C−H activation of aliphatic amines
without unnecessary mask2017.11.25
M2 Takaya Togo
1Outline
1.Introduction
2.Free amines as DG
 Discovery of new activation mode
 Mechanistic studies
 Application of the reaction mode

3. In situ installed and removed DG

2

Importance of amine compounds

Njardarson, J.-T. etal . J. Med. Chem. 2014, 57, 10257
3

Precedent

C−H activation on aliphatic amines requires
their derivatization with directing groups .
Daugulis, O. et al. J. Am. Chem. Soc. 2005, 127, 13154
4

Problem of C-H activation of amine compoundsBis amine complex is more stable than mono amine complex.

The reaction doesn’t proceed well.

Yatsimirsky, A. - K. et al J. Chem. Soc., Dalton Trans. 1985, 2629. 5

Goal of C-H activation of amine compounds

C-H functionalization of amines directly

Synthesis of amine derivatives easily
6

2.Free amines as DG

Prof. Matthew J. Gaunt
Recent report
1. Nature 2014, 510, 129
Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles
2. J. Am. Chem. Soc. 2015, 137, 10632
Mechanistic Insights into the Palladium-Catalyzed Aziridination of
Aliphatic Amines by C–H Activation

3. Angew. Chem. Int. Ed. 2015, 54, 15840
Ligand-Enabled Catalytic C[BOND]H Arylation of
Aliphatic Amines by a Four-Membered-Ring Cyclopalladation Pathway

7

Discovery of new activation mode

Content
They developed a new palladium-catalysed C-H bond activation mode
without any DG.

Gaunt, M. - J. et al. Nature 2014, 510, 129

8

Four-membered-ring cyclopalladation

Amine-directed four-membered-ring cyclopalladation
determined by single-crystal X-ray diffraction9

C-H functionalization

Mild chemical oxidants allow access toC–H functionalization pathways.

Sanford, M. -S. et al. Nature 2012, 484, 177

10Scope of the reaction

11

Uses of aziridines

12Mechanistic studies

Content✔ Mechanistic studies in detail✔ Device for accelerating the reaction✔ Insights into the regioselectivity and the chemoselectivity

Gaunt, M. - J. et al. J. Am. Chem. Soc. 2015, 137, 10632

13

Proposed mechanism based on our previous study

14

Measurement of the KIE

C−H bond cleavage occurs as part of the TOLS.
15

Reaction profiles of two sterically different amines

monocoordinated species
activebis-amine complex
inactive

Yatsimirsky, A. - K. et al J. Chem. Soc., Dalton Trans. 1985, 2629.16

Product concentration / M

Reaction profiles of two sterically different amines

Time / minutes
17

Product concentration / M

Alteration of the mono-/bis-amine equilibrium

Time / minutes

Both species reacted at the same rate.

18

Kinetic Studies

Product concentration / M(2) The reaction rate decreases.

Time / minutes(1) The reaction rate increases.
19

(1) Why does the reaction rate increase?

Hypothesis(by-)product catalyzes the reaction?
→ Which (by-)product is important for the reaction?

20

Which (by-)product is important for the reaction?

When AcOH was added to the reaction,a marginal increase was observed

21

Concentration of AcOH

The optimal amount of AcOH loading was found to be 20 equiv.

22

Putative role of acid

✔The presence of acid set up an equilibrium
between the protonated and free based amine.
✔Other acids were also found to give rate acceleration.

Shi, Z. et al. J. Am. Chem. Soc. 2007, 129, 766623

(2) Why does the reaction rate decrease at the end?

On-cycle

Off-cycleA mathematical description allow the qualitative insights.
24Initial rate of the reaction

Initial rate can be considered a constant.

25

Change of the reaction rate

Reaction rate changes to first-orderwith respect to substrate at the end.
26

Interpretation of Kinetic Studies
Product concentration / M(2) The reaction rate decreases.

Time / minutes(1) The reaction rate increases.

(1) Why does the reaction rate increase?
> Less palladium is sequestered in unproductive offcycle bis-amine complex because of AcOH.
(2) Why does the reaction rate decrease?
>Reaction rate changes as the reaction proceeds.
27Role of Acetic Anhydride% Substrate

Effect of Acetic Anhydride✔ Changing the concentrationof acetic anhydride had little effect.
Time / minutes

Concentration / M

Effect of water✔ Water was found to be
detrimental to the reaction.
Time / minutes

28

Product concentration / M

Optimized conditions

Time / minutes✔ Addition of 20 equiv of acetic acid and2 equiv of acetic anhydride led to an improved reaction.

29

Explanation of the regioselectivity and chemoselectivity

DFT studies insights into
1. the regioselectivity of the C−H activation2. the chemoselectivity of the C−N reductive elimination.

30

The regioselectivity of the C−H activation
TS‡1
TS‡2

TS‡2 is more stable than TS‡1.
31

Important factor for the regioselectivity

Bonding energy

Distortion−Interaction Analysis
ΔEINT
ΔEDIST

Activation energy
ΔE‡

Acidity of the C−H bonds closest to
the carbonyl lowers the energy
required to cleave the C−H bond
32

The chemoselectivity of the C−N reductive elimination

33

Final Catalytic Cycle

34

Application of the reaction modeContent✔ They expand the toolbox of direct functionalization reactions
to an arylation process by the reaction mode.

Gaunt, M. - J. et al. Angew. Chem. Int. Ed. 2015, 54, 15840

35

Proposed reaction mechanism

Yu, J. –Q. et al. J. Am. Chem. Soc. 2011, 133, 18183
36
Gaunt, M. - J. et al. Angew. Chem. Int. Ed. 2015, 54, 15840

Scope of the reaction

37

Further conversion of the products

Gaunt, M. -J. et al. Chem. Sci. 2011, 2, 312
Zhao, S. -Y. et al. Chem. Sci. 2014, 5, 4962
38
Chen, G. et al. Org. Lett. 2012, 14, 2948

Summary of 2nd part
Summary of the presentation✔ They developed a new palladium-catalysed C-H bond activation mode.
✔ They reported the detailed mechanistic studies.
✔ The reaction mode can be used for further application.

Limitation
Substrate scope

Outlook
These insights lead to the rational design of related C−H functionalization
reactions.
39

3. In situ installed and removed DG
Concept

Recent report
1. Ge, H. –B. et al. Nat. Chem. 2017, 9, 26
2. Dong, G. et al. Angew. Chem. Int. Ed. 2016, 55, 9084
3. Murakami, M. et al. Angew. Chem. Int. Ed. 2017, 56, 1073

40

Additive screening

Aldehyde and carboxylic acid are important moiety.

Ge, H. –B. et al. Nat. Chem. 2017, 9, 26

41

Proposed intermediate

42

Proposed mechanism

43Substrate scope
1.5 equiv

Steric hindrance and Thorpe-Ingold effect are important.
44

Summary
Summary of 3rd part
✔ They developed aC-H activation of primary amine with additive astransient directing group.

Limitation
Substrate scope

Outlook
Expanding the scope

45

Summary

ProblemStrategy1: Free amines as DG

Strategy2: In situ installed and removed DG

46

Appendix

47

Appendix1

Gaunt, M. - J. et al. J. Am. Chem. Soc. 2015, 137, 10632 48

Appendix2Gaunt, M. - J. et al. Nature 2014, 510, 12949

Appendix3Gaunt, M. - J. et al. J. Am. Chem. Soc. 2015, 137, 10632 50

Appendix4: autoinduction

Gaunt, M. - J. et al. J. Am. Chem. Soc. 2015, 137, 10632 51