Synthesis of Functionalized Ketones from Acid Chlorides and Organolithiums by Extremely Fast Micromixing

Article abstract of DOI:10.1002/chem.201900743

Synthesis of ketones containing various functional groups from acid chlorides bearing electrophilic functional groups and functionalized organolithiums was achieved using a flow microreactor system. Extremely fast mixing is important for high chemoselectivity.

Full text of DOI:10.1002/chem.201900743

A Journal of
Accepted Article
Title: Synthesis of Functionalized Ketones from Acid Chlorides and
Organolithiums by Extremely Fast Micromixing
Authors: Aiichiro Nagaki, Kengo Sasatsuki, Satoshi Ishiuchi, Nobuyuki
Miuchi, Masahiro Takumi, and Jun-ichi Yoshida
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To be cited as: Chem. Eur. J. 10.1002/chem.201900743
Link to VoR: http://dx.doi.org/10.1002/chem.201900743
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Synthesis of Functionalized Ketones from Acid Chlorides and
Organolithiums by Extremely Fast Micromixing
Aiichiro Nagaki,* Kengo Sasatsuki, Satoshi Ishiuchi, Nobuyuki Miuchi, Masahiro Takumi, and Jun-ichi
Yoshida*
electrophiles by taking advantage of flow microreactor systems.
However, the following two problems must be solved to realize
the present transformation.
Abstract: Synthesis of ketones having various functional groups from
acid chlorides bearing electrophilic functional groups and
functionalized organolithiums was achieved using a flow microreactor
system. Extremely fast mixing is important for high chemoselectivity.
1.
Overreaction (competitive consecutive reactions)
Reactions of carboxylic acid chlorides and organometallics
correspond to a straightforward method for synthesis of ketones
and enjoy a broad range of synthetic applications.[1] For such
reactions, relatively soft organometallics including organozincs,
cadmiums, and coppers have been used.[2] These
organometallics are often prepared from the corresponding hard
organometallics such as organolithiums and magnesiums by
metal exchange reactions. The direct use of hard organometallics
is problematic because of inevitable overreaction to give tertiary
alcohols.[3] In fact, it is described in organic chemistry textbooks
that hard organometallics cannot be used for ketone synthesis.
Although Sato et. al reported that ketones could be generated by
slowly adding a Grignard reagent to an excess amount of an acid
chloride solution,[4] applications of this procedure is limited.
Instead of acid chlorides, N-methoxy-N-methylamides
(Weinreb amides) are generally used for ketone synthesis using
hard organometallics.[5] However, Weinreb amides are often
prepared from acid chlorides, therefore, direct use of acid
chlorides is more straightforward.[6] In addition, it is quite difficult
or even impossible to use functionalized Weinreb amides,
because many electrophilic functional groups react faster than
Weinreb amide group.[7] Recently, Charette et. al have reported a
novel chemoselective method on the basis of an
activation/addition sequence from secondary amides. In this
2.
Reaction with an electrophilic functional group in an acid
chloride (FG2) (competitive parallel reactions)
We have reported previously that extremely fast 1:1
micromixing[9-11] greatly improved the selectivity of competitive
consecutive reactions[12] as well as that for intramolecular
competition of two functional groups.[13] Selectivity which is quite
close to the kinetically based one was achieved.
Herein, we report that selective synthesis of ketones can be
accomplished by extremely fast 1:1 micromixing of organolithiums
and acid chlordies using a flow microreactor systems. Moreover,
the chemoselective reactions of acid chlorides having
electrophilic functional groups with functionalized organolithiums
leads gives doubly functionalized ketones. Futhermore, the
successful present method has been put on the formal synthesis
of HIV nonnucleoside reverse transcriptase inhibitor,
method,
a highly electrophilic imidoyl triflate intermediate
generation leads to the exceptional functional group tolerance for
reactions with Grignard reagents, giving functionalized ketones
after work-up of subsequent acidic.[8] However, the starting
materials are usually synthesized from acid chlorides. In addition,
it is also required to use two equivalents of organometallics and
GW678248[14]
.
Tf2O as activators. Therefore, development of
a more
We firstly examined the reaction of benzoyl chloride with n-
butyllithium in a conventional batch reactor (in a round bottom
flask with a magnetic stirrer). Benzoyl chloride (1) was reacted
with one equivalent of n-butyllithium. After reacting for 10 min,
methanol was added for the reaction quenching. GC analysis was
performed to determine the yield of 1-phenylpentan-1-one (2), the
desired monoalkylation product, and that of 5-phenylnonan-5-ol
(3), the undesired dialkylation product. The conversion of 1 was
determined by the yield of methyl benzoate. The addition of
benzoyl chloride to a stirred solution of n-butyllithium produced 2
in low yields (Table 1). The reverse addition gave better results.
However, the yield of 2 and selectivity were not acceptable. In
addition, the yield of 2 decreased with an increase in the
temperature. Although the selectivity generally depends on the
size and shape of the reactor, the stirring method, and the speed
of the addition, the present results show that it is impossible to
straightforward chemoselective transformation using acid
chlorides is highly desirable.
We have already reported that electrophilic-functionalized
organolithiums can be generated and reacted with subsequently
Prof. A. Nagaki, S. Ishiuchi, K. Sasatsuki, N. Miuchi, M. Takumi
Department of Synthetic and Biological Chemistry,
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
Fax: (+81)75-383-2729
E-mail: anagaki@sbchem.kyoto-u.ac.jp
Prof. J. Yoshida
National Institute of Technology, Suzuka College
Shiroko-cho, Suzuka, Mie, 510-0294 (Japan)
Fax: (+81)59-387-0338
E-mail: j-yoshida@jim.suzuka-ct.ac.jp
Emeritus Professor, Kyoto University
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achieve good selectivity in this type of competitive consecutive
reactions using the conventional batch method.
Table 3. The reaction of various acid halides with n-butyllithium
(1 eq) using a flow microreactor system.
Table 1. Reactions of benzoyl chloride (1) and one equivalent of
n-BuLi using a conventional batch reactor.
Recently, we have reported that electrophilic-functionalized
organolithiums can be generated and used for a subsequent
reaction before the decomposition by virtue of high-resolution
control of the reaction time in flow microreactors.[15] The present
finding prompted us to integrate the generation of such unstable
functionalized organolithiums and their reactions with acid
chlorides using the flow microreactor consisting of two
micromixers (M1 and M2) and two microtube reactors (R1 and
R2) (Figure 2).
In the next step, this reactions were performed using a flow
microreactor composed of a micromixer (M ( = 250 m)) and a
microtube reactor (R) (Figure 1).
Figure 1. A flow microreactor system for the reaction of benzoyl
chloride (1) with one equivalent of n-BuLi.
o
Good selectivity was achieved at -70 C (Table 2), although
the selectivity depends on the flow rate (See the Supporting
Information for more details).
Figure 2. An integrated flow microreactor system for the selective
reactions of acid chlorides with organolithiums bearing a
functional group (FG1) generated by halogen-lithium exchange of
aryl halides.
Table 2. Effect of temperature for reactions of benzoyl chloride
(1) and n-BuLi (1 eq) using a flow microreactor system
As shown in Table 4, reactions of benzoyl chloride (1),
thiophene-2-carbonyl chloride, and 3,5-dimethoxybenzoyl
chloride with aryllithiums bearing electrophilic functional groups
such as alkoxycarbonyl, nitro, and cyano groups resulted in the
corresponding ketones in good yields and selectivities. For
lithiation of functional bromobenzenes, either n-BuLi or s-BuLi
was used, but for iodobenzenes, phenyllithium was used as a
) was optimized
individually. Notably, aliphatic pivaloyl chloride can also be used
for this reaction.
It is well known that the mixing speed in a micromixer
increases with an increase in the flow rate. For example, an
increase in the total flow rate resulted in an increase in the yield
of 2 while the yields of 3 decreases. Further increase does not
affect the yield of 2 and the selectivity. Therefore, the results
mean that extremely fast mixing is responsible for high selectivity.
With the remarkable effect of micromixing on the selectivity in
hand, we next examined reactions of other acid halides such as
benzoyl bromide and thiophene-2-carbonyl chloride with n-
butyllithium. As shown in Table 3, high selectivity was obtained by
using a flow microreactor system, whereas the use of a batch
reactor resulted in much lower selectivity.
lithiating agent. The residence time (tR1
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yield with the total flow rate, 15 mL/min. Extremely fast
micromixing seems to be responsible for high selectivity.
Table 4. Reactions of acid chlorides with functionalized
organolithiums.
Based on the remarkable effect of fast micromixing on
selectivity, we next examined the reactions of various acid
chlorides having an electrophilic functional group (FG2) such as
an nitro, cyano, alkoxyl carbonyl, bromo groups with aryllithiums
bearing electrophilic functional groups (FG1) such as nitro, cyano,
t-butoxycarbony, and bromo groups
(Figure 3). The
corresponding ketones were obtained in good yields without
affecting FG1 and FG2 (Table 6).
Figure 3. A flow microreactor system for the selective reactions
of acid chlorides having a fuctional group FG2 with organolithiums
bearing a functional group FG1 generated by halogen-lithium
exchange.
a For more detailed conditions, see supporting infomation.
Table 6. Reactions of acid chlorides bearing electrophilic
functional groups with functionalized organolithiums.
Next challenge was the reactions of acid chlorides bearing
electrophilic functional groups.[16] We chose to study the reactions
of 4-methoxycarbonylbenzoyl chloride (4) with one equivalent of
n-BuLi. The conventional batch method led to the productuion of
a mixture of three products: 5, 6, and 7, although acid chlorides
are generally much more reactive than esters toward nucleophiles
(Table 5).
Table 5. Reactions of 4-methoxycarbonylbenzoyl chloride (4) and
n-BuLi (1 eq) using a conventional batch reactor.
Addition of n-butyllithium to a 4 solution at -70 oC resulted in
the formation of desired 5 in only 19% yield, and significant
amounts of 6 (3%) and 7 (3%) were produced. The reverse
addition caused a much lower yield of 5. The present results
indicate the limitation of the batch method.
Next, the reactions were examined by using
a flow
microreactor composed of a T-shaped micromixer ( = 250 m;
M) and a microtube reactor (R) shown in Figure 1.
The selectivity was moderate at low flow rate (See the
Supporting Information for more details). However, an increase in
the flow rate resulted in an increasing in the yield of 5 with the
expense of the yields of 6 and 7. Desired 5 was obtained in 77%
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The present method was put on synthesis of a key
intermediate for the synthesis of HIV nonnucleoside reverse
transcriptase inhibitor, GW678248, which has recently been
reported by Boone's group.[14] The bromine-lithium exchange
reaction of 3-bromo-5-chlorobenzonitrile and the subsequent
reaction with 5-chloro-2-methoxybenzoyl chloride using a flow
microreactor afforded the desired ketone in 52% yield, which can
be converted to GW678248 according to the literature procedure.
(Figure 4).
In conclusion, we have developed a flow-microreactor
method for selective reactions of carboxylic acid chlorides with
organolithiums which enables straightforward and protecting-
group-free synthesis[17] of functionalized ketones. Extremely fast
1:1 mixing using a micromixer is important for high selectivity.
Successfull application to the synthesis of a key intermediate for
GW678248 demonstrates the power of the method. It is hoped
that the method will make significant contribution to synthesis of
a variety of organic compounds having ketone functionality.
Figure 4. Formal total synthesis of GW678248, HIV
nonnucleoside reverse transcriptase inhibitor.
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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.
26288049), Scientific Research (S) (no. 26220804), Scientific
Research (S) (no. 25220913), Scientific Research (C) (no.
17865428), AMED (no. 18061567), the Japan Science and
Technology Agency’s (JST) A-step program (no. 18067420), and
the Ogasawara Foundation for the Promotion of Science &
Engineering
Keywords: flow microreactor • functionalized ketones
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Entry for the Table of Contents
COMMUNICATION
Aiichiro Nagaki,* Kengo Sasatsuki,
Satoshi Ishiuchi, Nobuyuki Miuchi,
Masahiro Takumi, and Jun-ichi Yoshida*
Page No. – Page No.
Flow Synthesis of Functionalized
Ketones by Direct Coupling of Acid
Chlorides and Organolithiums
Selective synthesis of ketones can be achieved by extremely fast 1:1 micromixing of
acid halides and organolithiums using a flow microreactor system. Moreover, the
chemoselective reactions of acid chlorides bearing electrophilic functional groups
with functionalized organolithiums were also carried out in this controlled system to
obtain the corresponding functionalized ketones.
Figure 1. A flow microreactor system for the reaction of benzoyl chloride (1) with one equivalent of n-BuLi.
Figure 2. An integrated flow microreactor system for the selective reactions of acid chlorides with organolithiums bearing a functional
group (FG1) generated by halogen-lithium exchange of aryl halides.
Figure 3. A flow microreactor system for the selective reactions of acid chlorides having a fuctional group FG2 with organolithiums
bearing a functional group FG1 generated by halogen-lithium exchange.
Figure 4. Formal total synthesis of GW678248, HIV nonnucleoside reverse transcriptase inhibitor.
Table 1. Reactions of benzoyl chloride (1) and one equivalent of n-BuLi using a conventional batch reactor.
yield [%]
temperature [oC]
method of addition
conversion [%]
2
29
8
3
-70
-40
-20
0
-70
-40
-20
0
addition of BuLi to 1
addition of BuLi to 1
addition of BuLi to 1
addition of BuLi to 1
addition of 1 to BuLi
addition of 1 to BuLi
addition of 1 to BuLi
addition of 1 to BuLi
69
66
83
93
49
69
83
94
33
31
21
11
22
29
20
8
4
trace
2
trace
trace
trace
Table 2. Effect of temperature for reactions of benzoyl chloride (1) and n-BuLi (1 eq) using a flow microreactor system
yield [%]
temperature [oC]
total flow rate [mL/min]
conversion [%]
2
3
-70
-40
-20
0
30.0
30.0
30.0
30.0
86
70
65
67
71
40
29
26
10
21
23
21
Table 3. The reaction of various acid halides with n-butyllithium (1 eq) using a flow microreactor system.
yield [%]
acid halide
reaction method
ketone
alcohol
batch macro
flow micro
29
71
33
10
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batch macro
flow micro
28
72
24
4
batch macro
flow micro
26
60
27
12
30.0
Table 4. Reactions of acid chlorides with functionalized organolithiums.
functionalized
organolitium
lithiating
agent
acid chloride
tR1 [s]
product
yield [%]
73
n-BuLi
n-BuLi
PhLi
0.48
6.0
6.0
73
69
s-BuLi
s-BuLi
5.9
6.1
90
78
s-BuLi
n-BuLi
5.9
94
90
0.47
Table 5. Reactions of 4-formylbenzoyl chloride (4) and n-BuLi (1 eq) using a conventional batch reactor.
yield [%]
temperature [oC]
method of addition
conversion [%]
5
6
7
addition of BuLi to
-70
-70
89
77
19
3
3
4
addition of 4 to
BuLi
1
0
23
Table 6. Reactions of acid chlorides bearing electrophilic functional groups with functionalized organolithiums.
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functionalized
organolitium
lithiating
agent
acid chloride
product
yield [%]
85
PhLi
n-BuLi
69
n-BuLi
n-BuLi
PhLi
92
90
77
87
70
87
PhLi
n-BuLi
n-BuLi
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