Fluoro-Substituted Methyllithium Chemistry: External Quenching Method Using Flow Microreactors

Article abstract of DOI:10.1002/anie.202003831

The external quenching method based on flow microreactors allows the generation and use of short-lived fluoro-substituted methyllithium reagents, such as fluoromethyllithium, fluoroiodomethyllithium, and fluoroiodostannylmethyllithium. Highly chemoselective reactions have been developed, opening new opportunities in the synthesis of fluorinated molecules using fluorinated organometallics.

Full text of DOI:10.1002/anie.202003831

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Accepted Article
Title: Fluoro-substituted Methyllithium Chemistry Based on A Novel
External Quenching Method Using Flow Microreactors
Authors: Aiichiro Nagaki, Marco Colella, Arianna Tota, Yusuke
Takahashi, Ryosuke Higuma, Leonardo Degennaro, Renzo
Luisi, and susumu ishikawa
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003831
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Fluoro-Substituted Methyllithium Chemistry: External Quenching Method Using
Flow Microreactors
[
a]
[a]
[b]
[b]
[b]
Marco Colella, Arianna Tota, Yusuke Takahashi, Ryosuke Higuma, Susumu Ishikawa,
[
a]
[a]
[b]
Leonardo Degennaro, Renzo Luisi, * and Aiichiro Nagaki *
Dedicated to the memory of Professor Jun-ichi Yoshida
Abstract: External quenching method based on flow
microreactors allowed generating and using of short-lived fluoro-
substituted methyllithiums such as fluoromethyllithium,
fluoroiodomethyllithium, and fluoroiodostannylmethyllithium.
Highly chemoselective reactions have been developed, opening
new opportunities in the synthesis of fluorinated molecules via
fluorinated organometallics.
Nevertheless, this approach is applicable to stable intermediates
whose lifetimes are over the order of minutes, and it is hardly
applicable when short-lived intermediates are involved in a
synthetic process. In this latter case, decomposition is expected
to occur faster than the reaction with the partner (Figure 1, c). All
those considerations are of paramount importance in the case of
short-lived organometallic species such as functionalized
organolithiums.[1]
Among
functionalized
organometallics,
The reaction using intermediates is a popular procedure in
organic synthesis. However, when reactive intermediates are
short-lived and unstable, these should be generated in the
presence of the reaction partner under internal quenching
conditions. That is because such intermediates react with the
reaction partner as soon as they are generated (Figure 1, a).
Nevertheless, this strategy will not be effective if the reaction
partner is highly reactive and incompatible with the conditions
employed for generating the desired intermediates (Figure 1, b).
To overcome the limitation of the internal quenching strategy, it
would be more advisable to accumulate the reactive
intermediates before meeting the reaction partner (i.e. external
quenching conditions).
fluorinated organolithiums – intended as reactive species bearing
the Li and F atoms on the same carbon – are emerging as useful
and overlooked reagents for the straightforward preparation of
fluoroalkylated molecules.[2] Notwithstanding the synthetic utility
of fluorinated organolithiums, their intrinsic chemical and thermal
instability limits the synthetic versatility, and internal quenching
methods are needed for batch applications. Recently, we reported
that fluoromethyllithium 2 and fluoroiodomethyllithium 3 could be
generated from readily available fluoroiodomethane 1, and
reacted with electrophiles under internal quenching conditions.[3]
However, when internal quenching mode is operated, three main
drawbacks can be envisaged: 1) Very reactive electrophiles can
give competitive reactions with the lithiating agents; 2) Accurate
information on the stability of the organolithium intermediate
cannot be obtained; 3) the use of functionalized electrophiles –
molecules bearing more than one electrophilic functional group –
could be problematic. Given the importance of fluorinated
organolithiums, we reasoned that the use of flow technology
would allow overcoming these issues.[4-6] In this paper, we use
flow microreactors to tackle with the high reactivity of fluorinated
organolithiums, and to realize an external quenching method of
such reactive species (Figure 2). By taking advantage of
extremely short residence times in flow microreactors, fluoro-
substitued methyllithiums were generated in the absence of the
electrophile, and reacted before decomposing. Moreover,
information on stability and lifetime of the lithiated intermediates
were obtained.
Figure 1. Strategy for the generation and use of reactive
intermediates
[a] M. Colella, A. Tota, Prof. Dr., L, Degennaro, Prof. Dr., R, Luisi
Department of Pharmacy – Drug Sciences
Flow Chemistry and Microreactor Technology FLAME-Lab
University of Bari “A. Moro”
Via E. Orabona 4, Bari, I – 70125
E-mail: renzo.luisi@uniba.it
[b] Dr. Y. Takahashi, R. Higuma, Prof. Dr., A. Nagaki
Figure 2. Flow microreactor for the generation of
Department of Synthetic and Biological Chemistry,
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
Fax: (+81)75-383-2729
fluoromethyllithium
fluoroiodomethane 1 in the absence of electrophiles. T-shaped
2
or fluoroiodomethyllithium
3
from
E-mail: anagaki@sbchem.kyoto-u.ac.jp
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micromixers: M1 (250 m) and M2 (250 m), microtube reactors:
R1 and R2.
with N-methoxy-N-methyl-3-phenylpropanamide and (b) trapping
reaction of fluoroiodomethyllithium 3 with chlorotributylstannane.
The flow microreactor shown in Figure 2, consisting of two T-
shaped micromixers (M1 and M2) and two microtube reactors (R1
and R2), was used for the optimization of the external quenching
of short-lived intermediates 2 and 3. This flow set-up allowed the
generation of reactive intermediates and their use before
decomposing by a fine control of the residence time from
milliseconds to seconds.[7]
The study started considering, as model reaction, the reaction of
fluoromethyllithium 2 with a Weinreb amide because of the low
yields observed under internal quenching conditions in a batch
reactor.[8] Fluoroiodomethane 1 was reacted with MeLi in M1 and
R1 to generate 2, which was subsequently reacted with N-
methoxy-N-methyl-3-phenylpropanamide in M2 and R2 to provide
the product 4a (Figure 3, a). The reaction was carried out varying
the temperature (T) and the residence time in R1 (tR1) and a
contour map was obtained (Figure 3, a). As reported in Figure 3
a), high yields of 4a (> 80%) could be obtained at short residence
times (tR1 < 12.9 ms), and low temperatures (< −60 °C). Working
at residence times > 13 ms and at higher temperatures caused a
drop of the yields of 4a. The temperature residence time contour
plot in Figure 3, a) is quite effective to unveil the stability of the
fluoromethyllithium intermediate. In fact, likely because of a fast
decomposition of 2, very low yields or traces of 4a were observed
working at temperature > −60 °C and with residence time in the
order of seconds. It is worth mentioning that such a fine-tuning of
the reaction conditions cannot be realized in batch reactor where
2
must be generated in the presence of the electrophile. Similarly,
the lithiation of 1 with LDA, to generate fluoroiodomethyllithium 3,
was optimized under flow conditions varying the temperature (T)
and the residence time in R1 (tR1) (Figure 3, b). In this case, in
order to directly trap the intermediate, chlorotributylstannane was
employed as ideal electrophile. The analysis of the contour maps
in Figure 3 b) clearly shows the higher thermal and chemical
stability of 3 if compared to 2. Remarkably, good yields of 5a (>
8
0%) could be obtained with residence times in the range of 10
ms up to 1 s, and temperatures from −78 °C up to −20 °C.
Running the flow reactor at −40 °C and using tR1 of 82 ms a nearly
quantitative yield of 5a was obtained, and these conditions were
used as optimal conditions for investigating the scope of this
protocol. The scope of the reaction of fluoromethyllithium 2 with
several Weinreb amides was explored using as optimal conditions
−
60 °C and 12.9 ms for tR1 (Table 1). In all cases examined, yields
of fluoroketones 4a-i were significantly improved, by using the
external quenching method in flow microreactors, compared with
[3a]
the internal quenching method in a conventional batch reactor.
o
R1
Under the optimized conditions (T = −40 C, t = 82.4 ms), the
reactions of fluoroiodomethyllithium 3 with electrophiles were
successfully carried out obtaining the desired adducts 5a-c, 6a-c
in excellent yields (Table 1). In all the examined cases, a
remarkable improvement of yields with respect to batch protocol
could be observed. Next, the chemoselectivity – intended here as
the preferential reaction of the organometallic intermediates with
one of the possible electrophilic reaction sites on the reaction
partner – was considered. For this purpose, the reactions of 2 with
prototypical
electrophile
methyl
4-
Figure 3. Effects of the temperature (T) and the residence time
(
(methoxy(methyl)carbamoyl)benzoate 7a was examined under
batch and flow conditions (Table 2).
tR1) on the yield. (a) Trapping reaction of fluoromethyllithium 2
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Table 1. External trapping of fluoromethyllithium
2
and
Table 2. Chemoselectivity of 2 in batch and flow conditions.a)
fluoroiodomethyllithium 3 with electrophiles under continuous flow
conditions.
Inspired by this remarkable result, we next investigated the
continuous flow reactions of fluoromethyllithium 2 with various
functionalized Weinreb amides, bearing an additional functional
group (i.e. Br, CN, C=O), (Table 3). The corresponding products
4
k-o could be obtained with good yields and excellent
chemoselectivity in favor of the amide functionality. Moreover, the
ketone functionality is favored with respect to the Weinreb amide
group, as in the reaction leading to 4o (65% yield). Similarly,
fluoroiodomethyllithium 3 was reacted, in continuous flow, with
ketones bearing additional electrophilic functional groups, such as
vinyl, bromo and cyano groups, obtaining the corresponding
fluoro epoxides 6d-f, bearing the untouched additional
electrophilic functional group on the aromatic ring. Since
compound 6f was very unstable in GC analysis and isolation
procedures, and it was difficult to remove unknown contaminants,
1
it was quantified only by H-NMR. It is worth pointing out, that this
flow approach to fluorinated derivatives also serves as a useful
method for protecting-group-free synthesis of polyfunctional
organic molecules.
By using a conventional batch method, under internal
quenching conditions, a mixture of products was obtained, and
the reaction disclosed a very low yield and selectivity returning
mainly competitive products 4j, 8-12 (Table 2). In striking contrast,
the reactions run under external quenching conditions using a
flow microreactor resulted more selective providing the product 4j
in 69% yield.
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Table 3. External trapping of fluoromethyllithium
fluoroiodomethyllithium 3 with polyfunctional electrophiles under
continuous flow conditions.a)
2
and
resulted in a very complex mixture when run under batch
conditions.
Figure 4. Integrated flow microreactor system for one-flow three
component coupling via double lithiation/trapping sequence.
In conclusion, external quenching method via short-lived
reactive intermediates based on flow microreactors allowed short-
lived fluoro-substituted methyllithiums such as fluoromethyllithium,
fluoroiodomethyllithium, and fluoroiodostannylmethyllithium to be
successfully generated and used for subsequent reactions with
highly reactive electrophiles and polyfunctional electrophiles. The
present findings open a new world of fluorine chemistry.
Acknowledgements
This work was partially supported by the Grant-in-Aid for Scientific
Research on Innovative Areas 2707 Middle molecular strategy
from MEXT (no. 15H05849), Scientific Research (B) (no.
2
6288049), Scientific Research (S) (no. 26220804), Scientific
Research (S) (no. 25220913), Scientific Research (C) (no.
7865428), AMED (no. 18ak0101090h), the Japan Science and
1
To further benchmark flow microreactor technology in taming
short-lived intermediates, a one-flow process including a double
lithiation/trapping sequence was attempted. A more complex flow
set up, consisting in four micromixers and five feeding streams
Technology Agency’s (JST) A-step program (no. 18067420),
CREST, and the Ogasawara Foundation for the Promotion of
Science & Engineering. This research was supported by the
project Laboratorio Sistema code PONa300369 financed by
MIUR, MISE, Horizon 2020 – PON 2014/2020 FARMIDIAB “code
(
Figure 4), was employed. Fluoroiodomethyllithium 3 was first
generated in M1/R1 (tR1 82 ms at -40 °C), and subsequently
trapped with chlorotrialkylstannanes in M2/R2 to furnish adducts
3
38”; the University of Bari – fondi di Ateneo 2018.
5
a, b. Such fluoroiodomethylstannane underwent to
a
Keywords: microreactor・fluoro-substituted methyllithium・ flow
chemistry
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Marco Colella, Arianna Tota, Yusuke
Takahashi, Ryosuke Higuma, Leonardo
Degennaro, Renzo Luisi,* and Aiichiro
Nagaki*Page No. – Page No.
Fluoro-substituted
Methyllithium
Chemistry Based on A Novel External
Quenching Method Using Flow
Microreactors
External quenching method based on flow microreactors allowed generating and
using short-lived fluoro-substituted methyllithiums such as fluoromethyllithium,
fluoroiodomethyllithium, and fluoroiodostannylmethyllithium. Highly chemoselective
reactions have been developed, opening new opportunities in the synthesis of
fluorinated molecules via fluorinated organometallics.
This article is protected by copyright. All rights reserved.