Benzyllithiums bearing aldehyde carbonyl groups. A flash chemistry approach

Article abstract of DOI:10.1039/c5ob00958h

Reductive lithiation of benzyl halides bearing aldehyde carbonyl groups followed by reaction with subsequently added electrophiles was successfully accomplished without affecting the carbonyl groups by taking advantage of short residence times in flow microreactors.

Full text of DOI:10.1039/c5ob00958h

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Benzyllithiums bearing aldehyde carbonyl groups.
A flash chemistry approach†
Cite this: DOI: 10.1039/c5ob00958h
Received 12th May 2015,
Accepted 21st May 2015
Aiichiro Nagaki, Yuta Tsuchihashi, Suguru Haraki and Jun-ichi Yoshida*
DOI: 10.1039/c5ob00958h
www.rsc.org/obc
Reductive lithiation of benzyl halides bearing aldehyde carbonyl use in the reactions with subsequently added electrophiles
groups followed by reaction with subsequently added electrophiles without affecting the aldehyde carbonyl groups.
was successfully accomplished without affecting the carbonyl
We first examined the generation of simple benzyllithiums
groups by taking advantage of short residence times in flow by reductive lithiation13 of benzyl halides (Fig. 1). This reaction
microreactors.
is problematic because of Wurtz-type coupling, i.e. the coup-
ling of benzyllithiums with starting benzyl halides. It was
reported that benzyllithium can be generated from benzyl
chloride by using lithium naphthalenide (LiNp) in a mixed
solvent (Et2O/THF/light petroleum = 4 : 3 : 1) at −95 °C in a
conventional batch reactor.9a However, the reaction in THF
and/or at higher temperatures such as −78 °C leads to a dra-
matic decrease in the yield because of Wurtz-type coupling.
We envisioned that extremely fast micromixing is effective to
avoid undesired Wurtz-type coupling because it is known that
the product selectivity of fast consecutive competitive reac-
tions14 can be dramatically improved by extremely fast micro-
mixing.15 Thus, we examined the reactions of benzyl halides
with LiNp in a flow microreactor system, which consists of two
T-shaped micromixers M1 (ϕ = 250 μm) and M2 (ϕ = 250 μm)
and two microtube reactors R1 (ϕ = 1000 μm, length = 3.5 cm
and R2 (ϕ = 1000 μm, length = 50 cm) (see the ESI† for details).
For the reactions with very short residence times such as 1.3 ms,
a built-in type system as shown in Fig. 2a (R1: ϕ = 250 μm,
Chemoselectivity is one of the central issues in chemistry and
chemical synthesis.1 One of the goals in synthetic chemistry is
the development of chemoselective transformations without
affecting the highly reactive functional groups that are not
involved in the desired transformation. We have been inter-
ested in organolithium reactions without affecting the alde-
hyde carbonyl groups as an extreme case of chemoselective
transformations.2 According to the textbooks of organic chem-
istry, organolithiums react with aldehydes very quickly and
they are not compatible with each other. On the other hand,
aldehyde carbonyl groups are very common functional groups
and organolithium reactions are frequently used in organic
synthesis.3 Therefore, if we could perform organolithium reac-
tions without affecting the aldehyde carbonyl groups, such
reactions would serve as powerful synthetic methods. We took
an approach to this challenge based on flash chemistry,4 in
which highly unstable reactive species are generated and trans-
ferred to another location to be used in the next reaction5
before they decompose by high-resolution residence time
control using flow microreactor systems.6–8 In fact, recently,
we had already reported the generation and reactions of
aryllithiums bearing ketone carbonyl groups.5e However, in
general, aldehyde carbonyl groups are more reactive than
ketone carbonyl groups. Therefore, faster generation is necess-
ary to solve the more challenging problem of aldehyde cases.
Here, we show that flash chemistry enables the generation of
benzyllithiums9–12 bearing aldehyde carbonyl groups and their
Department of Synthetic and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Nishikyo-ku, Kyoto, 615-8510, Japan.
E-mail: yoshida@sbchem.kyoto-u.ac.jp
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00958h
Fig. 1 Generation and reactions of benzyllithiums bearing aldehyde
carbonyl groups.
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be carried out at −95 °C in a conventional batch macro
reactor. It is also advantageous that THF can be used instead
of the mixed solvent. Furthermore, benzyl bromide can be
used as a starting material, although such transformation is
impossible in a conventional batch macro reactor. These
remarkable features seem to be ascribed to the extremely fast
micromixing of benzyl halide and LiNp at 1 : 1 molar ratio.
Under the optimized conditions, the reactions of benzyl-
lithium with other electrophiles, such as methyl iodide, alde-
hydes, ketones, trimethylsilyl chloride, and isocyanates, were
examined. As shown in Table 2, the corresponding products
were obtained in good yields. Notably, the lithiation of
2-(chloromethyl)thiophene followed by the reaction with an
Fig. 2 Flow microreactor systems. (a) Built-in type system, (b) modular
type system.
Table 2 The generation of benzyllithiums followed by reaction with an
electrophilea
length = 1.0 cm) was used, whereas a conventional modular
type system was used for the reactions with longer residence
times (Fig. 2b).
Yieldb
(%)
Benzyl halides
Electrophile
MeOH
Product
89c
Because it is well known that the mixing speed in a micro-
mixer depends on the inner diameter and the flow rate,16 we
examined the reactions by varying the inner diameter of M1
and the flow rates of the solution of benzyl halide and LiNp.
The 1 : 1 molar ratio of benzyl halide and LiNp was maintained
in all experiments. Methanol was used as an electrophile and
the reactions were carried out at 20 °C using a conventional
modular type system (Fig. 2b). As summarized in Table 1, the
yield of the desired protonated product, toluene, increased
with a decrease in the inner diameter. The yield also increased
with an increase in the flow rate. Satisfactory yields were
obtained with M1 of 250 μm inner diameter and the total flow
rate of 9.0 mL min−1 in the case of benzyl chloride. In the case
of benzyl bromide, a higher flow rate was necessary to obtain
satisfactory yields, presumably benzyl bromide is more reactive
toward benzyllithium than benzyl chloride. Anyway, it is note-
worthy that the flow microreactor system enables the gene-
ration of benzyllithium at 20 °C, although the reactions should
Mel
82c
80
PhCHO
(CH3)2CO
Ph2CO
42c
93
Me3SiCl
80c
MeOH
80c
Mel
82c
75
Table 1 Effect of the flow rate and the inner diameter of M1 on the
lithiation of benzyl halides using the flow microreactor systema
PhCHO
Flow rate (mL min−1
)
Inner
diameter
Yieldb (%)
Ph2CO
71
X
Benzyl halide LiNp Total of M1 (μm) Toluene Bibenzyl
Cl
6.0
6.0
3.0
6.0
6.0
6.0
12
3.0
1.5
3.0
3.0
1.5
3.0
3.0
3.0
6.0
1.5
0.75
9.0
9.0
4.5
9.0
9.0
9.0
18
4.5
2.25 250
500
250
250
800
500
250
250
250
70
89
81
15
38
77
80
49
39
13
4
4
29
30
10
8
24
30
MeOH
Mel
97c
72c
Br
a R1: ϕ = 250 μm, L = 3.5 cm, 20 °C. Benzyl chloride: total flow rate =
9 ml min−1. Benzyl bromide, 2-(chloromethyl)thiophene: flow rate of
a R1: ϕ = 250 μm, L = 3.5 cm, 20 °C. b Determined by GC using an benzyl halide = 18 ml min−1 b Isolated yield. c Determined by GC
.
internal standard.
using an internal standard.
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electrophile was successfully carried out without ring-opening,
although conventional batch reactions often suffer from this
side reaction.17 The productivity of the present method is high
enough for laboratory synthesis. In the case of the reaction of
benzyllithium with benzophenone, a 15 min operation gave
1.09 g of the desired product (see the ESI† for details).
Table 3 The generation of benzyllithiums bearing ketone and aldehyde
carbonyl groups followed by reaction with an electrophilea
Yieldb
Benzyl halides
Electrophile Product
PhNCO
(%)
78
With the successful generation of benzyllithiums by virtue
of extremely fast micromixing in hand, we next examined the
generation and reactions of benzyllithiums bearing carbonyl
groups. In this case the high-resolution residence time control
is critical because such benzyllithiums should be transferred
extremely quickly to another location to be used in the reac-
tion with electrophiles before they decompose. Temperature–
residence time mapping serves as a powerful tool for optimiz-
ing the residence time. Fig. 3a shows the contour plots with
scattered overlay of the yields of the protonated product for the
lithiation of p-propanoylbenzyl chloride, which has a ketone
PhCHO
88
PhNCO
PhCHO
60
64
Me3SiOTf
PhCHO
68
67
PhCHO
89
PhNCO
PhCHO
77
83
PhCHO
MeOTf
85
41c
PhCHO
55
58
Me3SiOTf
Fig. 3 Effects of the temperature and the residence time in R1 on the
yield of the protonated product for the lithiation of (a) p-propanoylben-
zyl chloride and (b) p-formylbenzyl chloride with LiNp followed by trap-
ping with methanol using the flow microreactor system. Contour plots
with scattered overlay of the yields of the protonated products, which
are indicated by numbered circles.
PhCHO
59d
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Table 3 (Contd.)
Benzyl halides
Organic & Biomolecular Chemistry
reaction of benzaldehyde with (5-formylthiophen-2-yl)methyl-
lithium followed by elimination with bis[α,α-bis(trifluoro-
methyl)benzenemethanolato]diphenylsulfur (Martin sulfurane)
gave aldehyde 1 in 61% isolated yield. The aldehyde carbonyl
group in 1 was used for subsequent reaction with benzyl-
lithium. The subsequent dehydration gave compound 2 (78%
isolated yield), in which one thiophene ring and two benzene
rings are connected by carbon–carbon double bonds.18
Yieldb
(%)
Electrophile Product
PhCHO
76e
In conclusion, flash chemistry using flow microreactor
systems enables the generation and reactions of benzyl-
lithiums bearing aldehyde carbonyl groups. Extremely fast
micromixing is responsible for the generation of benzyl-
lithiums avoiding Wurtz-type coupling, and high-resolution
residence time control is responsible for survival of aldehyde
carbonyl groups. The present findings open a new aspect of
protecting-group-free19 organolithium chemistry.
PhCHO
77
72
a R1: ϕ = 250 μm, L = 1.0 cm, −78 °C. b Isolated yield. c Determined by
GC. d Diastereomeric ratio = 88 : 12 (determined by 1H NMR spectra).
e Diastereomeric ratio = 60 : 40 (determined by 1H NMR spectra).
Acknowledgements
carbonyl group, followed by trapping with methanol. The yield
decreases with an increase in the residence time in R1. The
yield also decreases with an increase in the temperature
although the effect of the temperature is not large. The
optimal yield (80%) was obtained with the residence time of
1.3 ms at −78 °C.
This work was partially supported by the Grant-in-Aid for
Scientific Research (S) (no. 26220804) and Scientific Research
(B) (no. 26288049). We also thank Taiyo Nippon Sanso for pro-
viding a low temperature cooling device and partial financial
support.
The effects of the residence time and the temperature are
more significant in the lithiation of p-formylbenzyl chloride,
which has an aldehyde carbonyl group (Fig. 3b). As can be
seen obviously by comparing Fig. 3a and b, p-formylbenzyl-
lithium is significantly less stable than p-propanoylbenzyl-
lithium. With the residence time of 1.3 ms at −78 °C, however,
p-formylbenzyllithium can be generated and used in the sub-
sequent reaction with methanol to give the protonated product
in a reasonable yield (68%). This means that the aldehyde car-
bonyl group can survive in the organolithium reaction.
Under the optimized conditions several benzyllithiums
bearing ketone and aldehyde carbonyl groups were generated
and reacted with several electrophiles including phenylisocya-
nate, benzaldehyde, TMSOTf, and MeOTf. The results are sum-
marized in Table 3. Such transformations are very difficult or
practically impossible by using conventional batch macro
reactors.
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