Nitro-substituted aryl lithium compounds in microreactor synthesis: Switch between kinetic and thermodynamic control

Article abstract of DOI:10.1002/anie.200904316

Be quick or take your time, depending on your goal: A microflow method for the generation and transformation of o-, m-, and p-nitro-substituted aryl lithium compounds enabled the selective use of either the kinetically or the thermodynamically preferred intermediate. In the example pictured, a residence time of 0.06 s at -48 °C led to the formation of 1, whereas 2 was obtained exclusively when the residence time was extended to 63 s.

Full text of DOI:10.1002/anie.200904316

Angewandte
Chemie
DOI: 10.1002/anie.200904316
Microreactors
Nitro-Substituted Aryl Lithium Compounds in Microreactor Synthesis:
Switch between Kinetic and Thermodynamic Control**
Aiichiro Nagaki, Heejin Kim, and Jun-ichi Yoshida*
The nitro group is one of the strongest electron-withdrawing
groups. It has great potential in the activation of organic
molecules to drive and direct reactions that are otherwise
difficult to perform. However, the use of nitro compounds in
organic synthesis[1] has been very limited, presumably because
of their incompatibility with various nucleophilic and electro-
philic reagents.[2] For example, a nitro group reacts with
Figure 1. A microflow system for the I–Li exchange reaction of 1
followed by the reaction of the lithiated species with electrophiles.
organometallic compounds, such as organolithium and
Flow rate of the solution of 1 (0.10m) in THF: 6.00 mLminÀ1; flow rate
Grignard reagents, very rapidly.[3] Therefore, the generation
of the solution of PhLi (0.42m) in Et2O and cyclohexane (72:28 v/v):
of aryl lithium and aryl magnesium compounds with a nitro
group in the ortho position is possible only at very low
temperatures.[4,5] Moreover, the generation of m- or p-nitro-
substituted aryl lithium and aryl magnesium compounds in a
conventional manner has been reported to be very difficult.[6]
We envisioned that the concept of flash chemistry could
provide a solution to this problem.[7]
1.50 mLminÀ1; flow rate of the solution of an electrophile (0.60m) in
THF: 3.00 mLminÀ1
.
at 08C when an appropriate residence time was chosen. The
possibility of carrying the reactions out at this temperature is
a significant advantage of a microflow system over a conven-
tional macrobatch system, which requires much lower tem-
peratures (yield of 2 (E = H): 70% from 1a, 43% from 1b,
39% from 1c at À788C). The yields of the reactions in the
microflow system decreased with an increase in tR, presum-
ably because of decomposition of the nitrophenyllithium
compounds. The o-nitrophenyllithium reagent generated
from 1a was more stable than the m- and p-nitrophenyl-
lithium species generated from 1b and 1c, respectively,
presumably because of a chelation effect. Slightly better
yields were observed when the reactions were carried out at
À288C.
Herein we report that a microflow system[8,9] enables the
generation and transformation of o-, m-, and p-nitro-substi-
tuted aryl lithium compounds in a controlled manner.[10]
Furthermore, either the kinetically preferred or the thermo-
dynamically preferred aryl lithium reagent can be used
selectively through control of the residence time.
In preliminary studies, we found that PhLi was an
effective reagent for the halogen–lithium exchange of hal-
onitrobenzenes, whereas MeLi, nBuLi, and sBuLi gave the
products in low yields (see the Supporting Information for
details). Therefore, we decided to use PhLi in the following
studies.
The microflow system used consisted of two T-shaped
micromixers (M1 and M2) and two microtube reactors (R1
and R2; Figure 1). Aryl lithium reagents were generated from
o-iodonitrobenzene (1a), m-iodonitrobenzene (1b), and p-
iodonitrobenzene (1c) by varying the temperature (T) of the
cooling bath and the residence time (tR) in R1, and were
trapped with methanol in R2.
Figure 2 summarizes the results obtained by varying the
temperature and residence time. Irrespective of the substitu-
tion pattern, the products were formed in high yields (> 80%)
Under the optimized conditions, lithium reagents derived
from 1a–c reacted with various electrophiles to give the
desired products in good yields (Table 1).
The reaction of 3 demonstrates the potential of the
microflow method (Figure 3). Treatment with PhLi (tR =
0.06 s at À488C) followed by an aldehyde gave the product
4 in 84% yield. Belardi and Micalizio recently used 3 in the
synthesis of macbecin I.[11] In their synthesis, 3 was reduced to
the amine and protected. An aryl lithium reagent containing a
protected amino group was then generated and treated with
an aldehyde.[12] After methylation, the amino group was
deprotected. The present transformation via a nitro-substi-
tuted aryl lithium reagent would serve as an alternative
straightforward route. After the treatment of lithiated 3 with
an aldehyde, O-methylation of the product and simple
reduction of the nitro group should give the desired com-
pound without protection–deprotection processes.[13]
[*] Dr. A. Nagaki, H. Kim, Prof. J. 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
Homepage: http://www.sbchem.kyoto-u.ac.jp/yoshida-lab/index_-
e.html
In the reaction of 3, an increase in tR led to the formation
of a significant amount of the isomeric product 5, which
resulted from isomerization of the aryl lithium reagent.[14]
With a residence time of 63 seconds, 5 was obtained
exclusively; thus, complete isomerization occurred during
this period of time. This experiment demonstrates that the
[**] This research 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.200904316.
Angew. Chem. Int. Ed. 2009, 48, 8063 –8065
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8063

Communications
Table 1: The I–Li exchange reaction of iodonitrobenzenes 1, followed by
reaction with an electrophile.[a]
1
Electrophile
MeOH
Product
Yield [%][b]
87
MeI
MeOTf
36
82
1a
1b
1c
Me3SiCl
Me3SiOTf
62
88
PhCHO
MeOH
93
87
MeI
MeOTf
44
86
Me3SiCl
PhCHO
85
93
MeOH
91
MeI
MeOTf
46
82
Me3SiCl
Me3SiOTf
70
80
PhCHO
86
Figure 2. Effects of the reaction temperature and residence time on
[a] For substrate 1a, T=08C (tR =0.01 s); for 1b and 1c, T=À288C (tR =
0.01 s). [b] The yield was determined by GC. Tf=trifluoromethanesul-
fonyl.
the yield of nitrobenzene in the I–Li exchange reaction of a) o-
iodonitrobenzene (1a), b) m-iodonitrobenzene (1b), and c) p-iodoni-
trobenzene (1c) with PhLi in the microflow system.
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 precooling 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 solution of iodonitrobenzene (1; 0.10m) in THF
(flow rate: 6.0 mLminÀ1) and a solution of PhLi (0.42m) in Et2O and
cyclohexane (72:28 v/v; flow rate: 1.5 mLminÀ1) were introduced into
M1 (f= 250 mm) by syringe pumps. The resulting solution was passed
through R1 and was mixed with a solution of an electrophile (0.60m)
in THF (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, the product solution was collected for 30 s
and quenched with H2O. The reaction mixture was analyzed by GC.
microflow method is very effective for the selective use of
either the kinetically formed or the thermodynamically
preferred organolithium reagent, whereby the desired reac-
tivity can be selected by controlling the residence time.
In conclusion, we have developed a microflow method for
the generation and transformation of o-, m-, and p-nitro-
phenyllithium reagents. Such reactions are very difficult or
impossible with a conventional macrobatch system. Further-
more, the selective use of either kinetically formed or
thermodynamically preferred organolithium reagents by
changing the residence time demonstrates the power of the
microflow method in organic synthesis.
Received: August 3, 2009
Published online: September 18, 2009
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Angewandte
Chemie
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