were introduced to M1 (ø = 250 μm) by syringe
pumping. The mixture was passed through R1 (residence time =
tR s) and was introduced to M2 (ø = 500 μm), where methanol
(neat, flow rate: 3.00 ml·min−1) was introduced. The resulting
mixture was passed through R2 (ø = 1000 μm, l = 50 cm, tR =
2.3 s). The temperature for the Br-Li exchange reaction and that
for the quenching with methanol were controlled by adjusting
the temperature of a cooling bath. The residence time (tR) was
adjusted by changing the length of the microtube reactor R1
with a fixed flow rate. After a steady state was reached, an
aliquot of the product solution was taken for 60 s. The amount
of 2-bromobiphenyl (2) and that of biphenyl (3) were determ-
Figure 2: Effect of temperature and residence time in Br-Li exchange
ined by GC.
reaction of 2,2′-dibromobiphenyl (1) using the microflow system; (a)
plots of recovery of 1 against the residence time, (b) plots of yields of 2
and 3 against the residence time. Flow rate of a solution of 2,2′-dibro-
mobiphenyl (1): 6.00 ml·min−1, flow rate of n-BuLi: 1.20 ml·min−1, flow
rate of methanol: 3.00 ml·min−1. Yields of 1, 2 and 3 were determined
by GC.
The results obtained with varying temperature (−78 to 24 °C)
and residence time (tR) in R1 (0.057–13 s) are shown in Figure
2 (see the Supporting Information for details). High yields and
high selectivities were obtained even at 0 °C (tR = 0.057 s: 2
(88%) and 3 (3%)), and 24 °C (tR = 0.057 s: 2 (85%) and 3
(4%)), demonstrating a significant advantage of the microflow
system. Extremely fast heat transfer of the microflow system
seems to be responsible for these results. In other words, Br-Li
As shown in Table 2, the selectivity increased with a decrease
in the diameter of M1, presumably because faster mixing can be
achieved with a mixer of a smaller diameter. The selectivity
also increased with an increase in the flow rate. It is known that
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Table 2: Effect of flow rate and inner diameter of M1 at 0 °C.a
flow rate of 1/THF
flow rate of
n-BuLi/hexane (mL/min)
inner diameter of M1
1 conversion
(%)b
2 yield (%)b
3 yield (%)b
(mL/min)
(μm)
6.00
3.00
1.50
0.600
6.00
6.00
1.20
0.600
0.300
0.120
1.20
250
250
250
250
500
800
97
90
76
69
93
79
88
80
57
41
77
62
3
7
15
19
7
1.20
9
aR1: ø = 500 μm, l = 3.5 cm, flow rate of methanol: 3.00 ml·min−1. b Determined by GC.
the mixing rate increases with an increase in the flow rate for atures such as 0 °C and 24 °C than those required for a conven-
other types of micromixers [57]. These observations indicate tional macrobatch processes.
that extremely fast 1:1 mixing in the microflow system is
responsible for selective monolithiation at much higher temper- Under the optimized reaction conditions (reaction temperature:
0 °C, tR: 0.057 s), reactions using other electrophiles (0.30 M in
THF) were examined. In all cases, the conversion of 1 was
Table 3: Br-Li exchange reaction of 2,2′-dibromobiphenyl (1) followed
higher than 95%. As summarized in Table 3, the reaction with
iodomethane gave 2-bromo-2′-methylbiphenyl (5) in 89% yield
with high selectivity. Chlorotrimethylsilane, benzaldehyde, and
benzophenone were also effective as electrophiles, and the
corresponding products derived from the monolithiated species
were obtained selectively in high yields. These results show that
the microflow system serves as an useful method for selective
monolithiation of 2,2′-dibromobiphenyl (1) followed by the
reaction with electrophiles.
by reaction with an electrophile using the microflow system.a
electrophile
yield (%)c
monosubstituted
major byproduct
product
MeIb
5
6
89
Trace
Synthesis of Unsymmetrically Substituted
Biaryls from 2,2′-Dibromobiphenyl (1) by
Me3SiClb
Sequential Introduction of Two Electrophiles
With successful monolithiation of 2,2′-dibromobiphenyl (1)
followed by the reaction with an electrophile using the micro-
flow system in hand, sequential introduction of two electro-
philes (E1 and E2) onto 2,2′-dibromobiphenyl (1) was examined
using an integrated microflow system composed of four
T-shaped micromixers (M1, M2, M3 and M4) and four micro-
tube reactors (R1, R2, R3 and R4) shown in Figure 3. In this
case, T-shaped micromixers M3 and M4 having the inside
diameter of 500 μm were used to suppress the pressure increase
because an increase in the numbers of micromixers and micro-
tube reactors in the system causes a signficant pressure increase.
7
8
80
3
PhCHO
9
10
90
Trace
PhCOPh
A solution of 2,2′-dibromobiphenyl (1) (0.10 M) in THF (flow
rate: 6.00 ml·min−1, 0.60 mmol min−1) and a solution of n-BuLi
(0.50 M) in hexane (flow rate: 1.20 ml·min−1, 0.60
mmol·min−1) were introduced to M1 (ø = 250 μm) by syringe
pumping. The mixture was passed through R1 (ø = 500 μm, l =
3.5 cm, tR = 0.057 s) and the resulting solution was introduced
to M2 (ø = 500 μm), where a solution of a first electrophile (E1)
11
12
93
2
aFlow rate of a solution of 1: 6.00 ml·min−1, flow rate of n-BuLi/hexane:
1.20 ml·min−1, R1: ø = 500 μm, l = 3.5 cm (tR = 0.057 s). The conver-
sion was higher than 95% in all cases. b R2: ø = 1000 μm, l = 200 cm,
flow rate of a solution of an electrophile: 4.00 ml·min−1. cDetermined by
GC.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Table 4: Synthesis of unsymmetrically substituted biaryls from 2,2′-
dibromobiphenyl (1) by sequential introduction of two electrophiles.a
dibromobiaryl
electrophile
yield (%)
E1: MeI E2:
PhCHO
1
13
70 b,e
E1: MeI E2:
Me3SiCl
14
Figure 3: A microflow system for sequential introduction of two electro-
philes. T-shaped micromixer: M1 (ø = 250 μm), M2 (ø = 500 μm), M3
(ø = 500 μm), and M4 (ø = 500 μm), microtube reactor: R1 (ø = 500
μm, l = 3.5 cm (tR: 0.057 s)), R2 (ø = 1000 μm, l = 200 cm (tR: 9.8 s)),
R3 (ø = 1000 μm, l = 200 cm (tR: 8.5 s)), and R4 (ø = 1000 μm, l = 50
cm (tR: 1.8 s)). Flow rate of a solution of a dibromobiaryl (0.10 M in
THF): 6.00 ml·min−1, flow rate of n-BuLi (0.50 M in hexane): 1.20
ml·min−1, flow rate of a solution of a first electrophile (E1) (0.50 M in
THF): 2.40 ml·min−1. flow rate of n-BuLi (1.00 M in hexane): 1.44
ml·min−1, flow rate of a solution of a second electrophile (E2) (0.90 M
in THF): 2.00 ml·min−1.
82 c,f
E1: MeI E2:
MeOCOCl
15
76 f
E1: PhCHO
E2:
(0.50 M) in THF (flow rate: 2.40 ml·min−1, 1.20 mmol·min−1)
was introduced. The mixture was passed through R2 (ø = 1000
μm, l = 200 cm, tR = 9.8 s) and the resulting solution containing
a monobromo compound was introduced to M3 (ø = 500 μm),
where a solution of n-BuLi (1.0 M) in hexane (flow rate: 1.44
ml·min−1, 1.44 mmol·min−1) was introduced. The mixture was
passed through R3 (ø = 1000 μm, l = 200 cm, tR = 8.5 s) and
the resulting solution containing a second aryllithium interme-
diate was introduced to M4 (ø = 500 μm), where a solution of a
MeOCOCl
16
75 d,f
aReactions were conducted in the microflow system shown in Figure 3
unless otherwise stated. b2-Methylbiphenyl was also produced as a
byproduct. cR4: ø = 1000 μm, l = 200 cm dR2: ø = 1000 μm, l = 50 cm,
benzaldehyde (0.30 M), methyl chlorocarbonate (0.30 M) eIsolated yield.
fDetermined by GC.
second electrophile (E2) (0.90 M) in THF (flow rate: 2.00 macrobatch reaction was studied (Scheme 3) and the results are
mL·min−1, 1.80 mmol·min−1) was introduced. Themixture was summarized in Table 5.
passed through R4 (ø = 1000 μm, l = 50 cm, tR = 1.8 s). The all
processes were conducted at 0 °C.
4-Bromobiphenyl (18) was obtained with high yield and
selectivity at −78 °C. However, the yield and selectivity
As summarized in Table 4, the sequential introductions of two decreased with an increase in the temperature. At higher
electrophiles were achieved successfully with various combina- temperatures 4-bromo-4′-butylbiphenyl (19) was produced
tions of electrophiles without isolation of monobromo biaryl presumably by the reaction of (4-bromobiphenyl-4′-yl)lithium
compound. It is interesting to note that the use of an aldehyde
(E1) and methyl chlorocarbonate (E2) as electrophiles led to
effective formation of a seven-membered ring lactone. This
integrated microflow synthesis serves as a straightforward and
powerful method for synthesizing unsymmetrically substituted
biaryls from 2,2′-dibromobiphenyl (1) and two electrophiles.
Br-Li Exchange Reaction of 4,4′-Dibromobi-
phenyl
Scheme 3: Br-Li exchange reaction of 4,4′-dibromobiphenyl (17) with
n-BuLi using a conventional macrobatch reactor.
Next, we examined Br-Li exchange reaction of 4,4′-dibromobi-
phenyl (17) with n-BuLi. The temperature effect for a
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Table 5: Br-Li exchange reaction of 4,4′-dibromobiphenyl (17) using a conventional macrobatch system.a
temperature (°C)
reaction time (min)
17 conversion (%)b
18 yield (%)b
3 yield (%)b
19 yield (%)b
−78
−48
−27
0
60
10
10
10
10
95
90
81
86
87
87
49
56
47
25
5
5
5
6
2
0
0
2
13
26
24
aA solution of 17 (0.10 M, 6.0 mL) in THF was stirred in a flask (20 mL). A solution of n-BuLi (0.50 M, 1.2 mL) in hexane was added dropwise for 1.0
min. After stirring, methanol (neat, 3.0 mL) was added dropwise for 1.0 min. After stirring for 10 min, the mixture was analyzed. bDetermined by GC.
Figure 4: Microflow system for Br-Li exchange reaction of 4,4′-dibromobiphenyl (17). T-shaped micromixer: M1 (ø = 250 μm) and M2 (ø = 500 μm),
microtube reactor: R1 and R2 (ø = 1000 μm, l = 50 cm), a solution of 4,4′-dibromobiphenyl (17): 0.10 M in THF, a solution of n-BuLi: 0.50 M in
hexane, a solution of an electrophile: 0.30 M in THF.
with 1-bromobutane that was produced by Br-Li exchange reac-
tion.
In the next step, the reaction was carried out using a microflow
system composed of two T-shaped micromixers (M1 and M2)
and two microtube reactors (R1 and R2) shown in Figure 4. A
solution of 4,4′-dibromobiphenyl (17) (0.10 M) in THF (flow
rate: 6.00 mL·min−1, 0.60 mmol·min−1) and a solution of
n-BuLi (0.50 M) in hexane (flow rate: 1.20 mL·min−1, 0.60
mmol·min−1) were introduced to M1 (ø = 250 μm) by syringe
pumping. The mixture was passed through R1 (residence time =
tR sec) and was introduced to M2 (ø = 500 μm), where meth-
anol (neat, flow rate: 3.00 ml·min-1) was introduced. The
resulting mixture was passed through R2 (ø = 1000 μm, l = 50
cm, tR = 2.3 s). The temperature for the Br-Li exchange reac-
tion and the quenching with methanol was controlled by
adjusting the temperature of a cooling bath. The residence time
was adjusted by changing the length of the microtube reactor
R1 with a fixed flow rate. After a steady state was reached, an
aliquot of the product solution was taken for 60 s. The amount
of 4-bromobiphenyl (18, product derived from monolithiation)
Figure 5: Effect of temperature and residence time in Br-Li exchange
and biphenyl (3, product derived from dilithiation) was determ-
reaction of 4,4′-dibromobiphenyl (17) using the microflow system; (a)
Plots of recovery of 17 against residence time, (b) Plots of yields of 18
and 3 against residence time. Flow rate of a solution of 4,4′-dibromobi-
phenyl (17): 6.00 mL·min−1, flow rate of n-BuLi/hexane: 1.20 mL·min−1,
flow rate of methanol: 3.00 mL·min−1. Yields of 3, 17 and 18 were
determined by GC.
ined by GC.
The results obtained with varying temperature (−78 to 24 °C)
and residence time in R1 (0.057–13 s) are shown in Figure 5
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Table 6: Br-Li exchange reaction of 4,4′-dibromobiphenyl (17) followed by the reaction with an electrophile using the microflow system.a
electrophile
yield (%)
monosubstituted product
disubstituted product
MeIb
20
21
85 c
4 c
PhCHO
22
23
83 d
6 d
PhCOPh
24
25
84 d
5 d
a Flow rate of a solution of 17: 6.00 mL·min−1, flow rate of n-BuLi/hexane: 1.20 mL·min, R1: ø = 500 μm, l = 3.5 cm (tR = 0.057 s). b R2: ø = 1000 μm, l
= 200 cm, flow rate of a solution of an electrophile: 4.00 mL·min−1. cDetermined by GC. dIsolated yield.
(see the Supporting Information for details). High yields and Under the optimized reaction conditions (reaction temperature:
high selectivities were obtained even at 0 °C (residence time of 0 °C, tR: 0.057 s), reactions using other electrophiles (0.30 M in
R1 = 0.057 s: 18 (88%) and 3 (4%)) and 24 °C (residence time THF) such as iodomethane, benzaldehyde, and benzophenone
of R1 = 0.057 s: 18 (85%) and 3 (4%)). At −48 °C and −78 °C, were examined to obtain the corresponding products in good
the Br-Li exchange reaction was not complete within 0.1 s. At yields at 0 °C as shown in Table 6. These results show that
higher temperatures, however, the Br-Li exchange reaction was microflow system serves as an useful method for selective
complete within 0.1 s. These tendencies are quite similar to monolithiation of 4,4′-dibromobiphenyl (17) followed by the
those for the 2,2′-dibromobiphenyl (1) case. Therefore, it is reaction with electrophiles.
reasonable to consider that (2-bromobiphenyl-2′-yl)lithium and
(4-bromobiphenyl-4′-yl)lithium have similar thermal stability.
Table 7: Synthesis of unsymmetrically substituted biaryls from 4,4′-diboromobiphenyl (17).a
dibromobiaryl
electrophile
yield (%)b
E1: MeI E2: Me3SiCl
17
26
71 c
E1: Me3SiCl E2: MeI
26
75 d
E1: MeI E2: MeOCOCl
27
56
aReactions were conducted in the microflow system shown in Figure 3 unless otherwise stated. bDetermined by GC. cR4: ø = 1000 μm, l = 200 cm.
dR4: ø = 1000 μm, l = 200 cm, flow rate of a solution of chlorotrimethylsilane (0.30 M): 2.00 mL·min−1, flow rate of a solution of iodomethane (0.50 M):
2.40 mL·min−1.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Table 8: Br-Li exchange reaction of other dibromobiaryls (28, 36) and 2,2′-dibromobibenzyl (43) followed by reactions with electrophiles.
dibromo compound
reaction
temp. (°C)
electrophile
yield (%)
systema
monosubstituted
disubstituted product
product
28
macrobatchb,c
−78
MeOH
E: -H
89
(29)
54f
95
6
(30)
5
macrobatchc,d
microflow
0
0
MeOH
MeOH
MeOH
MeI
E: -H
E: -H
E: -H
E: -Me
4
microflow
24
0
92
5
microflow e
93
3
(32)
90g
(34)
(33)
2g
(35)
microflow
0
PhCHO
E:
-CH(OH)Ph
36
macrobatchb,c
−78
MeOH
E: -H
90
(37)
86
10
(38)
13
macrobatchc,d
microflow
0
0
MeOH
MeOH
MeOH
MeI
E: -H
E: -H
E: -H
E: -Me
93
1
microflow
24
0
92
2
microflowe
85
Trace
(40)
traceg
(42)
(39)
82g
(41)
microflow
0
PhCHO
E:
-CH(OH)Ph
43
macrobatchb,c
−78
MeOH
E: -H
85
(44)
27
10
(45)
15
macrobatchc,d
microflow
0
0
MeOH
MeOH
MeOH
Mel
E: -H
E: -H
E: -H
E: -Me
80
10
microflow
24
0
77
11
microflowe
81
4
(46)
66g
(48)
(47)
7g
microflow
0
PhCHO
E:
-CH(OH)Ph
(49)
aMicroflow reactions were carried out under the following conditions unless otherwise stated. R1: ø = 500 μm, l = 3.5 cm, R2: ø = 1000 μm, l = 50 cm,
flow rate of a solution of a dibromobiaryl compound: 6.00 mL·min−1, flow rate of n-BuLi/hexane: 1.20 mL·min−1, flow rate of a solution of an electrophile:
3.00 mL·min−1. Yields were determined by GC otherwise stated. bReaction time: 60 min. cA solution of dibromo compound (0.10 M, 6.0 mL) in THF was
stirred in a flask (20 mL). A solution of n-BuLi (0.50 M, 1.2 mL) in hexane was added dropwise for 1.0 min. After stirring, methanol (neat, 3.0 mL) was
added dropwise for 1.0 min. After stirring for 10 min, the mixture was analyzed. dReaction time: 10 min. eR2: ø = 1000 μm, l = 200 cm, flow rate of a
solution of an electrophile: 4.00 mL·min−1. f 2-Bromo-7-butyl-9,9-dioctylfluorene (31) was also produced as a byproduct. gIsolated yield.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
Synthesis of Unsymmetrically Substituted
Biaryls from 4,4′-Dibromobiphenyl (17) by
diate reacted with various electrophiles to give the corres-
ponding products in high yields with high selectivity.
Sequential Introduction of Two Electrophiles
With successful monolithiation of 4,4′-dibromobiphenyl (17)
followed by the reaction with an electrophile using the micro-
Synthesis of Unsymmetrically Substituted
Biaryls by Sequential Introduction of Two
flow system in hand, sequential introduction of two electro- Electrophiles
philes (E1 and E2) onto 4,4′-dibromobiphenyl (17) was carried With successful monolithiation of dibromobiaryls such as 2,7-
out using an integrated microflow system composed of four dibromo-9,9-dioctylfluorene (28) and 2,2′-dibromobinaphthyl
T-shaped micromixers and four microtube reactors shown in (36) followed by the reaction with an electrophile using the
Figure 3. As summarized in Table 7, the sequential introduc- microflow system in hand, sequential introduction of two elec-
tions of two electrophiles were achieved successfully without trophiles (E1 and E2) onto dibromobiaryls was carried out using
isolation of a monobromo biaryl compound.
an integrated microflow system composed of four T-shaped
micromixers and four microtube reactors shown in Figure 3.
Br-Li Exchange Reaction of Other Dibromobi-
aryls and 2,2′-Dibromobibenzyl (43)
As summarized in Table 9, the sequential introductions of two
We next examined the reactions of other dibromobiaryls such as electrophiles were achieved successfully with various combina-
2,7-dibromo-9,9-dioctylfluorene (28), and 2,2′-dibromo-1,1′- tions of electrophiles without isolation of monobromo biaryl
binaphthyl (36) [58] using the microflow system. As summar- compounds. This integrated microflow synthesis serves as a
ized in Table 8, monolithiation was achieved with high straightforward and powerful method for synthesizing unsym-
selectivity even at 0 °C and 24 °C. Such high selectivity is diffi- metrically substituted biaryls from dibromobiaryls and two
cult to obtain with macrobatch reactors at similar temperatures electrophiles.
such as 0 °C. It is also noteworthy that monolithiation of 2,2′-
dibromobibenzyl (43) can be achieved with high selectivity In conclusion, we have developed an efficient method for
even at 0 °C and 24 °C. The resulting organolithium interme- selective monolithiation of dibromobiaryls at 0 °C by virtue of
Table 9: Synthesis of unsymmetrially substituted biaryls from dibromobiaryls by sequential introduction of two electrophiles.a
dibromobiaryl
electrophile
yield (%)
E1: MeI E2: MeOCOCl
28
50
51 b
E1: MeI E2: PhCHO
36
51
71 c
E1: MeI E2: PhCOPh
52
78 c
aReactions were conducted in the microflow system shown in Figure 3 unless otherwise stated. bDetermined by GC. cIsolated yield.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 16.
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have also been achieved using the integrated microflow
systems. Unsymmetrically substituted biaryls were obtained in
high selectivity. The results obtained in this study speak well
for the potential of integrated microflow systems in multi-step
synthesis in flash chemistry [59-61], and the method adds a new
dimension to the synthesis of unsymmetrically substituted
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This work was financially supported in part by a Grant-in-Aid
for Scientific Research from the Japan Society for the Promo-
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