Aryllithium compounds bearing alkoxycarbonyl groups: Generation and reactions using a microflow system

Article abstract of DOI:10.1002/anie.200803205

Go with the flow: An effective method for the generation and reaction of aryllithium compounds bearing an alkoxycarbonyl group is developed using microflow systems with very short residence times together with fast mixing and efficient temperature control. A wide range of alkoxycarbonyl groups including ethoxycarbonyl and methoxycarbonyl groups are tolerant of the microflow conditions. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200803205

Angewandte
Chemie
DOI: 10.1002/anie.200803205
Microreactors
Aryllithium Compounds Bearing Alkoxycarbonyl Groups: Generation
and Reactions Using a Microflow System**
Aiichiro Nagaki, Heejin Kim, and Jun-ichi Yoshida*
[
1]
Control of reactive intermediates to selectively obtain
desired products is a central issue in organic synthesis. In
macrobatch processes, generation of a reactive intermediate
usually takes minutes or hours. If the lifetime of the
intermediate is shorter than the generation or accumulation
time, it is difficult to obtain a solution of that intermediate
because it undergoes decomposition during the accumulation.
In such a case, a subsequent reaction using the intermediate
cannot be performed. Therefore, the generation of reactive
intermediates is usually carried out at very low temperatures
compounds suffers from the same problem of undesirable
reaction of organolithium species with such functional groups.
Such organometallic compounds can also be prepared directly
without using organolithium reagents. However, direct prep-
aration requires the use of highly reactive precursors such as
organic iodides, which are usually more difficult to prepare.
We envisaged that the concept of flash chemistry using a
microflow system would solve this problem.
[15]
We focused on the Br/Li exchange reaction of alkyl o-
[
7]
bromobenzoates. The Br/Li exchange reaction of alkyl
bromobenzoates, followed by reaction with an electrophile,
can be performed in a conventional macrobatch reactor only
with tert-butyl bromobenzoates at very low temperatures (e.g.
À1008C). The use of esters of secondary and primary alcohols
dramatically decreases the yields. To confirm this assumption,
we reexamined the Br/Li exchange reactions of tert-butyl o-
bromobenzoate (1a), isopropyl o-bromobenzoate (1b), ethyl
o-bromobenzoate (1c), and methyl o-bromobenzoate (1d) in
a conventional macrobatch reactor (Table 1).
[
2,3]
to avoid undesired decomposition. In flash chemistry using
[
4,5]
a microflow system,
a reactive intermediate can be rapidly
generated and transferred for use in a subsequent reaction
before decomposition, because the residence time can be
significantly reduced. Therefore, chemical conversions that
are impossible in conventional macroreactors can become
possible using microflow reactors. Herein, we report that
aryllithium compounds having a highly reactive alkoxycar-
bonyl group, such as ethoxycarbonyl and methoxycarbonyl,
can be easily generated and used for reactions with electro-
[
6]
[
7]
philes by exploiting the features of microflow systems.
Organolithium compounds, such as aryllithiums, have
been widely used in organic synthesis because of their high
Table 1: The Br/Li exchange reaction of alkyl o-bromobenzoates
(
BrC H CO R) followed by reaction with ROH in a conventional macro-
6 4 2
batch reactor.
[8,9]
reactivity. However, organolithium compounds suffer from
[
10]
a problem of functional group compatibility. In fact, it is
difficult to prepare organolithium compounds incorporating
many functional groups, for example alkoxycarbonyl groups,
because such functional groups react with organolithium
species. To overcome this problem, generation reactions, such
as Br/Li exchange reactions of organic bromides, are often
conducted at very low temperatures. It is, however, still
difficult to prepare organolithium compounds having highly
reactive functional groups, such as methoxycarbonyl and
[
a]
o-Bromobenzoates
Yield of 3 [%]
R=tert-butyl: 1a
R=isopropyl: 1b
R=ethyl: 1c
61
12
0
R=methyl: 1d
0
[11]
ethoxycarbonyl groups. The second approach is the use of
less-reactive, hence more-stable, organometallic com-
[
a] A solution of sBuLi in hexane/cyclohexane was added dropwise to a
solution of o-bromobenzoates 1 in THF at À788C. After stirring for
10 min at À788C, an alcohol was added as an electrophile (3.0 equiv).
After stirring for 10 min at À788C, the yield of the product 3 was
determined by GC.
[
12]
[13]
pounds, such as organomagnesium and organozinc com-
[
14]
pounds.
However, preparation of such organometallic
compounds by a metal-exchange reaction from organolithium
[
*] Dr. A. Nagaki, H. Kim, 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
The exchange reaction of 1a at À788C, followed by
quenching with an alcohol, gave tert-butyl benzoate (3a) in
6
1% yield. This yield can be attributed to partial decom-
position of 2a at this temperature. At lower temperatures
[
11]
(
À1008C), this reaction affords higher yields. The use of 1b
E-mail: yoshida@sbchem.kyoto-u.ac.jp
as the starting material caused a further decrease in the yield
of 3. Moreover, in reactions of 1c and 1d, the desired products
were not obtained at all (Table 1).
[
**] This work was financially supported in part by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion of
Science and NEDO projects.
We then examined the reactions using a microflow system
consisting of two T-shaped micromixers (M1 and M2) and two
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803205.
Angew. Chem. Int. Ed. 2008, 47, 7833 –7836
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7833

Communications
microtube reactors (R1 and R2; Figure 1). The reactions were
carried out with varying temperatures (T) and residence times
R
[16,17]
(
t ) in R1. The results are summarized in Figure 2,
in
R
which the yield of 3 is plotted against T and t in R1 as a
contour map with a scattered overlay.
Figure 1. A microflow system for the Br/Li exchange reaction of alkyl o-
bromobenzoates followed by reaction with electrophiles (see text for
details).
In reactions of tert-butyl o-bromobenzoate (1a), 3a was
obtained in high yields (> 80%, brown region) for a wide
range of temperatures and residence times. At low temper-
atures and short residence times the yield of 3a was low
presumably because of an incomplete Br/Li exchange reac-
tion. Low yields also occurred in the high-temperature/long-
residence-time region, probably as a result of the decom-
position of 2a.
In the case of isopropyl o-bromobenzoate (1b), the
reaction profile was similar, although the high-yield region
became smaller. The reaction of ethyl o-bromobenzoate (1c)
also exhibited a similar profile. The high-yield region shifted
to a lower temperature and shorter residence-time, probably
because of faster decomposition of the organolithium com-
pound 2c. However, it is noteworthy that the reaction can be
effectively carried out to give 3c in 90% yield by using an
appropriate temperature (À488C) and residence time
(
0.06 s).
Of even greater significance is the fact that 3d can be
obtained in relatively good yields (> 70%, not shown) from
methyl o-bromobenzoate (1d), although the high-yield region
(> 80%) disappeared, presumably because of the small steric
demand of the methoxycarbonyl group for the reaction with
organolithium species, leading to the formation of side-
products.
These results clearly show that the stability of the
organolithium compounds decreases in the order 2a > 2b >
2
c > 2d. However, it is important to note that the Br/Li
exchange reaction followed by reaction with an electrophile
can be successfully carried out without significant decom-
position of the organollithium intermediate (2) by optimizing
temperature and residence time, even in the case of the
methyl ester.
Under the optimized conditions obtained for the Br/Li
exchange reaction followed by reaction with an alcohol, the
reactions of 2a–2d with other electrophiles, such as methyl
Figure 2. Effects of temperature and residence time of R1 on the yield
of 3 in the Br/Li exchange reaction of 1 with sBuLi followed by reaction
with ROH in the microflow system (
&
: <20%,
&
: 20–40%, : 40–
&
R
60%,
&
: 60–80%,
&
: >80%). T=temperature, t =residence time in
R1.
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Angewandte
Chemie
iodide, methyl triflate, trimethylsilyl chloride, trimethylsilyl
triflate, and benzaldehyde were examined. The reactions were
successful and the corresponding products were obtained in
good yields (Table 2). Interestingly, methyl iodide can be used
as an electrophile for the reactions of 1a and 1b whereas, for
the reactions of 1c and 1d, methyl triflate should be used
instead. The reaction of the aryllithium with methyl iodide is
slow, and therefore only the more sterically demanding tert-
butoxycarbonyl and isopropoxycarbonyl groups can survive
until the reaction is complete. However, the reaction of the
aryllithium with methyl triflate is much faster. Therefore, the
reaction can be conducted at much lower temperatures with
shorter residence times. Consequently, even the less sterically
demanding ethoxycarbonyl and methoxycarbonyl groups can
survive until the reaction is complete.
Table 2: The optimized Br/Li exchange reaction of alkyl o-bromoben-
[
a]
zoates 1 followed by reaction with an electrophile (E).
Ester
E
Product
Yield [%]
93
In summary, we have developed an effective method for
the generation and reaction of aryllithium compounds having
an alkoxycarbonyl group. The key features of the method are
tBuOH
3a
4a
5a
[
18]
a very short residence time, together with fast mixing and
efficient temperature control in microflow systems. A wide
range of alkoxycarbonyl groups including ethoxycarbonyl and
methoxycarbonyl groups can tolerate the microflow condi-
tions. These results bode well for the utility of flash chemistry
and the reported method adds a new dimension in the
chemistry of functionalized organolithium compounds and
their applications in organic synthesis.
MeI
88
96
1
1
1
1
a
b
c
Me SiCl
3
PhCHO
6
82
87
iPrOH
3b
Experimental Section
General procedure: A microflow system consisting of two T-shaped
micromixers (M1 and M2), two microtube reactors (R1 and R2), and
three tube pre-cooling units (P1 (inner diameter f= 1000 mm, length
L = 100 cm), P2( f= 1000 mm, L = 50 cm), and P3 (f= 1000 mm, L =
MeI
MeOTf
62
82
4
b
Me SiCl
5b
6
93
66
90
3
1
00 cm)) was used. A solution of an alkyl bromobenzoate (0.10m) in
À1
THF (flow rate: 6.0 mLmin ) and a solution of sBuLi (0.42m) in n-
hexane/cyclohexane (19:31 v/v, flow rate: 1.5 mLmin ) were intro-
À1
PhCHO
EtOH
duced to M1 (f= 250 mm) by syringe pumps. The resulting solution
was passed through R1 (variable f and L) and was mixed with a
À1
solution of an electrophile (0.60m) in THF (flow rate: 3.0 mLmin
)
in M2( f= 250 mm). The resulting solution was passed through R2
f= 1000 mm, L = 50 cm). After a steady state was reached, the
3c
(
product solution was collected for 30 s and quenched with 1m aqueous
hydrochloric acid. The reaction mixture was analyzed by gas
chromatography. After extraction, the crude product was purified
by flash chromatography.
MeI
MeOTf
12
62
4
5
c
c
Me SiCl
61
79
3
Me SiOTf
3
Received: July 3, 2008
Published online: September 9, 2008
PhCHO
6
70
Keywords: arenes · electrophilic substitution · lithiation ·
.
microreactors · reactive intermediates
MeOH
MeOTf
3d
4d
5d
74
65
82
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85
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R
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t =0.06 s), 1d: À488C (t =0.02 s).
R
R
(
Angew. Chem. Int. Ed. 2008, 47, 7833 –7836
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7835

Communications
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