A flow microreactor system enables organolithium reactions without protecting alkoxycarbonyl groups

Article abstract of DOI:10.1002/chem.201000876

A flow microreactor system consisting of micromixers and microtube reactors provides an effective tool for the generation and reactions of aryllithiums bearing an alkoxycarbonyl group at para-, meta-, and ortho-positions. Alkyl p- and m-lithiobenzoates were generated by the I/Li exchange reaction with PhLi. The Br/Li exchange reactions with sBuLi were unsuccessful. Subsequent reactions of the resulting aryllithiums with electrophiles gave the desired products in good yields. On the other hand, alkyl o-lithiobenzoates were successfully generated by the Br/ Li exchange reaction with sBuLi. Subsequent reactions with electrophiles gave the desired products in good yields.

Full text of DOI:10.1002/chem.201000876

FULL PAPER
DOI: 10.1002/chem.201000876
A Flow Microreactor System Enables Organolithium Reactions without
Protecting Alkoxycarbonyl Groups
Aiichiro Nagaki, Heejin Kim, Yuya Moriwaki, Chika Matsuo, and Jun-ichi Yoshida*[a]
Abstract: A flow microreactor system
consisting of micromixers and micro-
tube reactors provides an effective tool
for the generation and reactions of ar-
yllithiums bearing an alkoxycarbonyl
group at para-, meta-, and ortho-posi-
tions. Alkyl p- and m-lithiobenzoates
were generated by the I/Li exchange
reaction with PhLi. The Br/Li exchange
reactions with sBuLi were unsuccessful.
Subsequent reactions of the resulting
aryllithiums with electrophiles gave the
desired products in good yields. On the
other hand, alkyl o-lithiobenzoates
were successfully generated by the Br/
Li exchange reaction with sBuLi. Sub-
sequent reactions with electrophiles
gave the desired products in good
yields.
Keywords:
aryllithium
·
flash chemistry · microreactors ·
organometallic
compounds
·
protecting groups
Introduction
as carboxylic acid, cyano, o-nitro, and amide groups, have
been carried out at low temperatures, such as À1008C.[10] In
contrast, similar transformations of aryllithiums bearing an
alkoxycarbonyl group are very limited since aryllithium
compounds self-condense or react with the alkoxycarbonyl
groups of the starting materials (Scheme 1).[11] If such aryl-
Protection and deprotection of functional groups has been
considered as an indispensable processes for synthesizing
complex organic molecules.[1] However, such processes in-
crease the steps required, diminishing the efficiency and
greenness of the synthesis. Recently, protecting-group-free
synthesis has attracted a great deal of attention.[2] From such
a viewpoint, chemical conversions by using organometallic
compounds, such as organolithium,[3] organomagnesium,[4]
organocopper,[5] and organozinc compounds,[6] bearing un-
protected functional groups would serve as powerful tools.[7]
Organolithium compounds exhibit the strongest anionic
character and are most reactive toward electrophiles among
such organometallics, and therefore are widely utilized in or-
ganic synthesis.[8–9] However, functionalized organolithium
compounds are the most difficult to prepare because of
their high reactivity toward functional groups, such as cyano,
nitro, and alkoxycarbonyl groups.[3] To overcome this restric-
tion, the organolithium reactions are often conducted at
very low temperatures. For example, transformations involv-
ing aryllithiums bearing electrophilic functional groups, such
Scheme 1. Generation and reaction of alkoxycarbonyl-substituted aryl-
lithiums.
lithiums bearing an alkoxycarbonyl group could be easily
generated and used for a reaction with an electrophile, pow-
erful synthetic transformations would be developed because
the unaffected alkoxycarbonyl groups in the products can be
readily used for subsequent reactions.
Recently, we have proposed the concept of flash chemis-
try,[12] chemical synthesis in which extremely fast reactions
are conducted in a highly controlled manner by using a flow
microreactor system.[13,14] The concept of flash chemistry has
been successfully applied to various organic reactions for
[a] Dr. A. Nagaki, H. Kim, Y. Moriwaki, C. Matsuo, Prof. J.-i. Yoshida
Department of Synthetic and Biological Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
Fax : (+81)75-383-2727
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000876.
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11167

synthesis including 1) reactions in which undesired byprod-
ucts are produced in a subsequent reaction,[15] 2) highly exo-
thermic reactions that are difficult to control,[16] and 3) reac-
tions in which a reactive intermediate easily decomposes in
conventional reactors.[17] Therefore, it is expected that chem-
ical conversions that are impossible in conventional reactors
can be made possible by using flow microreactors. For ex-
ample, we have already reported that highly reactive aryl-
lithium compounds bearing an alkoxycarbonyl group, such
as ethoxycarbonyl and methoxycarbonyl groups, at the
ortho-position can be rapidly generated and used in a subse-
quent reaction before decomposition in a flow microreactor
system by virtue of an extremely short residence time.[18]
It has been reported that ortho-, meta-, and para-tert-bu-
toxycarbonyl-substituted aryllithiums could be generated by
halogen–lithium exchange reactions in conventional macro-
batch reactors only at À1008C in spite of the presence of a
highly sterically demanding tert-butyl group.[11] Generation
and reactions of aryllithium compounds bearing an isopro-
poxycarbonyl group at the ortho-position could also be ach-
ieved though the yield was moderate. Presumably, the car-
bonyl group facilitates the halogen–lithium exchange reac-
tion as a directing group. However, a similar transformation
of aryllithiums bearing an isopropoxycarbonyl group at the
meta- and para-position has been known to be impossible
because of the lack of the directing effect.[11] In the ortho
case, the coordination of the carbonyl oxygen atom in a
neighboring position to lithium seems to accelerate the rate
of the halogen–lithium exchange reaction, which may be
much faster than the nucleophilic attack on the carbonyl
group. In the meta and para cases, however, such coordina-
tion is impossible, and therefore the rate of halogen–lithium
exchange and that of the nucleophilic attack seem to be
closer, giving rise to lower selectivity. In general, it is well
known that the transformations involving aryllithium com-
pounds bearing an electrophilic functional group in the
para- and meta-position are more difficult than those in the
ortho-position.[3,11] Furthermore, generation and reactions of
aryllithium compounds bearing less sterically demanding al-
koxycarbonyl groups, such as ethoxycarbonyl and methoxy-
carbonyl, have also been known to be impossible.
compounds bearing an alkoxycarbonyl group at the ortho-
position.
Results and Discussion
Generation and reactions of alkyl p-lithiobenzoates by Br/Li
exchange: First, we examined Br/Li exchange reactions of
alkyl p-bromobenzoates (p-BrC6H4CO2R, 1) to generate the
corresponding alkyl p-lithiobenzoates 2. It is well known
that the Br/Li exchange reaction of alkyl bromobenzoates
followed by a reaction with an electrophile, can be per-
formed in a conventional macrobatch reactor only when
tert-butyl bromobenzoates are used at very low tempera-
tures, such as À1008C.[11] The use of esters bearing less steri-
cally demanding alkoxycarbonyl groups, such as isopropoxy-
carbonyl, ethoxycarbonyl, and methoxycarbonyl groups, is
known to be unsuccessful. To confirm this, we re-examined
the Br/Li exchange reactions of alkyl p-bromobenzoates 1,
such as tert-butyl p-bromobenzoate (1a), isopropyl p-bromo-
benzoate (1b), ethyl p-bromobenzoate (1c), and methyl p-
bromobenzoate (1d) in a conventional macrobatch reactor
(Table 1). Thus, a solution of sBuLi in hexane/cyclohexane
Table 1. The Br/Li exchange reaction of alkyl p-bromobenzoates (1) fol-
lowed by reaction with ROH in a conventional macrobatch reactor.[a]
Alkyl p-bromobenzoates
(p-BrC6H4CO2R)
Conversion of 1
[%]
Yield of 3 [%]
tert-butyl p-bromobenzoate (1a)
isopropyl p-bromobenzoate (1b)
ethyl p-bromobenzoate (1c)
methyl p-bromobenzoate (1d)
98
74
82
42
35 (49)[b]
trace (7)[b]
0
0
[a] A solution of sBuLi in hexane/cyclohexane (0.42m) was added drop-
wise to a solution of alkyl p-bromobenzoates (p-BrC6H4CO2R, 1) in THF
(0.10m) at À788C. After the mixture had been stirred for 10 min at
À788C, ROH was added as an electrophile (3.0 equiv). After further stir-
ring for 10 min at À788C, the yield of the product (3) was determined by
GC analysis. [b] After stirring for 1.0 min at À788C, ROH was added as
an electrophile (3.0 equiv).
In this study we tried to solve these challenging problems,
namely, the generation and reactions of aryllithium com-
pounds bearing an alkoxycarbonyl group in the para- and
meta-positions by using flow microreactors. In the ortho
case, halogen–lithium exchange reactions are facilitated by
the coordination of the carbonyl group to lithium. However,
as stated above, in the para and meta cases such a directing
effect is absent, and therefore it is more difficult to accom-
plish the halogen–lithium exchange reaction without decom-
position of the resulting organolithium species. We wish to
report herein that aryllithium compounds bearing an alkoxy-
carbonyl group in the para- and meta-position could also be
generated and used for reactions with electrophiles by
choosing appropriate precursors and reaction conditions in
flow microreactor systems. We also report the full details of
the study on the generation and reactions of aryllithium
was added dropwise (1 min) to a solution of alkyl p-bromo-
benzoates (1) in THF in a 20 mL round-bottomed flask at
À788C to generate the corresponding alkyl p-lithioben-
zoates 2. To evaluate the yield of 2, the corresponding alco-
hol (ROH: R=tBu, iPr, Et, Me) was added after stirring for
10 min at À788C, and the yield of the protonated product 3
was determined by GC analysis. We assumed that the yield
of 2 was very similar to that of 3 because the protonation
with alcohols should be very fast.
The reaction of 1a (R=tBu) at À788C gave the desired
product 3a in 35% yield (Table 1). A low yield of 3 seems
to be attributed to partial decomposition of 2a at this tem-
perature. According to the literature,[11] the reaction should
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Generation and Reactions of Aryllithium Compounds
FULL PAPER
be carried out at À1008C, because significant amounts of
byproducts were produced when the reaction was conducted
at À788C. In the case of 1b (R=iPr), only a trace amount
of 3b was obtained. Moreover, in the cases of 1c (R=Et)
and 1d (R=Me), the desired products were not obtained at
all.
Next, the reaction was conducted in a flow microreactor
system consisting of two T-shaped micromixers (M1 and
M2) and two microtube reactors (R1 and R2) as shown in
Scheme 2. A solution of alkyl p-bromobenzoate 1 (0.10m in
Scheme 2. A flow microreactor system for the Br/Li exchange reaction of
alkyl p-bromobenzoates 1 with sBuLi followed by reaction with the alco-
hol. T-shaped micromixer: M1 (f =250 mm) and M2 (f =250 mm), mi-
crotube reactor: R1 and R2 (f =1000 mm, L=50 cm). Flow rate of a so-
lution of 1 (0.10m in THF): 6.00 mLminÀ1; flow rate of a solution of
sBuLi (0.42m in hexane/cyclohexane): 1.50 mLminÀ1; flow rate of a solu-
tion of an alcohol (ROH, 0.60m in THF): 3.00 mLminÀ1
.
THF; flow rate: 6.00 mLminÀ1, 0.60 mmolminÀ1) and a solu-
tion of sBuLi (0.42m in hexane/cyclohexane; flow rate:
1.50 mLminÀ1, 0.63 mmolminÀ1) were introduced to M1
(f=250 mm) by syringe pumps. The mixture was passed
through R1 and was introduced to M2 (f=250 mm), at
which point an alcohol (ROH, 0.60m in THF; flow rate:
3.00 mLminÀ1, 1.80 mmolminÀ1) was introduced. The result-
ing mixture was passed through R2 (f=1000 mm, L=50 cm,
2.2 s). The reaction temperature (T) was controlled by ad-
justing the temperature of a cooling bath. The residence
time in R1 (tR) was adjusted by changing the length and di-
ameter of R1 with a fixed flow rate. After a steady state was
reached, an aliquot of the product solution was taken for
30 s. The amount of product 3 was determined by GC analy-
sis.
The results obtained with varying temperature (À78
~208C) and residence time tR (0.01 ~6.3 s) are summarized
in Figure 1, in which the yield of 3 is plotted against the
temperature and tR as a contour map with scattered overlay
(see the Supporting Information for details).
In the case of 1a (R=tBu), the desired product 3a was
obtained in high yields (>80%) over a wide range of tem-
peratures and residence times, which demonstrated that the
flow microreactor system is more efficient for the genera-
tion and reactions of tert-butyl p-lithiobenzoates under
milder conditions than conventional macrobatch reactors.
At low temperatures and short residence times the yields
were low, presumably because of incomplete Br/Li exchange
reactions. Low yields were also observed in the high-temper-
ature long-residence-time region, probably because of the
decomposition of aryllithium intermediates 2a.
Figure 1. Effects of temperature (T) and residence time (tR) on the yield
of alkyl benzoates 3 in the Br/Li exchange reaction of p-BrC6H4CO2R 1.
a) tert-Butyl p-bromobenzoate (1a) and b) isopropyl p-bromobenzoate
(1b) with sBuLi followed by reaction with ROH by using the flow micro-
reactor system. Counter plots with scatter overlay of the yields (%) of 3.
In the case of 1b (R=iPr), the yields were much lower.
This is presumably because the isopropyl group is less steri-
cally demanding than the tert-butyl group. Therefore, it was
difficult to generate aryllithium compounds bearing an iso-
propoxycarbonyl group in the para-position without decom-
position even in a flow microreactor system that uses the
Br/Li exchange reaction. This means that it is also quite dif-
ficult to generate aryllithium compounds bearing ethoxycar-
bonyl and methoxycarbonyl groups in the para-position in a
similar manner.
Generation and reactions of alkyl p-lithiobenzoates by I/Li
exchange: To solve the problem, we decided to conduct the
I/Li exchange reaction of alkyl p-iodobenzoates (p-
IC6H4CO2R, 4) because I/Li exchange reactions are general-
ly much faster than the corresponding Br/Li exchange reac-
tions.[5b,19] Alkyl p-iodobenzoates 4 were selected as precur-
sors to generate the corresponding alkyl p-lithiobenzoates 2.
Before using a flow microreactor system, the reaction in a
conventional macrobatch reactor was examined. It is note-
worthy that PhLi, which is less nucleophilic than sBuLi,
could be used for I/Li exchange reactions. Thus, a solution
of PhLi in Et2O/cyclohexane was added dropwise (1 min) to
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J.-i. Yoshida et al.
a solution of 4 in THF in a 20 mL round-bottomed flask at
À788C. After stirring for 10 min at À788C, the correspond-
ing alcohol (ROH: R=tBu, iPr, Et, Me) was added as an
electrophile. The yield of the protonated product 3 was de-
termined by GC analysis.
The reactions of tert-butyl p-iodobenzoate (4a) proceeded
at À788C to give 3a (81%), after treatment with tert-butyl
alcohol (Table 2). These results indicate that iodobenzoates
0.63 mmolminÀ1) were introduced to M1 (f=250 mm) by sy-
ringe pumps. The mixture was passed through R1, and was
introduced to M2 (f=250 mm), at which point an alcohol
(ROH, 0.60m in THF; flow rate: 3.00 mLminÀ1, 1.80 mmol
minÀ1) was introduced. The resulting mixture was passed
through R2 (f=1000 mm, L=50 cm, 2.2 s). The reaction
temperature was controlled by adjusting the temperature of
a cooling bath. The residence time in R1 was adjusted by
changing the length and diameter of R1 with a fixed flow
rate. After a steady state was reached, an aliquot of the
product solution was taken for 30 s. The amount of 3 was
determined by GC analysis. The results obtained with vary-
ing temperature (À78–08C) and tR (0.01–6.3 s) are shown
in Figure 2 (see the Supporting Information for details).
In the case of 4a (R=tBu), the corresponding product 3a
was obtained in high yields (>80%) for a wide range of
temperatures and residence times. The reaction can be con-
ducted even at 08C, which demonstrates a significant ad-
vantage of flow microreactor systems. This means that the
present reaction can be inherently conducted at 08C, al-
though the reaction in conventional macrobatch reactors re-
quires over-cooling because of insufficient heat removal. At
low temperatures and short residence times the yield was
low, presumably because of incomplete I/Li exchange reac-
tion. Low yields were also observed in the high-temperature
long-residence-time region, probably because of the decom-
position of aryllithium intermediates 2a. In the case of 4b
(R=iPr), a similar reaction profile was observed, although
the high-yield region became smaller. However, it is note-
worthy that the present reaction can be effectively per-
formed to give desired product 3b in >80% yield by choos-
ing an appropriate temperature (À488C) and residence time
(0.01 s). The reaction of 4c also exhibited a similar profile.
The ridge shifted to a lower temperature and shorter resi-
dence time region, because of faster decomposition of orga-
nolithium compounds 2c. More astounding is the observa-
tion that methyl benzoates (2d) can be obtained in good
yields (>80%) from 4d, although the high-yield region was
very small presumably because steric hindrance of the me-
thoxycarbonyl group is small.
These results clearly show that the stability of the aryl-
lithium compounds decreases in the order of 2a (R=tBu)>
2b (R=iPr)>2c (R=Et)>2d (R=Me). The present tem-
perature–residence time profile is quite effective at unveil-
ing the features of the I/Li exchange reaction and stability
of the resulting aryllithium intermediate. In addition, it is
important to note that the I/Li exchange reaction followed
by reaction with an electrophile can be successfully carried
out without significant decomposition of the aryllithium in-
termediate 2 by optimizing temperature and residence time
even in the methyl ester case. Under the optimized condi-
tions, the reactions of 2a–d with other electrophiles, such as
methyl iodide, methyl triflate, trimethylsilyl chloride, trime-
thylsilyl triflate, and benzaldehyde, were examined. As
shown in Table 3, the reactions took place successfully and
the corresponding products were obtained in good yields. It
is interesting that methyl iodide can be used as an electro-
Table 2. The I/Li exchange reaction of alkyl p-iodobenzoates (4) with
PhLi followed by reaction with ROH in a conventional macrobatch reac-
tor.[a]
Alkyl p-iodobenzoates
(p-IC6H4CO2R)
Conversion of 4 [%]
Yield of 3 [%]
tert-butyl p-iodobenzoate (4a)
isopropyl p-iodobenzoate (4b)
ethyl p-iodobenzoate (4c)
100
100
100
67
81 (99)[b]
7 (24)[b]
trace
methyl p-iodobenzoate (4d)
trace
[a] A solution of PhLi in Et2O/cyclohexane (0.42m) was added dropwise
(1 min) to a solution of alkyl p-iodobenzoates (p-IC6H4CO2R, 4) in THF
(0.10m) in a 20 mL round-bottomed flask at À788C. After the mixture
had been stirred for 10 min at À788C, ROH was added as an electro-
phile. After further stirring for 10 min at À788C, the yield of the product
(3) was determined by GC analysis. [b] After the mixture had been
stirred for 1.0 min at À788C, ROH was added as an electrophile
(3.0 equiv).
are more effective than bromobenzoates as precursors of ar-
yllithium compounds. However, in the case of isopropyl p-
iodobenzoate (4b), the yield of the desired product was
very low. In the case of ethyl and methyl p-iodobenzoates
(4c and 4d), the desired products were obtained only in
trace amounts.
Next, we examined the reactions in a flow microreactor
system consisting of two T-shaped micromixers (M1 and
M2) and two microtube reactors (R1 and R2) (Scheme 3).
A solution of alkyl p-iodobenzoate 4 (0.10m in THF; flow
rate: 6.00 mLminÀ1, 0.60 mmolminÀ1) and a solution of PhLi
(0.42m in Et2O/cyclohexane; flow rate: 1.50 mLminÀ1,
Scheme 3. A flow microreactor system for the I/Li exchange reaction of
alkyl p-iodobenzoates 4 with PhLi followed by reaction with the alcohol.
T-shaped micromixer: M1 (f =250 mm) and M2 (f =250 mm), microtube
reactor: R1 and R2 (f =1000 mm, L=50 cm). Flow rate of a solution of
4 (0.10m in THF): 6.00 mLminÀ1; flow rate of a solution of PhLi (0.42m
in Et2O/cyclohexane): 1.50 mLminÀ1; flow rate of a solution of an alcohol
(0.60m in THF): 3.00 mLminÀ1
.
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Generation and Reactions of Aryllithium Compounds
FULL PAPER
Table 3. The I/Li exchange reaction of alkyl p-iodobenzoates 4 followed
by reaction with an electrophile.[a]
Ester
E
Product
Yield [%]
85
tBuOH
MeI
74
87
Me3SiCl
PhCHO
67[b]
iPrOH
89
MeI
MeOTf
38
82
Me3SiCl
PhCHO
EtOH
74
79
84
MeI
MeOTf
25
77
Me3SiCl
67
88
Me3SiOTf
PhCHO
81
MeOH
80
81
81
MeOTf
Me3SiOTf
PhCHO
80
[a] Alkyl p-iodobenzoates 4 in THF (0.10m), PhLi in Et2O/cyclohexane
(0.42m), and an electrophile (3.0 equiv, 0.60m) were reacted in the flow
microreactor system at the following optimized temperatures: 4a: 08C,
4b: À488C, 4c: À588C, 4d: À788C. tR was 0.01 s in all cases. The yield of
the product was determined by GC analysis unless otherwise stated.
[b] Isolated yield.
Figure 2. Effects of temperature (T) and residence time (tR) on the yield
of alkyl benzoates in the I/Li exchange reaction of p-IC6H4CO2R 4.
a) tert-Butyl p-iodobenzoate (4a), b) isopropyl p-iodobenzoate (4b),
c) ethyl p-iodobenzoate (4c), and d) methyl p-iodobenzoate (4d) with
PhLi followed by reaction with ROH by using the flow microreactor
system. Counter plots with scatter overlay of the yields (%) of 3.
more sterically demanding tert-butoxycarbonyl groups can
survive until the reaction is complete. However, methyl tri-
flate is more reactive, and therefore can trap less stable aryl-
lithium compounds before they decompose.
phile for the reactions of 4a, whereas methyl triflate should
be used for the reactions of 4b–d. The reaction of the aryl-
lithium with methyl iodide is slow, and therefore only the
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J.-i. Yoshida et al.
Generation and reactions of alkyl m-lithiobenzoates by Br/
Li exchange: Next, we examined the Br/Li exchange reac-
tions of alkyl m-bromobenzoates (m-BrC6H4CO2R, 5), such
as tert-butyl m-bromobenzoate (5a), isopropyl m-bromoben-
zoate (5b), ethyl m-bromobenzoate (5c), and methyl m-bro-
mobenzoate (5d). Reactions in a conventional macrobatch
reactor were carried out and the results are summarized in
Table 4.
Table 4. The Br/Li exchange reaction of alkyl m-bromobenzoates 5 fol-
lowed by reaction with ROH in a conventional macrobatch reactor.[a]
Alkyl m-bromobenzoates
(m-BrC6H4CO2R)
Conversion of 5
[%]
Yield of 3 [%]
tert-butyl m-bromobenzoate (5a)
isopropyl m-bromobenzoate (5b)
ethyl m-bromobenzoate (5c)
methyl m-bromobenzoate (5d)
96
80
73
56
40
5
trace
0
[a] A solution of sBuLi in hexane/cyclohexane (0.42m) was added drop-
wise to a solution of alkyl m-bromobenzoates (m-BrC6H4CO2R, 5) in
THF (0.10m) at À788C. After the mixture had been stirred for 10 min at
À788C, ROH was added as an electrophile (3.0 equiv). After further stir-
ring for 10 min at À788C, the yield of the product (3) was determined by
GC analysis.
Figure 3. Effects of temperature (T) and residence time (tR) on the yield
of alkyl benzoates 3 in the Br/Li exchange reaction of m-BrC6H4CO2R 5.
a) tert-Butyl m-bromobenzoate (5a) and b) isopropyl m-bromobenzoate
(5b) with sBuLi followed by reaction with ROH by using the flow micro-
reactor system. Counter plots with scatter overlay of the yields (%) of 3.
Reactions of 5a (R=tBu) at À788C gave the desired
product (3a) in 40% yield (Table 4). Presumably partial de-
composition of 6a took place at this temperature because it
is reported in the literature[11] that the reaction should be
carried out at À1008C. The use of 5b (R=iPr) caused a sig-
nificant decrease in the yield of the product (3b). Moreover,
in the case of 5c (R=Et) and 5d (R=Me), the yields of the
desired products were negligibly low.
Next, the reactions were conducted in the flow microreac-
tor. A solution of alkyl m-bromobenzoate 5 (0.10m in THF;
flow rate: 6.00 mLminÀ1, 0.60 mmolminÀ1) and a solution of
sBuLi (0.42m in hexane/cyclohexane; flow rate:
1.50 mLminÀ1, 0.63 mmolminÀ1) were introduced to M1
(f=250 mm) by syringe pumps. The mixture was passed
through R1 and was introduced to M2 (f=250 mm), at
which point an alcohol (ROH, 0.60m in THF; flow rate:
3.00 mLminÀ1, 1.80 mmolminÀ1) was introduced. The result-
ing mixture was passed through R2 (f=1000 mm, L=50 cm,
2.2 s). The reaction temperature was controlled by adjusting
the temperature of a cooling bath. The residence time in R1
was adjusted by changing the length and diameter of R1
with a fixed flow rate. After a steady state was reached, an
aliquot of the product solution was taken for 30 s. The
amount of 3 was determined by GC analysis.
perature and tR as a contour map with scattered overlay (see
the Supporting Information for details).
In the case of 5a (R=tBu), the desired product 3a was
obtained in high yields (>80%) over a wide range of resi-
dence times and temperatures. In the case of 5b (R=iPr),
the yields were much lower. This is presumably because the
isopropyl group is less sterically demanding than the tert-
butyl group. Therefore, it was difficult to generate aryllithi-
um compounds bearing an isopropoxycarbonyl group in the
meta-position without decomposition even in a flow micro-
reactor system that uses the Br/Li exchange reaction.
Generation and reactions of alkyl m-lithiobenzoates by I/Li
exchange: Next, we examined the I/Li exchange reaction of
alkyl m-iodobenzoates 7 to generate the corresponding m-
alkoxycarbonyl-substituted phenyllithiums 6. Before using a
flow microreactor system, the reaction in a conventional
macrobatch reactor was examined and the results are sum-
marized in Table 5.
The reaction of tert-butyl m-iodobenzoate 7a proceeded
at À788C to give 3a (78%), after treatment with tert-butyl
alcohol (Table 5). These results indicate that iodobenzoates
are more effective than bromobenzoates as precursors of ar-
The results obtained with varying temperature (À78
~208C) and residence time (0.01 ~6.3 s) are summarized in
Figure 3, in which the yield of 3 is plotted against the tem-
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Generation and Reactions of Aryllithium Compounds
FULL PAPER
Table 5. The I/Li exchange reaction of alkyl m-iodobenzoates (7) with
PhLi followed by reaction with ROH in a conventional macrobatch reac-
tor.[a]
Alkyl m-iodobenzoates
(m-IC6H4CO2R)
Conversion of 7 [%]
Yield of 3 [%]
tert-butyl m-iodobenzoate (7a)
isopropyl m-iodobenzoate (7b)
ethyl m-iodobenzoate (7c)
100
100
98
78
12
trace
trace
methyl m-iodobenzoate (7d)
54
[a] A solution of PhLi in Et2O/cyclohexane (0.42m) was added dropwise
(1 min) to a solution of alkyl m-iodobenzoates (m-IC6H4CO2R, 7) in
THF (0.10m) in a 20 mL round-bottomed flask at À788C to generate lith-
iobenzoates 6. After the mixture had been stirred for 10 min at À788C,
ROH was added as an electrophile. After further stirring for 10 min at
À788C, the yield of the product (3) was determined by GC analysis.
yllithium compounds. However, in the case of isopropyl m-
iodobenzoate (7b), the yield of the desired product was
very low. In the case of ethyl and methyl iodobenzoates (7c
and 7d), the desired products were obtained only in trace
amounts.
Next, we examined the reactions in a flow microreactor
system. As shown in Figure 4, in the case of 7a (R=tBu),
the corresponding product 3a was obtained in high yields
(>80%) for a wide range of temperatures and residence
times. In the case of 7b (R=iPr), a similar reaction profile
was observed, although the high-yield region became small-
er. The reaction of 7c also exhibited a similar profile,
though the ridge shifted to a lower temperature and shorter
residence time region because of faster decomposition of or-
ganolithium compounds 6c. Methyl benzoates (3d) can be
obtained in good yields (> 80%) from 7d, although the
high-yield region was very small. These results clearly show
that the stability of the aryllithium compounds decreases in
the order of 6a (R=tBu)>6b (R=iPr)>6c (R=Et)>6d
(R=Me). It is also noteworthy that the comparison between
Figures 4 and 2 revealed that m-lithiobenzoates and p-lithio-
benzoates have similar stability. Under the optimized condi-
tions, the reactions of 6a–d with other electrophiles were ex-
amined and the results are shown in Table 6.
Generation and reactions of alkyl o-lithiobenzoates by Br/Li
exchange: Finally, we studied the Br/Li exchange reactions
of alkyl o-bromobenzoates (o-BrC6H4CO2R, 8), such as tert-
butyl o-bromobenzoate (8a), isopropyl m-bromobenzoate
(8b), ethyl o-bromobenzoate (8c), and methyl o-bromoben-
zoate (8d). First, we re-examined the reaction in a conven-
tional macrobatch reactor (Table 7). Thus, a solution of
sBuLi in hexane/cyclohexane was added dropwise (1 min) to
a solution of alkyl o-bromobenzoates in THF in a 20 mL
round-bottomed flask at À788C to generate alkyl o-lithio-
benzoates (9). After stirring for 10 min at À788C, the corre-
sponding alcohol (ROH) was added as an electrophile.
Figure 4. Effects of temperature (T) and residence time (tR) on the yield
of alkyl benzoates in the I/Li exchange reaction of m-IC6H4CO2R 7.
a) tert-Butyl m-iodobenzoate (7a), b) isopropyl m-iodobenzoate (7b),
c) ethyl m-iodobenzoate (7c), and d) methyl m-iodobenzoate (7d) with
PhLi followed by reaction with ROH by using the flow microreactor
system. Counter plots with scatter overlay of the yields (%) of 3.
After stirring for 10 min at À788C, the yield of the product
(3) was determined.
Chem. Eur. J. 2010, 16, 11167 – 11177
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J.-i. Yoshida et al.
Table 6. The I/Li exchange reaction of alkyl m-iodobenzoates (7) fol-
Table 6. (Continued)
Ester
lowed by reaction with an electrophile.[a]
E
Product
Yield [%]
81[b]
Ester
E
Product
Yield [%]
90
PhCHO
tBuOH
[a] Alkyl m-iodobenzoates 7 in THF (0.10m), PhLi in Et2O/cyclohexane
(0.42m), and an electrophile (3.0 equiv, 0.60m) were reacted in the flow
microreactor system at the following optimized temperatures: 7a: 08C,
7b: À488C, 7c: À588C, 7d: À588C. tR was 0.01 s in all cases. The yield of
the product was determined by GC analysis unless otherwise stated.
[b] Isolated yield.
MeI
78
94
Me3SiCl
Table 7. The Br/Li exchange reaction of alkyl o-bromobenzoate 8 fol-
PhCHO
90
84
lowed by reaction with ROH in a conventional macrobatch reactor.[a]
iPrOH
MeI
MeOTf
34
75
Alkyl o-bromobenzoates
(o-BrC6H4CO2R)
Conversion of 8
[%]
Yield of 3 [%]
tert-butyl o-bromobenzoate (8a)
isopropyl o-bromobenzoate (8b)
ethyl o-bromobenzoate (8c)
methyl o-bromobenzoate (8d)
100
100
100
100
61
12
0
Me3SiCl
PhCHO
EtOH
78
67
81
0
[a] A solution of sBuLi in hexane/cyclohexane (0.42m) was added drop-
wise to a solution of alkyl o-bromobenzoates (o-BrC6H4CO2R, 8) in THF
(0.10m) at À788C. After the mixture had been stirred for 10 min at
À788C, ROH was added as an electrophile (3.0 equiv). After further stir-
ring for 10 min at À788C, the yield of the product (3) was determined by
GC analysis.
Reactions of 8a (R=tBu) at À788C gave the desired
product tert-butyl benzoate (3a) in 61% yield. The moder-
ate yield seems to be attributed to partial decomposition of
the corresponding aryllithium intermediate 9a at this tem-
perature, because it is reported in the literature[11] that the
reaction should be carried out at À1008C. The use of 8b
(R=iPr) gave rise to very low yield of the desired product
(3b, 12%). Moreover, in the case of 8c (R=Et) and 8d
(R=Me), the desired products (3c and 3d) were not ob-
tained at all.
MeI
MeOTf
21
78
Me3SiOTf
PhCHO
74
72[b]
Next, we examined the reactions by using a flow micro-
reactor system consisting of two T-shaped micromixers (M1
and M2) and two microtube reactors (R1 and R2;
MeOH
85
79
87
Scheme 2).
A solution of alkyl o-bromobenzoates (o-
BrC6H4CO2R, 8, 0.10m in THF; flow rate: 6.00 mLminÀ1,
0.60 mmolminÀ1) and a solution of sBuLi (0.42m in hexane/
cyclohexane; flow rate: 1.50 mLminÀ1, 0.63 mmolminÀ1)
were introduced to M1 (f=250 mm) by syringe pumps. The
mixture was passed through R1 and was introduced to M2
(f=250 mm), at which point a solution of ROH (0.60m in
THF; flow rate: 3.00 mLminÀ1, 1.80 mmolminÀ1) was intro-
duced. The resulting mixture was passed through R2 (f=
1000 mm, L=50 cm, 2.2 s). The temperature for the Br/Li
exchange reaction and that for the quenching with ROH
were controlled by adjusting the temperature of a cooling
MeOTf
Me3SiOTf
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Generation and Reactions of Aryllithium Compounds
FULL PAPER
bath. The residence time in R1 (tR) was adjusted by chang-
ing the length and the diameter 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 30 s. The
amount of 3 was determined by GC analysis. The results ob-
tained with varying temperature (À78–208C) and tR
(0.01–6.3 s) are shown in Figure 5 (see the Supporting Infor-
mation for details).
In the case of 8a (R=tBu), 3a was obtained in high
yields (>80%) even at 08C, which demonstrates a signifi-
cant advantage of flow microreactor systems. At low tem-
peratures and short residence times the yield of 3a was low
presumably because of an incomplete Br/Li exchange reac-
tion. A low yield was also observed at the high-temperature
long-residence-time region, probably because of the decom-
position of the corresponding aryllithium intermediate 9a.
In the case of 8b (R=iPr), a similar reaction profile was
observed, although the high-yield region became smaller.
The reaction of 8c (R=Et) also exhibited a similar profile.
The ridge shifted to a lower temperature and shorter resi-
dence-time region, but the reaction was effectively per-
formed to give 3c in 90% yield by choosing an appropriate
temperature (À488C) and tR (0.06 s). Moreover, 3d can be
obtained in relatively good yields (> 70%) from 8d (R=
Me), although the high-yield region disappeared presumably
because of the small steric demand of the methoxycarbonyl
group.
These results clearly show that the stability of the aryl-
lithium intermediates decreases in the order of 9a (R=
tBu)>9b (R=iPr)>9c (R=Et)>9d (R=Me). These ten-
dencies are quite similar to those for the p- and m-bromo-
benzoate case. However, it is important to note that the
high-yield region is bigger for o-bromobenzoate cases in
comparison with those for p- and m-bromobenzoate cases
(Figures 1, 3, and 5). This is attributed to the fact that the
Br/Li exchange reactions of o-bromobenzoates are faster
than those of p- and m-bromobenzoates. Coordination of
the alkoxycarbonyl group to Li seems to accelerate the Br/
Li exchange reaction. Therefore, it is possible to conduct the
Br/Li exchange reactions to generate sufficient amounts of
o-lithiobenzoates before decomposition by choosing appro-
priate temperatures and residence times.
Under the optimized conditions, the reactions of 9a–d
with other electrophiles, such as methyl iodide, methyl tri-
flate, trimethylsilyl chloride, trimethylsilyl triflate, and ben-
zaldehyde, were examined. As shown in Table 8, the reac-
tions took place successfully and the corresponding products
were obtained in good yields.
Figure 5. Effects of temperature (T) and residence time (tR) on the yield
of alkyl benzoates 3 in the Br/Li exchange reaction of alkyl o-bromoben-
zoates 8. a) tert-Butyl o-bromobenzoate (8a), b) isopropyl o-bromoben-
zoate (8b), c) ethyl o-bromobenzoate (8c), and d) methyl o-bromoben-
zoate (8d) with sBuLi followed by reaction with ROH by using the flow
microreactor system. Counter plots with scatter overlay of the yields (%)
of 3.
Conclusion
Generation of p-, m-, and o-alkoxycarbonyl-substituted aryl-
lithium compounds followed by reaction with electrophiles
has been accomplished by using a flow microreactor system
consisting of micromixers and microtube reactors by virtue
of precise residence time control and temperature control.
Chem. Eur. J. 2010, 16, 11167 – 11177
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11175

J.-i. Yoshida et al.
Table 8. The Br/Li exchange reaction of alkyl o-bromobenzoates 8 fol-
tions. The present method enables not only the generation
of a variety of tert-butoxycarbonyl-substituted aryllithiums
at much higher temperatures than those required for con-
ventional macrobatch reactors but also the generation of
more unstable isopropoxycarbonyl-, ethoxycarbonyl-, and
methoxycarbonyl-substituted aryllithiums, which are practi-
cally impossible to achieve by using conventional macro-
batch reactors. Therefore, the present method serves as a
straightforward and powerful method for introducing sub-
stituents into the benzene ring of alkyl benzoates without
protecting the alkoxycarbonyl group. The observations illus-
trated here open a new possibility of organic synthesis via
unstable functionalized organolithiums.
lowed by reaction with an electrophile.[a]
Ester
E
Product
Yield [%]
93
tBuOH
MeI
88
96
Me3SiCl
PhCHO
82
Experimental Section
iPrOH
87
General procedure for the I/Li exchange reaction of alkyl iodobenzoates
followed by reaction with electrophiles in a flow microreactor system: A
flow microreactor system consisting of two T-shaped micromixers (M1
and M2), two microtube reactors (R1 and R2), and three tube pre-cool-
ing units (P1 (inner diameter f=1000 mm, length L=100 cm), P2 (f=
1000 mm, L=50 cm) and P3 (f=1000 mm, L=100 cm)) was used. A solu-
tion of alkyl iodobenzoates (0.10m) in THF (flow rate: 6.0 mLminÀ1) and
a solution of PhLi (0.42m) in Et2O/cyclohexane (72:28 v/v; flow rate:
1.5 mLminÀ1) were introduced to M1 (f=250 mm). The resulting solution
was passed through R1 (f=250 mm, L=3.5 cm, 0.01 s) and was mixed
with a solution of electrophile (0.60m) in THF (Et2O in the case of
MeOTf and Me3SiOTf; flow rate: 3.0 mLminÀ1) in M2 (f=250 mm). The
resulting solution was passed through R2 (f=1000 mm, L=50 cm). After
a steady state was reached, an aliquot of the product solution was collect-
ed for 30 s while being quenched with sat. NH4Cl aqueous solution. The
reaction mixture was analyzed by GC analysis. After extraction, the
crude product was purified by flash chromatography.
MeI
MeOTf
62
82
Me3SiCl
PhCHO
93
66
EtOH
90
MeI
MeOTf
12
62
Me3SiCl
Me3SiOTf
61
79
Acknowledgements
PhCHO
MeOH
70
74
The authors gratefully acknowledge financial support from a Grant-in-
Aid for Scientific Research (grant nos. 20245008, and 20750077) from the
JSPS and NEDO projects.
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Chem. Eur. J. 2010, 16, 11167 – 11177

Generation and Reactions of Aryllithium Compounds
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a highly controlled
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Received: April 8, 2010
Published online: August 16, 2010
Chem. Eur. J. 2010, 16, 11167 – 11177
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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