Micromixing enables chemoselective reactions of difunctional electrophiles with functional aryllithiums

Abstract

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.

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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 microreactors^5–7 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.

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.

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

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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 : 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.

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

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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)

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

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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

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

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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

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

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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
	Batch macro	—	28	25
	Flow micro	2.5	15	38
	Flow micro	10	60	20
	Flow micro	30	73	7
	Batch macro	—	29	26
	Flow micro	2.5	13	35
	Flow micro	10	55	14
	Flow micro	30	71	7
	Batch macro	—	56	5
	Flow micro	2.5	56	13
	Flow micro	10	83	0
	Flow micro	30	84	0
	Batch macro	—	36
	Flow micro	2.5	29
	Flow micro	10	72
	Flow micro	30	76
	Batch macro	—	65
	Flow micro	2.5	54
	Flow micro	10	88
	Flow micro	30	89
	Batch macro	—	5	1
	Flow micro	2.5	43	0
	Flow micro	10	73	0
	Flow micro	30	82	0
	Batch macro	—	18	4
	Flow micro	2.5	25	8
	Flow micro	10	81	2
	Flow micro	30	91	1

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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

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 (t^R1) for the halogen–lithium exchange reaction was optimized individually (see ESI† for the details).

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.
	BuLi			78
	PhLi			79
	PhLi			67
	BuLi			86
	PhLi			90
	PhLi			78
	BuLi			86
	PhLi			69
	PhLi			74
	BuLi			75
	BuLi			79
	PhLi			90
	PhLi			72
	BuLi			74
	PhLi			74
	PhLi			71
	BuLi			60 (33 : 67)^a
	BuLi			64

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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).

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 (%)
			65
			30
			73
			51
			52

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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.

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

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