Flow Chemistry~‘‘micro’’ flow to ‘‘fine’’ flow~

2018/9/22 (Sat.)
Literature Seminar

Taiki Fujita (M2)Introduction of Flow
Batch vs Flow
Batch reaction

Laboratory scale
Fine chemicals

Flow reaction

Large scale industry production

In flow reaction, introduction, reaction and recovery are conducted continuously.

Nagaki A. J. Synth. Org. Chem. 2015, 73, 423. 2

Introduction of Flow
Batch vs Flow
Batch reaction

Flow reaction

The merit of flow method
Saving space, time and cost.
Safe reaction
Unique reactivity …
Nagaki A. J. Synth. Org. Chem. 2015, 73, 423. 3

Character of Flow Reactor
Time is controlled by space

reaction time ≡ residence time

Nagaki A. J. Synth. Org. Chem. 2015, 73, 423.

4

Flash Chemistry and Jun-ichi Yoshida

Micro flow chemistry is effective
method when the reaction is very fastor unstable intermediate generate.

Flash chemistry ; using rapidly
generated unstable intermediate foranother reaction.

Yoshida J. et al. Synlett, 2011, 9, 1189. 5

Characteristic Feature of Micro Reactor

High speed collision-type

Multilamination-type

Nagaki A. J. Synth. Org. Chem. 2015, 73, 423.

6Characteristic Feature of Micro Reactor

can be used another reaction.

Yoshida J. et al. Chem. Sus. Chem. 2011, 4, 331. 7

Fast Mixing ~ Friedel-Crafts Reaction ~Competitive Consecutive Reactions

Disguised Chemical Selectivity

Yoshida J. et al. J. Am. Chem. Soc. 2005, 127, 11666.
Rys P. et al. Acc. Chem. Res. 1976, 10, 345.

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CFD Simulation for DCS

Yoshida J. et al. J. Am. Chem. Soc. 2005, 127, 11666.

9Friedel-Crafts Aminoalkylation‘Cation Pool’

In situ, protonated and inactive

Yoshida J. et al. J. Am. Chem. Soc. 2005, 127, 11666.

10Friedel-Crafts Aminoalkylation in Batch

Yoshida J. et al. J. Am. Chem. Soc. 2005, 127, 11666.

11Friedel-Crafts Aminoalkylation in Flow

Flow rate is also important factor for mixing efficiency.
Yoshida J. et al. J. Am. Chem. Soc. 2005, 127, 11666.

12Precis Temperature Control-110 ºC

At -78 ºC, desired product was not obtained completely.

Yoshida J. et al. J. Am. Chem. Soc. 2007, 129, 3046.

Temperature-residence time map iseffective to optimize reaction condition.
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Temperature-residence time map

Decompose to benzyne

Insufficient generation of ArLi

Yoshida J. et al. J. Am. Chem. Soc. 2007, 129, 3046. 14

Sequential Reactions

Even at higher temperature,reaction proceed smoothly.

Yoshida J. et al. J. Am. Chem. Soc. 2007, 129, 3046.

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Precise Residence Time Control

Yoshida J. et al. J. Am. Chem. Soc. 2011, 133, 3744. 16

Asymmetric Carbolithiation

Yoshida J. et al. J. Am. Chem. Soc. 2011, 133, 3744. 17

Screening

The importance ofdirecting groupc nBuLi 0.67M in Tol, 3.0 ml/min

Yoshida J. et al. J. Am. Chem. Soc. 2011, 133, 3744. 18

Optimize the condition%ec (R) = R/(R+S)*100 ; er = 93:7 → ec =93%

ec decreased with increasing tR and temperature
because of epimerization.

yield increased with increasing tR and temperature.

Very small domain

Quantitative evaluation of asymmetric reaction.

Yoshida J. et al. J. Am. Chem. Soc. 2011, 133, 3744. 19

Room Temperature Swern Oxidation

Yoshida J. et al. Angew. Chem. Int. Ed. 2005, 44, 2413. 20

Side Reactions
Usually, below -50 ºC

At higher temperature
I is stabele only below-30 ºC.

MTM ether

TFA ester

Yoshida J. et al. Angew. Chem. Int. Ed. 2005, 44, 2413. 21

Microreactor
Yoshida J. et al. Angew. Chem. Int. Ed. 2005, 44, 2413.

The Key : control of M1 and R122

Results
V = desired product, VI = MTM ether, VII = TFA ester· Precise temperature control· Extremely fast and efficient mixing· Short residence time
Yoshida J. et al. Angew. Chem. Int. Ed. 2005, 44, 2413. 23

TM-Free Three Components Coupling

Yoshida J. et al. J. Am. Chem. Soc. 2014, 136, 12245. 24

R1 : Benzyne ControlBromine/lithium exchange is not so fast.

Key :Prevent decomposing to benzyne

Iodine/lithium exchange is so fast.

Yoshida J. et al. J. Am. Chem. Soc. 2014, 136, 12245. 25

R2 : Carbolithiation with Functionalized ArLi
Precedent Works
Aryl conpounds, containing electrophilic groups, can be used.
Nitrile, Nitro, Ester and even Ketone groups are tolerated.

10 ms is not
Only 3 ms RT
effective

Yoshida J. et al. Nat. Commun. 2011, 136, 12245.

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For the Extremely Fast Mixing
Integrated devices
achieved this fast mixing.

Yoshida J. et al. Nat. Commun. 2011, 136, 12245.

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R2 : Carbolithiation with Functionalized ArLi

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Substrate Scope and Application

Nitrile, Nitro are tolerated.

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Short Summary of Micro Flow30

Flow ‘‘Fine’’ Synthesis

Kobayashi S. Chem. Asian. J. 2016, 11, 425.

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Total Synthesis of (R)– and (S)-Rolipram

Kobayashi S. et al. Nature, 2015, 520, 329. 32

Retrosynthesis of Rolipram

Kobayashi S. et al. Nature, 2015, 520, 329. 33

Aldol Reaction

Not necessary

For the following step
Kobayashi S. et al. Nature, 2015, 520, 329. 34

Catalytic Asymmetric 1,4-Addition

Kobayashi S. et al. Nature, 2015, 520, 329. 35

PS Chiral Ca Catalyst in Batch

Kobayashi S. et al. Chem. Eur. J. 2012, 18, 13624.

36PS Chiral Ca Catalyst in Flow

Kobayashi S. et al. Chem. Eur. J. 2012, 18, 13624.

37Synthesis of γ-lactams

Kobayashi S. et al. Nature, 2015, 520, 329. 38

Immobilized Catalyst for Toxic Metals
・MC (Microencapsulated) Catalyst

・PI (Polymer-Incarcerated) Catalyst
e.g. Kobayashi S. et al. Science, 2004,304, 1305.

小林修 JST-ERATO

研究成果集 39

Hydrogenation in FlowKobayashi S. et al. Nature, 2015, 520, 329.

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Hydrolysis and Decarboxylation

Kobayashi S. et al. Nature, 2015, 520, 329. 41

Summary of Rolipram

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Summary43