Full Text

Turn on search term navigation

ARTICLE

Received 5 Jan 2011 | Accepted 2 Mar 2011 | Published 5 Apr 2011 DOI: 10.1038/ncomms1264

Protecting-group-free synthesis has received signicant recent research interest in the context of ideal synthesis and green sustainable chemistry. In general, organolithium species react with ketones very rapidly, and therefore ketone carbonyl groups should be protected before an organolithium reaction, if they are not involved in the desired transformation. If organolithium chemistry could be free from such a limitation, its power would be greatly enhanced. Here we show that a ow microreactor enables such protecting-group-free organolithium reactions by greatly reducing the residence time (0.003 s or less). Aryllithium species bearing ketone carbonyl groups are generated by iodinelithium exchange reactions of the corresponding aryl iodides with mesityllithium and are reacted with various electrophiles using a ow-microreactor system. The present method has been successfully applied to the formal synthesis of Pauciorol F.

A ow-microreactor approach to protecting-group-free synthesis using organolithium compounds

Heejin Kim1, Aiichiro Nagaki1 & Jun-ichi Yoshida1

1 Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan. Correspondence and requests for materials should be addressed to J.-i.Y. (email: [email protected]).

NATURE COMMUNICATIONS | 2:264 | DOI: 10.1038/ncomms1264 | www.nature.com/naturecommunications

ARTICLE

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1264

Continuous-ow microreactors based on microuidics13 have been recognized as powerful tools for chemical synthesis, and studies on their characteristic features have uncovered

a rich variety of synthetic applications in recent years425. Flow-

microreactor synthesis has also received much attention from the viewpoint of synthesis based on reaction integration2630 and green

sustainable synthesis31. Such successful applications speak well for the power of the ow-microreactor method in chemical synthesis. It is important to note that the reaction time in a ow microreactor is dened as the residence time between a reagent inlet and the quencher inlet, which can be controlled precisely and reduced to millisecond order by adjusting the length between these positions and the ow speed. On the basis of such a feature of ow microreactors, we have recently proposed the concept of ash chemistry3235,

which enables the use of short-lived highly reactive intermediates for synthesis. Such intermediates can be rapidly generated and transferred to another location in the ow system for use in subsequent reactions before they decompose. It is also noteworthy that the total production capacity over time of continuous-ow microre-actors is much greater than may be imagined, although the reactors capacity at any one time is small. Therefore, ow-microreactor synthesis can be used not only for laboratory-scale synthesis but also for the production of chemical substances on an industrial scale. In fact, there are ow microreactors that t in the palm of the hand and can produce several tons of products per year36,37. Armed with

an understanding of the essential principles, chemists are now in a position to enhance the capability of ow microreactions and to develop new synthetic transformations that are difficult to achieve by conventional batch reactions.

Organolithium species38,39 serve as powerful reagents in organic

synthesis. However, they are not compatible with electrophilic functional groups such as ketone carbonyl groups. In fact, organolithium species react with ketones very rapidly. In some cases, organolithium species can be generated in the presence of ketones and quenched insitu by the ketone carbonyl group40. However, if a ketone carbonyl group is not involved in the desired transformation, it should be protected before an organolithium reaction, although ketone carbonyl groups survive in reactions of some less reactive organometallics4143. Therefore, if organolithium reactions can be conducted without protecting the ketone carbonyl groups, the power of organolithium chemistry will be greatly enhanced.

Here we show that a ow microreactor enables protecting-group-free organolithium reactions by greatly reducing the residence time (0.003 s or less); aryllithium species bearing ketone carbonyl groups are generated by iodinelithium exchange reactions of the corresponding aryl iodides with mesityllithium and are reacted with

various electrophiles using a ow-microreactor system by greatly reducing the residence time (0.003 s or less). We also show that the present method has been successfully applied to the formal synthesis of Pauciorol F.

ResultsGeneration and reactions of acyl-substituted aryllithiums. We began our investigation by conducting the iodinelithium exchange reaction of o- and p-acyliodobenzenes followed by trapping with methanol using the ow-microreactor system, as shown in Figure 1 (see also Supplementary Fig. S1). Mesityllithium was rst generated by a brominelithium exchange reaction of 2-bromo-1,3,5-trimethylbenzene (mesityl bromide) and n-butyllithium at 0 C,

MesLi MeOH

n-Bu

1 2 3

i-Pr

n-Bu

b c

100

90 80 70 60 50 40 30 20 10

100

90 80 70 60

Yield (%)

50 40 30 20 10

0 0 0.5 1

Residence time in R2 (s) Residence time in R2 (s)

1.5 2 2.5 3 0 0.005 0.01 0.015

Figure 2 | The effect of residence time in R2 for the reaction of o-pentanoyliodobenzene (1). (a) Reaction of 1 with MesLi to yield o-pentanoyl-substituted phenyllithium (2) followed by trapping with MeOH to produce protonated product 3. Undesired dimerization of 2 gave by-product 4. (b) Plots of the yield of 3 and 4 against the residence time in R2 ( < 3 s). (c) Plots of the yield of 3 and 4 against the residence time in R2 ( < 0.015 s).

a b

MesBr

E: electrophile

n-BuLi

0 C

70 C

Figure 1 | A ow-microreactor system. (a) A schematic diagram of the system. 2-Bromo-1,3,5-trimethylbenzene (mesityl bromide, MesBr) was reacted with n-butyllithium using T-shaped micromixer M1 and microtube reactor R1 at 0 C. The resulting mesityllithium solution was reacted with an acyliodobenzene in T-shaped micromixer M2 and microtube reactor R2 at 70 C. The resulting short-lived acylphenyllithium species was trapped with an electrophile using T-shaped micromixer M3 and microtube reactor R3 at 70 C. (b) An integrated device in which M2 (inner diameter: 250 m),

R2 (inner diameter: 250 m, length: 1.0 cm) and M3 (inner diameter: 250 m) are combined.

NATURE COMMUNICATIONS | 2:264 | DOI: 10.1038/ncomms1264 | www.nature.com/naturecommunications

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1264

ARTICLE

Table 1 | Generation of acyl-substituted aryllithiums and reactions with electrophiles in a ow-microreactor system.

Entry Substrate Electrophile Product Yield* Entry Substrate Electrophile Product Yield*

n-Bu

t-Bu

n-Bu

MeOH

90 (91) 13

t-Bu

PhNCO

H N

2 Me3SiOTf

n-Bu

SiMe3

86 (91) 14

MeOH

SnBu3

3 Bu3SnCl

n-Bu

86 15 PhCHO

73 (75)

CO2Me

4 MeO2CCl

n-Bu

68 (70) 16 PhCOMe

Ph Me 25

n-Pr

Ph Me

5 PhCOMe O

81 17 Ph

PhNCO

H N

6 PhCOCy O

n-Pr

Ph Cy12

n-Bu

81 18 n-Bu

MeOH

H 67

HO n-Bu

7 PhCHO

60 19 PhNCO

n-Bu

H N

MeOH

83 20

MeOH

54 (76)

9 Me3SiOTf

SiMe3

81 (84) 21 PhCHO

10 MeO2CCl Et

CO2Me

65 (69) 22

n-Bu

MeOH

n-Bu

MeOH

77 23 PhCHO

S HO

H N

12 MeOTf

42 24 PhNCO

n-Bu

THF, tetrahydrofuran.

Reaction conditions: acyliodobenzene (0.20 M in THF), MesLi (1.3 equivalent in THF/hexane, generated in situ), electrophile (2.0 equivalent in THF or Et O), residence time in R =0.003 s. *Isolated yields unless otherwise stated.GC (gas chromatography) yields obtained using an internal standard. Residence time in R =0.0015 s.

NATURE COMMUNICATIONS | 2:264 | DOI: 10.1038/ncomms1264 | www.nature.com/naturecommunications

ARTICLE

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1264

because preliminary studies showed that mesityllithium was the most eective compound for this purpose. The iodinelithium exchange reaction of an acyliodobenzene using the resulting mesityllithium was conducted at 70 C. The short-lived acylphenyllithium species thus produced was trapped with methanol as an electrophile at 70 C (Fig. 1a).

We focused on the generation of o-pentanoyl-substituted phenyllithium (2) generated from o-pentanoyliodobenzene (1). Methanol was used as a quenching electrophile (Fig. 2a). The reactions were carried out with variation in the residence time in R2, and the yield of the protonated product 3 was determined by gas chromatography (GC). The yield of 3 increased with a decrease in the residence time (Fig. 2b, see also Supplementary Table S1). However, acceptable yields were not obtained even at the minimum limit of the residence time of our current system (0.01 s), although this residence time was successful for the generation of alkoxycarbonyl-44, nitro-45 and cyano-substituted46 aryllithiums. Aryllithium 2 bearing a ketone carbonyl group decomposed very rapidly, the major by-product being dimeric compound 4.

To avoid the decomposition of 2, we developed a new integrated device in which two T-shaped micromixers and one microreactor are combined (Fig. 1b). Although the Reynolds number is ~102,

extremely fast mixing takes place at the T-shaped mixers, presumably because of engulfment ow47. Using this device, the residence time could be reduced to 0.003 s, giving rise to a dramatic increase in the yield of product 3 (Fig. 2c). The result clearly indicates that a ketone carbonyl group could survive a residence time of a few milliseconds.

At a residence time of 0.003 s, generation of various o-acyl-substituted aryllithium species followed by reactions with various electrophiles including Me3SiOTf, Bu3SnCl and ClCO2Me were successfully conducted, and the corresponding products bearing unchanged ketone carbonyl groups were obtained in good yields and productivity (0.250.54 mmol min 1; Table 1, entries 112). It is interesting that some ketones could be used as electrophiles, although they should be more reactive than the carbonyl group of the acylphenyllithium species (entries 5 and 6).

The generation and reaction of p-acyl-substituted phenyllithiums led to slightly lower yields of the products (entries 1321) compared with the corresponding o-acyl-substituted phenyllithiums, presumably because of the lack of coordination of the carbonyl group to lithium. In particular, in the case of p-acetylphenyllithium (6) generated from p-acetyliodobenzene (5), the protonated product 7 was obtained only in moderate yield (54%, entry 20). This problem could be solved by further reducing the residence time in R2, which was achieved by increasing the ow rate using a high-pressure syringe pump. As shown in Figure 3, the yield of 7 increased with a decrease in the residence time, and an acceptable yield (76%) was obtained at a residence time of 0.0015 s (see also Supplementary Table S2). This residence time also allowed efficient reaction with PhCHO to produce the corresponding product in 78% yield (entry 21). Heteroaromatic iodides such as 1-(5-iodothiophen-2-yl)pentan-1-one 31 could also be lithiated and the resulting organolithium compounds were eectively trapped with electrophiles without aecting the ketone carbonyl group (entries 2224).

Application to formal synthesis of Pauciorol F. Using the present method, Pauciorol F48, a natural product isolated from stem bark, which has recently been synthesized by Snyders group49,50 and Sar-

pongs group51, was synthesized. The starting material 35 was prepared from commercially available 3,5-dimethoxyphenylmagnesium chloride in two steps (67% yield; Fig. 4). The iodinelithium exchange reaction of 35 followed by reaction with 3,5-dimethoxybenzaldehyde was conducted using a ow-microreactor system consisting of the integrated device (residence time in R2: 0.003 s) to produce 36 (ref. 49) in 81% isolated yield. Presumably, dehydration

took place upon acidic work-up. Treatment of 36 with HCl/i-PrOH in the presence of O2 in a batch reactor gave 37 in 75% yield, which can be converted to Pauciorol F by one-pot hydrogenation and epimerization (87%)51 followed by deprotection (86%)49,50.

Discussion

Recently, the construction of complicated organic molecules without using protecting groups (protecting-group-free synthesis)52,53,

especially from the viewpoints of atom economy54, step economy55 and redox economy56, has received signicant research interest in the context of ideal synthesis57 and green sustainable chemistry58. Generally, skeleton-building steps are the most difficult with respect to avoiding usage of protecting groups because such steps oen use strongly basic nucleophilic reagents. Among such reagents, organolithium reagents are the most reactive. However, a major drawback of organolithium species is that they are too reactive and rapidly react with electrophilic functional groups such as ketone carbonyl groups, which are oen present in the desired target organic structures. Therefore, organic textbooks say that a ketone carbonyl group should be protected before an organolithium reaction if it is not involved in the desired transformation. However, we have demonstrated here that aryl- and heteroaryllithium species bearing ketone carbonyl groups can be generated and used for desired reactions by greatly reducing the residence time in a ow microreactor to a few milliseconds. Within such an extremely short residence time, the organolithium intermediates can survive and be used for reactions with various external electrophiles without aecting the ketone carbonyl group in the same molecule.

The formal synthesis of Pauciorol F achieved in this study (Fig. 4) demonstrates the potential of the present ow-microreactor approach. Although the synthesis by Snyders group based on a biomimetic strategy and the synthesis by Sarpongs group based on a Larock annulations strategy are elegant and concise, our synthesis is comparable from the viewpoints of atom economy and step economy. Because the productivity of the present method is relatively high (1.06 g for 5 min operation), it is hoped that the ow-microre-actor method will provide a green and sustainable way of producing useful compounds such as Pauciorol F in the pharmaceutical and ne chemicals industries in the future.

The present approach based on control of the residence time in a ow microreactor serves as a powerful method for protecting-group-free synthesis using organolithium reagents, which

MesLi MeOH

5 6 7

Yield (%)

0 0 0.002 0.004

Residence time in R2 (s)

0.006 0.008 0.01

Figure 3 | The effect of residence time in R2 for the reaction of p-acetyliodobenzene (5). (a) Reaction of 5 with MesLi to yield p-acetylphenyllithium (6) followed by trapping with MeOH to produce protonated product 7. (b) Dependence of the yield of 7 on the residence time in R2 ( < 0.01 s).

NATURE COMMUNICATIONS | 2:264 | DOI: 10.1038/ncomms1264 | www.nature.com/naturecommunications

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1264

ARTICLE

O OMe

OMe

MeO

MgCl Cl

MeO

CuCN

I2, PhI(AcO)2

35 67%

OMe

Flow microreactor

MeO

1. MesLi

OMe

MeO

3. H+

OMe

36 81%

MeO

OMe

Conc. HCl

OMe

2 Steps

OMe

MeO

37 75%

Pauciflorol F

Figure 4 | Formal total synthesis of Pauciorol F. The ow-microreactor reaction of iodoketone 35 gave compound 36 (81% yield, 1.06 g for 5 min operation), which can be converted to Pauciorol F according to the literature procedure.

is complementary to other approaches using less reactive and more chemoselective reagents. Although the ow-microreactor approach is still in its infancy, it is clearly capable, powerful and useful from both scientic and practical viewpoints. Currently, work to expand further the capability of ow-microreactor synthesis is in progress.

Methods

General procedure. A ow-microreactor system consisting of three T-shaped micromixers (M1, M2 and M3) and three microtube reactors (R1, R2 and R3) was used. A solution of mesityl bromide in tetrahydrofuran (THF; 0.18 M, ow rate: 5.0 ml min 1) and a solution of n-BuLi in hexane (0.43 M, ow rate: 1.8 ml min 1) were introduced to M1 (inner diameter: 250 m). The resulting solution was passed through R1 and was mixed with a solution of acyliodobenzene in THF (0.20 M, ow rate: 3.0 ml min 1) in M2 (inner diameter: 250 m). The resulting solutionwas passed through R2 and then mixed with a solution of an electrophile (0.60 M, ow rate: 2.0 ml min 1) in M3 (inner diameter: 250 m). The resulting solution was passed through R3. Aer a steady state was reached, the product solution was collected for 30 s while being quenched with aqueous sat. NH4Cl solution (2 ml). The aqueous layer was extracted three times with ether (25 ml). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was puried by chromatography. Details of the synthesis, purication and characterization are given in Supplementary Figures S2S25.

Formal total synthesis of Pauciorol F. In all, 1 M CuCN2LiCl THF solution (44 ml, 44.0 mmol) was added dropwise to a solution of 3,5-dimethoxyphenylmagnesium chloride (0.5 M in THF, 80 ml, 40.0 mmol) at 25 C for 10 min. Aer being stirred for 40 min at 20 C, 4-methoxyphenylacetyl chloride (9.793 g, 53.0 mmol) was added dropwise for 5 min. The solution was slowly warmed to 10 C for 1 h, and the reaction was quenched by slow addition of sat. NH4Cl solution (120 ml). The organic layer was separated and the aqueous layer was extracted with Et2O (150 ml3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was puried by column chromatography (CHCl3) and washed with cold hexane to obtain 1-(3,5-dimethoxyphenyl)-2-

(4-methoxyphenyl)ethanone in 91% yield (Supplementary Fig. S26).

Iodobenzene diacetate (242.0 mg, 0.75 mmol) was added to a solution of 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone (146.8 mg, 0.51 mmol) and iodine (70.9 mg, 0.28 mmol) in CH2Cl2 (4 ml) at 0 C. Aer being stirred at0 C for 10 h, the solution was slowly warmed to ambient temperature. Aer being stirred for 14 h, the reaction was quenched by addition of half-saturated Na2S2O3

solution (10 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (25 ml3). The combined organic layers were dried over

Na2SO4 and concentrated. The crude product was puried by column chroma-

tography (hexane/AcOEt = 4:1) to obtain 1-(2-iodo-3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone (35) in 74% yield (Supplementary Fig. S27).

The ow-microreactor system shown in Figure 1a containing the integrated device (Fig. 1b) was used. A solution of 2-bromomesitylene (0.18 M in THF, 5.0 ml min1) and a solution of n-BuLi (0.43 M in hexane, 1.8 ml min1) were introduced to M1 (inner diameter: 250 m) by syringe pumps. The resulting solution was passed through R1 (inner diameter: 1,000 m, length: 210 cm (100 cm at0 C, 10 cm at ambient temperature and 100 cm at 70 C)) and was subsequently mixed with a solution of acyliodobenzene 35 (0.20 M in THF, 3.0 ml min1) at M2 (inner diameter: 250 m). The resulting solution was passed through R2 (inner diameter: 250 m, length: 1.0 cm) and 3,5-dimethoxybenzaldehyde (0.60 M in THF, 2.0 ml min1) was added at M3 (inner diameter: 250 m). The resulting solution was passed through R3 (inner diameter: 1,000 m, length: 50 cm). Aer a steady state was reached, the product solution was collected for 5 min while being quenched with H2O (20 ml). Aer 1 M HCl solution (80 ml) was added, the organic layer was separated and the remaining aqueous layer was extracted with Et2O (100 ml3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was puried by column chromatography (hexane/AcOEt = 2:1) to obtain 3-(3,5-dimethoxyphenyl)-4,6-dimethoxy-1-(4-methoxybenzylidene)-1,3-dihydroisobenzofuran (36) in 81% yield (1.058 g; Supplementary Fig. S28).

Aqueous conc. HCl solution (4 ml) was added dropwise for 30 min to a solution of 36 (44.0 mg, 0.101 mmol) in i-PrOH (20 ml) at 25 C. Aer being stirred for12 h under an oxygen atmosphere, the reaction was quenched by slow additionof aqueous sat. NaHCO3 solution (60 ml) and water (40 ml) at 0 C. The organic layers were extracted with AcOEt (40 ml3) and washed with brine (40 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was puried by column chromatography (hexane/AcOEt = 3:1) to obtain 3-(3,5-dimethoxyphenyl)-4,6-dimethoxy-2-(4-methoxyphenyl)-1H-inden-1-one (37) in 75% yield (Supplementary Fig. S29), which can be converted to Pauciorol F by one-pot hydrogenation and epimerization followed by deprotonation.

References

1. Whitesides, G. The origins and the future of microuidics. Nature 442, 368373 (2006).

2. deMello, A. J. Control and detection of chemical reactions in microuidic systems. Nature 442, 394402 (2006).

3. Song, H., Chen, D. L. & Ismagilov, R. F. Reactions in droplets in microuidic channels. Angew.Chem.Int.Ed. 45, 73367356 (2006).

4. Ley, S. V. The changing face of organic synthesis. Tetrahedron 66, 62706292 (2010).

5. Marrea, S. & Jensen, K. F. Synthesis of micro and nanostructures in microuidic systems. Chem.Soc.Rev. 39, 11831202 (2010).

6. Frost, C. G. & Mutton, L. Heterogeneous catalytic synthesis using microreactor technology. GreenChem. 12, 16871703 (2010).

NATURE COMMUNICATIONS | 2:264 | DOI: 10.1038/ncomms1264 | www.nature.com/naturecommunications

ARTICLE

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1264

7. Hessel, V., Renken, A., Schouten, J. C. & Yoshida, J. MicroProcessEngineering: AComrehensiveHandbook Vol. 13 (Wiley-VCH, 2009).

8. Lin, W., Wang, Y., Wang, S. & Tseng, H. Integrated microuidic reactors. NanoToday 4, 470481 (2009).

9. Geyer, K., Gustafsson, T. & Seeberger, P. H. Developing continuous-ow microreactors as tools for synthetic chemists. Synlett 23822391 (2009).10. Hartman, R. L. & Jensen, K. F. Microchemical systems for continuous-ow synthesis. LabChip 9, 24952507 (2009).

11. Ziogas, A. etal. Electrochemical microstructured reactors: design and application in organic synthesis. J.Appl.Electrochem. 39, 22972313 (2009).

12. Fukuyama, T., Rahman, Md.T., Sato, M. & Ryu, I. Adventures in inner space: microow systems for practical organic. Synlett 151163 (2008).

13. Kockmann, N., Gottsponer, M., Zimmermann, B. & Roberge, D. M. Enabling continuous-ow chemistry in microstructured devices for pharmaceutical and ne-chemical production. Chem.Eur.J. 14, 74707477 (2008).

14. Bentio-Lpez, F., Egberink, R. J. M., Reinhoudt, D. N. & Verboom, W. High pressure in organic chemistry on the way to miniaturization. Tetrahedron 64, 1002310040 (2008).

15. Wilms, D., Klos, J. & Frey, H. Microstructured reactors for polymer synthesis: a renaissance of continuous ow processes for tailor-made macromolecules? Macromol.Chem.Phys. 209, 343356 (2008).

16. Ahmed-Omer, B., Brandt, J. C. & Wirth, T. Advanced organic synthesis using microreactor technology. Org.Biomol.Chem. 5, 733740 (2007).

17. Watts, P. & Wiles, C. Recent advances in synthetic micro reaction technology. Chem.Commun. 443467 (2007).

18. Kobayashi, J., Mori, Y. & Kobayashi, S. Multiphase organic synthesis in microchannel reactors. Chem.AsianJ. 1, 2235 (2006).

19. Geyer, K., Code, J. D. C. & Seeberger, P. H. Microreactors as tools for synthetic chemiststhe chemists round-bottomed ask of the 21st century? Chem.Eur.J. 12, 84348442 (2006).

20. Doku, G. N., Verboom, W., Reinhoudt, D. N. & van den Berg, A. On-microchip ultiphase chemistrya review of microreactor design principles and reagent contacting modes. Tetrahedron 61, 27332742 (2005).

21. Watts, P. & Haswell, S. J. The application of micro reactors for organic synthesis. Chem.Soc.Rev. 34, 235246 (2005).

22. Kiwi-Minsker, L. & Renken, A. Microstructured reactors for catalytic reactions. CatalysisToday 110, 214 (2005).

23. Kikutani, Y. & Kitamori, T. Micro-ow reaction systems for combinatorial syntheses. Macromol.RapidCommun. 25, 158168 (2004).

24. Jhnisch, K., Hessel, V., Lwe, H. & Baerns, M. Chemistry in microstructured reactors. Angew.Chem.Int.Ed. 43, 406446 (2004).

25. Schwalbe, T., Autze, V., Hohmann, M. & Stirner, W. Novel innovation systems for a cellular approach to continuous process chemistry from discovery to market. Org.ProcessRes.Dev. 8, 440454 (2004).

26. Suga, S., Yamada, D. & Yoshida, J. Cationic three-component coupling involving an optically active enamine derivative from time integration to space integration of reactions. Chem.Lett. 39, 404406 (2010).

27. Webb, D. & Jamison, T. F. Continuous ow multi-step organic synthesis. Chem.Sci. 1, 675680 (2010).

28. Sahoo, H. R., Kralj, J. G. & Jensen, K. F. Multistep continuous-ow microchemical synthesis involving multiple reactions and separations. Angew.Chem.Int.Ed. 46, 57045708 (2007).

29. Kirschning, A., Solodenko, W. & Mennecke, K. Combining enabling techniques in organic synthesis: continuous ow processes with heterogenized catalysts. Chem.Eur.J. 12, 59725990 (2006).

30. Lee, C.- C. etal. Multistep synthesis of a radiolabeled imaging probe using integrated microuidics. Science 310, 17931796 (2005).

31. Mason, B. P., Prince, K. E., Steinbacher, J. L., Bogdan, A. R. & McQuade, D. T. Greener approaches to organic synthesis using microreactor technology. Chem. Rev. 107, 23002318 (2007).

32. Yoshida, J. Flash chemistry: ow microreactor synthesis based on high-resolution reaction time control. Chem.Record 10, 332341 (2010).

33. Yoshida, J. FlashChemistryFastOrganicSynthesisinMicrosystems (Wiley, 2008).

34. Yoshida, J., Nagaki, A. & Yamada, T. Flash chemistry: fast chemical synthesis by using microreactors. Chem.Eur.J. 14, 74507459 (2008).

35. Yoshida, J. Flash chemistry using electrochemical method and microsystems. Chem.Commun. 45094516 (2005).

36. Wakami, H. & Yoshida, J. Grignard exchange reaction using a microow system: from bench to pilot plan. Org.ProcessRes.Dev. 9, 787791 (2005).

37. Roberge, D. M., Zimmermann, B., Rainone, F., Gottsponer, M., Eyholzer, M. & Kochmann, N. Microreactor technology and continuous processes in the ne chemical and pharmaceutical industry: is the revoluiton underway? Org.ProcessRes.Dev. 12, 905910 (2008).

38. Schlosser, M. The organometallic approach to molecular diversityhalogens as helpers. Eur.J.Org.Chem. 21, 39753984 (2001).

39. Whisler, M. C., MacNeil, S., Snieckus, V. & Beak, P. Beyond thermodynamic acidity: a perspective on the complex-induced proximity eect (CIPE) in deprotonation reactions. Angew.Chem.Int.Ed. 43, 22062225 (2004).

40. Rutherford, J. L., Ferry, G., Hawkins, J. M. & Lyme, O. Preparation of novel substituted haloarene compounds US 7,273,938 B2 (2007).

41. Yang, X. & Knochel, P. Selective functionalization of imidazoles via an iodinecopper exchange reaction. Chem.Commun. 21702172 (2006).

42. Yang, X., Rotter, T., Piazza, C. & Knochel, P. Successive iodine-magnesium or -copper exchange reactions for the selective functionalization of polyhalogenated aromatics. Org.Lett. 5, 12291231 (2003).

43. Kneisel, F. F. & Knochel, P. Synthesis and reactivity of aryl- and heteroaryl-magnesium reagents bearing keto groups. Synlett 17991802 (2002).

44. Nagaki, A., Kim, H. & Yoshida, J. Aryllithium compounds bearing alkoxycarbonyl groups: generation and reactions using a microow system. Angew.Chem.Int.Ed. 47, 78337836 (2008).

45. Nagaki, A., Kim, H. & Yoshida, J. Nitro-substituted aryl lithium compounds in microreactor synthesis: switch between kinetic and thermodynamic control. Angew.Chem.Int.Ed. 48, 80638065 (2009).

46. Nagaki, A., Kim, H., Usutani, H., Matsuo, C. & Yoshida, J. Generation and reaction of cyano-substituted aryllithium compounds using microreactors. Org.Biomol.Chem. 8, 12121217 (2010).

47. Soleymani, A., Youse, H. & Turunen, I. Dimensionless number for identication of ow patterns inside a T-micromixer. Chem.Eng.Sci. 63, 52915297 (2008).

48. Ito, T. etal. Three new resveratrol oligomers from the stem bark of Vatica pauciora. J.Nat.Prod. 67, 932937 (2004).

49. Snyder, S. A., Breazzano, S. P., Ross, A. G., Lin, Y. & Zografos, A. L. Total synthesis of diverse carbogenic complexity within the resveratrol class from a common building block. J.Am.Chem.Soc. 131, 17531765 (2009).

50. Snyder, S. A., Zografox, A. L. & Lin, Y. Total synthesis of resveratrol-based natural products: a chemoselective solution. Angew.Chem.Int.Ed. 46, 81868191 (2007).

51. Jerey, J. L. & Sarpong, R. Concise synthesis of Pauciorol F using a Larock annulation. Org.Lett. 11, 54505453 (2009).

52. Young, I. S. & Baran, P. S. Protecting-group-free synthesis as an opportunity for invention. Nat.Chem. 1, 193204 (2009).

53. Homann, R. W. Protecting-group-free synthesis. Synthesis 35313541 (2006).54. Trost, B. M. The atom economya search for synthetic efficiency. Science 254, 14711477 (1991).

55. Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Acc.Chem.Res. 41, 4049 (2008).

56. Burns, N. Z., Baran, P. S. & Homann, R. W. Redox economy in organic synthesis. Angew.Chem.Int.Ed. 48, 28542867 (2009).

57. Hendrickson, J. B. Systematic synthesis design. IV. Numerical codication of construction reactions. J.Am.Chem.Soc. 97, 57845800 (1975).

58. Poliako, M., Fitzpatrick, J. K., Farren, T. R. & Anastas, P. T. Green chemistry: science and politics of change. Science 297, 807809 (2002).

Acknowledgments

We thank the Grant-in-Aid for Scientic Research on Innovative Areas 2105 Organic Synthesis Based on Reaction Integration Development of New Methods and Creation of New Substances from the Ministry of Education, Culture, Sports, Science & Technology, Japan for nancial support. H.K. acknowledges JSPS for nancial support.

Author contributions

H.K. assisted in conducting and analysing the chemical experiments. A.N. conceived and designed the experiments. J.-i.Y. designed, directed the project and wrote the manuscript with contributions from H.K. and A.N. All authors contributed to discussions.

Additional information

Supplementary Information accompanies this paper at http://www.nature.com/ naturecommunications

Competing nancial interests: The authors declare no competing nancial interests.

Reprints and permission information is available online at http://npg.nature.com/ reprintsandpermissions/

How to cite this article: Yoshida, J.-i. etal. A ow-microreactor approach to protecting-group-free synthesis using organolithium compounds. Nat.Commun. 2:264 doi: 10.1038/ncomms1264 (2011).

NATURE COMMUNICATIONS | 2:264 | DOI: 10.1038/ncomms1264 | www.nature.com/naturecommunications

Word count: 4771

Show less

Abstract

Translate

Protecting-group-free synthesis has received significant recent research interest in the context of ideal synthesis and green sustainable chemistry. In general, organolithium species react with ketones very rapidly, and therefore ketone carbonyl groups should be protected before an organolithium reaction, if they are not involved in the desired transformation. If organolithium chemistry could be free from such a limitation, its power would be greatly enhanced. Here we show that a flow microreactor enables such protecting-group-free organolithium reactions by greatly reducing the residence time (0.003 s or less). Aryllithium species bearing ketone carbonyl groups are generated by iodine-lithium exchange reactions of the corresponding aryl iodides with mesityllithium and are reacted with various electrophiles using a flow-microreactor system. The present method has been successfully applied to the formal synthesis of Pauciflorol F.

Details

Title

A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds

Author

Kim, Heejin; Nagaki, Aiichiro; Yoshida, Jun-ichi

Pages

264

Publication year

2011

Publication date

Apr 2011

Publisher

Nature Publishing Group

e-ISSN

20411723

Source type

Scholarly Journal

Language of publication

English

DOI

https://doi.org/10.1038/ncomms1264

ProQuest document ID

925973543

A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds

Jump to:

Full Text

Abstract

Details

Suggested sources