Micromixing enables chemoselective reactions of difunctional electrophiles with functional aryllithiums

Aiichiro Nagaki*a, Satoshi Ishiuchia, Keita Imaia, Kengo Sasatsukia, Yuichi Nakaharab and Jun-ichi Yoshida*a
aDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan. E-mail: yoshida@sbchem.kyoto-u.ac.jp; anagaki@sbchem.kyoto-u.ac.jp
bProcess Engineering Group, Fundamental Technology Labs. Institute of Innovation, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kanagawa 210-8681, Japan

Received 7th September 2017 , Accepted 6th October 2017

First published on 16th October 2017


Generation of highly unstable functional aryllithiums followed by chemoselective reactions with difunctional electrophiles were successfully achieved using flow microreactor systems equipped with micromixers to give highly functionalized compounds without protecting functional groups. Extremely fast micromixing is responsible for high chemoselectivity.


Introduction

Protecting groups have been indispensable for synthesizing complex highly functionalized organic molecules, although the use of a protective group needs at least two additional synthetic steps, protection and deprotection. Recently, protecting group-free-synthesis has attracted a great deal of attention.1

In this regard, the generation of organolithiums2 bearing unprotected functional groups has been investigated extensively (Scheme 1(a)).3 Various electrophilic functional groups can be compatible with organolithium reactions if we use flow microreactors.4 Micromixing using flow microreactors5–7 enables selective lithiation without affecting the functional group, whereas the precise residence time control enables the effective use of short-lived organolithium intermediates for the subsequent reaction with electrophiles. Reactions of such functional organolithiums with electrophiles give difunctional products.


image file: c7re00142h-s1.tif
Scheme 1 Synthetic approaches to functionalized organic molecules using organolithium reactions.

Another approach to difunctional compounds using organolithium chemistry is the reaction of unfunctionalized organolithiums with difunctional electrophiles (Scheme 1(b)). However, it is usually difficult or impossible to achieve chemoselective reactions8 without affecting less electrophilic functionality even if one equivalent of an organolithium is used. However, recently, we reported extremely fast micromixing9 dramatically improves the chemoselectivity.10

The combination of the first and the second approaches is also effective (Scheme 1(c)). Chemoselective reactions of functional organolithiums with difunctional electrophiles should give trifunctional products.

In this paper, we report the full details of such approaches based on extremely fast micromixing using flow microreactor systems, which serve as powerful and straightforward methods for protecting group-free-synthesis of highly functionalized organic molecules.

Generation of functional aryllithiums

First we show the effect of mixing on the efficiency of functional aryllithium generation. Although aryllithiums bearing various electrophilic functional groups have been successfully generated using flow microreactors, we focus on the generation of 4-cyanophenyllithium by bromine–lithium exchange of 4-cyanobromobenzene with n-butyllithium (n-BuLi) as a representative (Scheme 1(a)).

The reaction of 4-cyanobromobenzene with one equivalent of n-BuLi was examined using a flow microreactor system composed of two micromixers (M1 and M2) and two microtube reactors (R1 and R2) shown in Fig. 1.


image file: c7re00142h-f1.tif
Fig. 1 A flow microreactor system for bromine–lithium exchange of 4-cyanobromobenzene with n-BuLi followed by reaction with methanol.

As shown in Table 1, the selective generation and reaction of 4-cyanophenyllithium was achieved and the desired compound was obtained in high yields at high flow rates. This indicates that the reaction selectivity depended on the flow speed because it is well known that flow speed increases with an increase with the flow rate.11 The decrease in the total flow rate caused the decrease of the yields presumably because n-BuLi attacked the cyano group of 4-cyanobromobenzene. In fact, at slower flow rates, the formation of 1-phenylpentan-1-one was observed by GC-mass analysis (see ESI for details). The present observations indicate that extremely fast mixing is responsible for the high selectivity in the generation of functional organolithiums.

Table 1 Bromine–lithium exchange of 4-cyanobromobenzene with n-BuLi followed by reaction with methanol
Total flow rate in M1 (ml min−1) Conversion (%) Yield (%)
2.5 100 36
5.0 100 61
10 100 75
20 100 85


Reaction of phenyllithium with difunctional electrophiles

The second approach is the reaction of unfunctionalized organolithiums with difunctional electrophiles. We chose to use phenyllithium as a representative organolithium reagent without functional groups.

First, we focused on aliphatic compounds having two different electrophilic functional groups such as aldehyde, ketone, and ester carbonyl groups.

The reaction of phenyllithium with 6-oxo-6-phenylhexanal (1) (1[thin space (1/6-em)]:[thin space (1/6-em)]1 molar ratio) was carried out using a flow microreactor system equipped with a micromixer (Fig. 2). A solution of 1 (0.10 M in THF, 12 ml min−1) and a solution of PhLi (0.42 M in Et2O/cyclohexane (74/26 v/v), 3.0 ml min−1) were introduced to M by syringe pumps, and the resulting mixture was passed through R (ϕ = 1000 μm, L = 100 cm). The yields of 6-hydroxy-1,6-diphenylhexan-1-one (2, mono-addition product), 6-hydroxy-6,6-diphenylhexanal (3, mono-addition product), and 1,1,6-triphenylhexane-1,6-diol (4, di-addition product) were determined by GC after aqueous work-up. As shown in Table 2, the reaction at a low flow rate (2.5 ml min−1) at −40 °C resulted in a low selectivity for 2, which was formed by selective nucleophilic attack of PhLi at the aldehyde carbonyl group. A significant amount of 4, which was derived from the nucleophilic attack of PhLi at both aldehyde and ketone carbonyl groups, was obtained. The increase in the flow rate resulted in an increase in the selectivity for 2, indicating that the selectivity for 2 increases with the mixing efficiency, because it is known that the mixing efficiency in a micromixer increases with an increase in the flow speed.11 The reaction at −78 °C also showed a similar selectivity. The highest yield of 2 (48%) was observed at the flow rate of 30 ml min−1 at −40 °C, although the selectivity is still not acceptable.


image file: c7re00142h-f2.tif
Fig. 2 A flow microreactor system for the reaction of phenyllithium with 1.
Table 2 Reactions of phenyllithium with 6-oxo-6-phenylhexanal (1)
Temperature (°C) Flow rate (ml min−1) Conversion (%) Yield (%)
2 3 4
−40 2.5 66 10 20 29
−40 10 65 36 12 19
−40 30 77 48 10 18
−70 2.5 67 11 23 26
−70 10 72 27 18 22
−70 30 73 44 12 17


The reactions of methyl 6-oxohexanoate (5) were also examined using a flow microreactor system. The yields of methyl 6-hydroxy-6-phenylhexanoate (6, mono-addition product), 6-oxo-6-phenylhexanal (1, mono-addition product), 6-hydroxy-1,6-diphenylhexan-1-one (2, di-addition product), 6-hydroxy-6,6-diphenylhexanal (3, di-addition product), and 1,1,6-triphenylhexane-1,6-diol (4, tri-addition product) were determined by GC after aqueous work-up. As shown in Table 3, the increase in the flow rate resulted in an increase in the selectivity for 6, indicating that the increase in the mixing efficiency increases the selectivity for the attack on the aldehyde carbonyl group. The desired product 6 was obtained in 72% yield.

Table 3 Reactions of phenyllithium with methyl 6-oxohexanoate (5)

image file: c7re00142h-u1.tif

Temperature (°C) Flow rate (ml min−1) Conversion (%) Yield (%)
6 1 2 3 4
−40 2.5 59 22 0 19 9 0
−40 10 82 69 0 4 2 5
−40 30 81 72 0 3 1 5
−70 2.5 62 22 0 15 11 2
−70 10 72 52 3 6 3 5
−70 30 74 60 2 4 2 5


Next, we turned our attention to the reactions with aromatic compounds bearing two electrophilic functional groups. In contrast to the aliphatic case, remarkable selectivity was observed in the aromatic case, although the selectivity strongly depends on the flow rate (Table 4). The yields of (4-(hydroxy(phenyl)methyl)phenyl)(phenyl)methanone (8, mono-addition product), 4-(hydroxydiphenylmethyl)benzaldehyde (9, mono-addition product), and (4-(hydroxy(phenyl)methyl)phenyl)diphenylmethanol (10, di-addition product) were determined by GC after aqueous work-up. The yield of 8 (mono-addition product) increases and that of 10 (di-addition product) decreases with an increase in the flow rate, indicating the importance of mixing efficiency. It is interesting to note that the yield of 9 also decreases with an increase in the flow rate, although the reason is not clear at present. Notably, the selectivity decreases with an increase in the diameter of micromixer. The mixing efficiency generally decreases with an increase in the inner diameter if the flow rate is the same. In contrast, the selectivity does not vary with the reaction temperature appreciably.

Table 4 Effect of inner diameter, temperature, and flow rate for the reaction of PhLi with 4-benzoylbenzaldehyde (7) using flow microreactors

image file: c7re00142h-u2.tif

Inner diameter in M (μm) Temperature (°C) Flow rate (ml min−1) Conversion (%) Yield (%)
8 9 10
800 −40 15 65 23 3 40
500 −40 15 71 34 3 32
250 −40 15 83 66 2 15
250 −78 15 78 60 4 17
250 −20 15 79 57 2 18
250 0 15 81 61 2 21
250 20 15 81 57 2 22
250 −40 0.63 61 7 5 40
250 −40 1.3 56 8 5 41
250 −40 2.5 60 15 5 38
250 −40 5.0 74 42 5 29
250 −40 10 82 60 3 20
250 −40 20 84 69 3 15
250 −40 25 78 70 2 8
250 −40 30 81 73 1 7


To get a deeper insight into the effect of micromixing on the selectivity, the reaction of PhLi with 4-benzoylbenzaldehyde was carried out in a conventional macrobatch reactor (a 50 ml round bottomed flask with a magnetic stirring) at various temperatures with varying the way of addition. The results are summarized in Table 5.

Table 5 Reactions of 4-benzoylbenzaldehyde (7) with one equivalent of phenyllithium using a conventional macro batch reaction

image file: c7re00142h-u3.tif

Temperature (°C) Method of addition Conversion (%) Yield (%)
8 9 10
−78 Addition of PhLi to 7 65 28 7 25
−40 Addition of PhLi to 7 64 23 7 26
−20 Addition of PhLi to 7 64 20 7 30
0 Addition of PhLi to 7 64 12 6 30
20 Addition of PhLi to 7 61 12 5 33
−78 Addition of 7 to PhLi 33 6 2 26
−40 Addition of 7 to PhLi 37 5 1 27
−20 Addition of 7 to PhLi 49 3 1 35
0 Addition of 7 to PhLi 51 2 1 37
20 Addition of 7 to PhLi 55 1 1 40
−78 Simultaneous addition of 7 and PhLi 51 16 9 26


The addition of one equivalent of phenyllithium to a stirred solution of 7 for 1.0 min at −78 °C gave 8 in only 28% yield, and a significant amount of 10 (25%) was produced together with unchanged 7. Interestingly, compound 9, which is formed by the reaction of PhLi with the ketone carbonyl group without affecting the more reactive aldehyde carbonyl group, was also obtained in 7% yield. The increase in the temperature caused a decrease in the yield of desired product 8. Moreover, the reverse addition resulted in lower yields of 8, and the simultaneous addition did not give better results.

Although the selectivity should also depend on the size and shape of the reactor, the stirring speed, and the speed of the addition, the present data demonstrate the limitations of the macrobatch method for achieving this type of chemoselectivity of fast reactions.

With the remarkable effect of micromixing on the selectivity in hand, we next examined the reactions of PhLi with various benzaldehyde having different electrophilic functional groups such as ketone carbonyl, ester carbonyl, nitro,12 and cyano groups. As shown in Table 6, high chemoselectivity was obtained by using the flow microreactor system, whereas the use of a batch reactor resulted in much lower selectivity. In all cases, the faster flow rates gave better selectivity. Furthermore, the reactions of PhLi with phenylisocyanates having a cyano or an alkoxycarbonyl group were also accomplished with high chemoselectivity, although the reactions in a batch reactor gave complex mixtures.

Table 6 The reaction of aromatic compounds having two different electrophilic functional groups with PhLi using the flow microreactors
Difunctional electrophiles Reaction method Flow rate (ml min−1) Yield (%)
Mono-addition product Di-addition product
image file: c7re00142h-u4.tif     image file: c7re00142h-u5.tif image file: c7re00142h-u6.tif
  Batch macro 28 25
Flow micro 2.5 15 38
Flow micro 10 60 20
Flow micro 30 73 7
image file: c7re00142h-u7.tif     image file: c7re00142h-u8.tif image file: c7re00142h-u9.tif
  Batch macro 29 26
Flow micro 2.5 13 35
Flow micro 10 55 14
Flow micro 30 71 7
image file: c7re00142h-u10.tif     image file: c7re00142h-u11.tif image file: c7re00142h-u12.tif
  Batch macro 56 5
Flow micro 2.5 56 13
Flow micro 10 83 0
Flow micro 30 84 0
image file: c7re00142h-u13.tif     image file: c7re00142h-u14.tif  
  Batch macro 36  
Flow micro 2.5 29  
Flow micro 10 72  
Flow micro 30 76  
image file: c7re00142h-u15.tif     image file: c7re00142h-u16.tif  
  Batch macro 65  
Flow micro 2.5 54  
Flow micro 10 88  
Flow micro 30 89  
image file: c7re00142h-u17.tif     image file: c7re00142h-u18.tif image file: c7re00142h-u19.tif
  Batch macro 5 1
Flow micro 2.5 43 0
Flow micro 10 73 0
Flow micro 30 82 0
image file: c7re00142h-u20.tif     image file: c7re00142h-u21.tif image file: c7re00142h-u22.tif
  Batch macro 18 4
Flow micro 2.5 25 8
Flow micro 10 81 2
Flow micro 30 91 1


Reactions of functional aryllithiums with difunctional electrophiles

Next, we focused on the third case (Scheme 1(c)); the reactions of aryllithiums bearing an electrophilic functional group (FG0) with difunctional electrophiles, i.e. compounds bearing two different electrophilic functional groups (FG1 and FG2) (Scheme 2). In this case, we have to worry about not only the competition between two electrophilic functional groups on the electrophile (FG1 and FG2) but also the competition between functional groups on the electrophile (FG1 and FG2) and a functional group on the nucleophile (FG0).13,14
image file: c7re00142h-s2.tif
Scheme 2 Reactions of functional aryllithiums with compounds bearing two electrophilic functional groups.

An aryllithium bearing an electrophilic functional group was generated by halogen–lithium exchange of the corresponding aryl halide using a flow microreactor system consisting of a T-shaped micromixer (ϕ = 250 μm) (M1), a V-shaped micromixer (ϕ = 250 μm) (M2) and two microtube reactors (R1 and R2) (Fig. 3). The residence time (tR1) for the halogen–lithium exchange reaction was optimized individually (see ESI for the details).


image file: c7re00142h-f3.tif
Fig. 3 A flow microreactor system for the reaction of compounds bearing two different electrophilic functional groups with functional aryllithium generated by halogen–lithium exchange.

As shown in Table 7, the aldehyde carbonyl group reacted selectively without affecting other electrophilic functional groups such as ketone carbonyl, ester carbonyl, nitro, and cyano groups to give desired compounds in good yields, when one equivalent of a functionalized aryllithium was used. Also, the functional groups on the aryllithiums were not affected. It is also noteworthy that aldehyde bearing two other electrophilic functional groups such an ester carbonyl group and a nitro group (a trifunctional electrophile) also reacted chemoselectively. Competition between an isocyanate group and other electrophilic functional groups using functionalized aryllithium is also interesting. As shown in Table 7, the nucleophilic addition took place selectively on the isocyanate group without affecting other functional groups on both the electrophile and the nucleophile. The reactions seem to be useful as they allow amides having two functional groups to be easily synthesized.

Table 7 Reactions of functional aryllithiums with difunctional electrophiles using the flow microreactor system
Functionalized aryl halide Lithiating agent Difunctional electrophile Product Yield (%)
a Diastereomer ratio.
image file: c7re00142h-u23.tif BuLi image file: c7re00142h-u24.tif image file: c7re00142h-u25.tif 78
image file: c7re00142h-u26.tif PhLi   image file: c7re00142h-u27.tif 79
image file: c7re00142h-u28.tif PhLi   image file: c7re00142h-u29.tif 67
image file: c7re00142h-u30.tif BuLi image file: c7re00142h-u31.tif image file: c7re00142h-u32.tif 86
image file: c7re00142h-u33.tif PhLi   image file: c7re00142h-u34.tif 90
image file: c7re00142h-u35.tif PhLi   image file: c7re00142h-u36.tif 78
image file: c7re00142h-u37.tif BuLi image file: c7re00142h-u38.tif image file: c7re00142h-u39.tif 86
image file: c7re00142h-u40.tif PhLi   image file: c7re00142h-u41.tif 69
image file: c7re00142h-u42.tif PhLi image file: c7re00142h-u43.tif image file: c7re00142h-u44.tif 74
image file: c7re00142h-u45.tif BuLi image file: c7re00142h-u46.tif image file: c7re00142h-u47.tif 75
image file: c7re00142h-u48.tif BuLi image file: c7re00142h-u49.tif image file: c7re00142h-u50.tif 79
image file: c7re00142h-u51.tif PhLi   image file: c7re00142h-u52.tif 90
image file: c7re00142h-u53.tif PhLi   image file: c7re00142h-u54.tif 72
image file: c7re00142h-u55.tif BuLi image file: c7re00142h-u56.tif image file: c7re00142h-u57.tif 74
image file: c7re00142h-u58.tif PhLi   image file: c7re00142h-u59.tif 74
image file: c7re00142h-u60.tif PhLi   image file: c7re00142h-u61.tif 71
image file: c7re00142h-u62.tif BuLi image file: c7re00142h-u63.tif image file: c7re00142h-u64.tif 60 (33[thin space (1/6-em)]:[thin space (1/6-em)]67)a
image file: c7re00142h-u65.tif BuLi image file: c7re00142h-u66.tif image file: c7re00142h-u67.tif 64


It is well known that a ketone carbonyl group reacts with organolithiums very rapidly. Therefore, aryllithiums bearing a ketone carbonyl group are very unstable and decompose very rapidly. However, with a flow microreactor system, aryllithiums bearing ketone carbonyl groups can be generated by iodine–lithium exchange reactions of the corresponding aryl iodides with mesityllithium and can be reacted with subsequently added electrophiles. Therefore, we examined the reactions of aryllithiums bearing a ketone carbonyl group with aromatic compounds having different electrophilic functional groups. A flow microreactor system consisting of three micromixers (M1, M2, and M3) and three microtube reactors (R1, R2, and R3) (Fig. 4) was used. A solution of mesityl bromide (0.090 M in THF, 5.0 mL min−1) and a solution of n-BuLi (0.22 M in hexane, 1.8 mL min−1) were introduced to M1, and the mixture was passed through R1 (ϕ = 1000 μm, L = 410 cm (200 cm at 0 °C, 10 cm at ambient temperature and 200 cm at −70 °C)). The resulting solution of mesityllithium was mixed with a solution of aryl iodide (0.10 M in THF, 3.0 mL min−1) in M2 (−70 °C), and the mixture was passed through R2 (ϕ = 250 μm, L = 1.0 cm, −70 °C). The resulting solution of an aryllithiums bearing a ketone carbonyl group was mixed with a solution of a compound bearing two different electrophilic functional groups (0.10 M in THF, 4.2 mL min−1) in M3 (−70 °C), and the mixture was passed through R3 (ϕ = 1000 μm, L = 200 cm, −70 °C).


image file: c7re00142h-f4.tif
Fig. 4 A flow microreactor system for the reaction of aryllithium bearing a ketone carbonyl group generated by iodine–lithium exchange with aromatic compounds having different electrophilic functional groups.

As shown in Table 8, benzaldehyde and isocyanate bearing another electrophilic functional group such as a ketone carbonyl group, an ester carbonyl group and a cyano group reacted chemoselectively without decomposition of aryllithium bearing a ketone carbonyl group.

Table 8 Reactions of compounds having different electrophilic functional groups with aryllithium bearing a ketone carbonyl group using the flow microreactor
Aryl halide having ketone carbonyl group Difunctional electrophile Product Yield (%)
image file: c7re00142h-u68.tif image file: c7re00142h-u69.tif image file: c7re00142h-u70.tif 65
image file: c7re00142h-u71.tif image file: c7re00142h-u72.tif image file: c7re00142h-u73.tif 30
image file: c7re00142h-u74.tif image file: c7re00142h-u75.tif image file: c7re00142h-u76.tif 73
image file: c7re00142h-u77.tif image file: c7re00142h-u78.tif image file: c7re00142h-u79.tif 51
image file: c7re00142h-u80.tif image file: c7re00142h-u81.tif image file: c7re00142h-u82.tif 52


Chemoselective three-component coupling using an integrated flow microreactor system

Integration of chemical reactions enhances the power and speed of organic synthesis, and recently it has been recognized that space-integration15 of reactions using flow microreactors is quite effective. Thus, we examined chemoselective three-component coupling using benzaldehyde having a ketone carbonyl group (7) in an integrated flow microreactor system consisting of four micromixers (M1, M2, M3, and M4) and three microtube reactors (R1, R2, R3, and R4) (Fig. 5). A solution of 4-bromobenzonitrile (0.10 M in THF, 5.8 mL min−1) and a solution of n-BuLi (0.42 M in hexane, 1.5 mL min−1) were introduced to M1, and the mixture was passed through R1. The resulting solution was mixed with a solution of 4-benzoylbenzaldehyde (0.10 M in THF, 5.8 mL min−1) in M2 and passed through R2. A solution of 1-iodo-4-nitrobenzene (0.10 M in THF, 6.4 mL min−1) and a solution of PhLi (0.42 M in Et2O/cyclohexane (74/26 v/v), 1.6 mL min−1) were introduced to M3 by syringe pumps and the mixture was passed through R3. Then, the two solutions produced in R2 and R3 were mixed in M4 and passed through R4. The reaction with p-cyanophenyllithium at the aldehyde carbonyl group followed by the reaction with p-nitrophenyllithium at the ketone carbonyl group was successfully achieved to obtain the desired product in 61% isolated yield. High productivity (156 mg min−1) of the present method, because of high flow rates and short residence times, is also noteworthy.
image file: c7re00142h-f5.tif
Fig. 5 Chemoselective three-component coupling using an integrated flow microreactor system.

Conclusions

In conclusion, we found that extremely fast micromixing enables highly chemoselective reactions of unstable functional aryllithiums with difunctional electrophiles. The present approach based on flash chemistry serves as a powerful method for protecting-group-free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was partially supported by the Grant-in-Aid for Scientific Research (B) (no. 26288049), Scientific Research on Innovative Areas 2707 Middle molecular strategy from MEXT (no. 15H05849), Scientific Research (S) (no. 26220804), Scientific Research (S) (no. 25220913), the Asahi Glass Foundation, and Ogasawara Foundation for the promotion of science and engineering.

Notes and references

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/c7re00142h

This journal is © The Royal Society of Chemistry 2017