Photoredox Synthesis of Amines
2024.05.02
Literature Seminar
M1 Hiroki KanamoriImportance of amines
alkaloids

antidepressants2

Methods for the synthesis of amines
Hoffman alkylation (1850 ~ )×overalkylation
× separation, atom economy

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Methods for the synthesis of amines
Reductive amination

Most widely used, but ...
×poor reactivity in the case of stericallyencumbered amines
×over-reaction in the case of small, nucleophilic
amines, and simple aldehydes
× toxic byproducts

amide/nitrile reduction

×challenging workup procedures× reactive aluminum hydrides withLewis or Brønsted acids4

Photoredox synthesis of β-amino ether
the first example of photocatalytic α-amino radical generation

radical-radical coupling
visible light
photoredox & thiol catalyst→ development of photocatalytic synthesis of amines
Dominik Hager, and David W. C. MacMillan J. Am. Chem. Soc. 2014, 136, 49, 16986–16989

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Contents
1.
2.
3.
4.

Introduction
Enantioselective photocatalytic reaction
Carbonyl alkylative amination
Reductive amination

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Enantioselective photocatalytic reaction

absolute stereocontrol
synergistic catalysis
visible light

D. Uraguchi et al. J. Am. Chem. Soc. 2015, 137, 43, 13768–13771

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P-spiro chiral aminophosphonium salts
a new class of organocatalysts

excellent yields & outstanding stereoselectivity
structurally modifiable
readily accessible
D. Enders and T. V. Nguyen. Org. Biomol. Chem. 2012, 10, 5327

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Chiral catalyst design
CF3B
CF3
4barfate• charged Brønsted acid catalyst→ efficient acidity to protons• double H-bond donor• positive charge→ for catalytic ion-pairing with anion radicalD. Uraguchi et al. J. Am. Chem. Soc. 2015, 137, 43, 13768–13771

9Comparison of H-bond donor & photosensitizer
CF3PhNH HN
P
NH HN

Ph
CF3BArF

1c・HBArF
F3C

BArF

CF3NHHNP
NHHN
F3C

CF35·HBArF

D. Uraguchi et al. J. Am. Chem. Soc. 2015, 137, 43, 13768–13771

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Proposed mechanism

D. Uraguchi et al. J. Am. Chem. Soc. 2015, 137, 43, 13768–13771

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Substrate scope
N
Ar

Ms

R’H

Ms

1c・HBArF (4 mol%)

RH

Ms
NH

3c (1 mol %)Msvisible lighttoluene, rt, 8 hAr

Ms

NH

NH

NR’NH
NN

N

R

F
85 %
97 % eeMs

90 %91 % ee

Ms

NHOMe
75 %
85 % ee

Ms

NH3cNHNNN

64 %
90 % ee

73 %91 % ee

65 %91 % ee

C6H13

D. Uraguchi et al. J. Am. Chem. Soc. 2015, 137, 43, 13768–13771

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Enantioselectivity

Catalytic efficiency was higher in aless coordinating solvent

2-phenyl groups→ cavity over the ionic H-bonding site
D. Uraguchi et al. J. Am. Chem. Soc. 2015, 137, 43, 13768–13771

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Contents
1.
2.
3.
4.

Introduction
Enantioselective photocatalytic reaction
Carbonyl alkylative amination
Reductive amination14

Carbonyl alkylative amination

streamlined synthesis of complex tertiary amines
metal-free and modular transformation
abundant feedstocks
R. Kumar et al. Nature 2020, 581, 415–420

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Optimization and controls

TTMSS : HAT
TBSOTf : Lewis acidlight : visible light
R. Kumar et al. Nature 2020, 581, 415–420

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Substrate scope

OOH
I

5-10 mol%
R. Kumar et al. Nature 2020, 581, 415–420

17Proposed mechanism

R. Kumar et al. Nature 2020, 581, 415–420

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Mechanistic study+ the reaction efficiency dropped under air
R. Kumar et al. Nature 2020, 581, 415–420

19Evidence in support of the proposed mechanism

adding an alkyl radical to an iminium ion :ΔG = - 6.2 kcal mol-1
ΔGTS = + 2.7 kcal mol-1
the length of the forming C–C bond
(2.3609 Å)

a strong dependence on the choice of silane
BDE:
TTMSS 84 kcal mol-1
ammonium ion 95 kcal mol-1
R. Kumar et al. Nature 2020, 581, 415–420

20Evidence in support of the proposed mechanism

The halogen abstraction
3˚ > 2˚ > 1˚ and R–I > R–Br

No ring-opened product was observed
formation of an α-amino radical does not occur.
R. Kumar et al. Nature 2020, 581, 415–420

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Studies into the role of visible light• Control experiment in the dark afforded no product.
Light is required for the reaction
The reaction proceeds efficiently in the presence of 455 nm
long-pass filter.
The reaction does not require high-energy UV-light•• The reaction is also operative under thermal conditions.
The main role of light is thought to be to provide a room
temperature initiation pathway for the silane-mediated radicalchain mechanism.
R. Kumar et al. Nature 2020, 581, 415–420

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The role of visible-light
Hypothesis 1 : ruled out
light-mediated homolysis of the C–I
bond of the alkyl iodide

Hypothesis 2 : ruled out
excited state enamine reduces alkyl iodide

R. Kumar et al. Nature 2020, 581, 415–420

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The role of visible-light

Hypothesis 3 : ruled out
interaction between TTMSS and alkyl iodide(halogen bonding or EDA complex)

R. Kumar et al. Nature 2020, 581, 415–420

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The role of visible-light
Hypothesis 4 : ruled out
EDA complex between theiminium ion and TTMSSHypothesis 5 : ruled out
EDA complex between enamine
and alkyl iodide

slight red-shift

R. Kumar et al. Nature 2020, 581, 415–420

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Hypothesis 6New band observed

excitation of reaction mixture (enamine, TTMSS, alkyl halide)R. Kumar et al. Nature 2020, 581, 415–420

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Contents
1.
2.
3.
4.

Introduction
Enantioselective photocatalytic reaction
Carbonyl alkylative amination
Reductive amination27

Reductive amination

visible lighttemporal & spatial control
scalable

X. Guo et al. Angew. Chem. Int. Ed. 2018, 57, 2469-2473

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Substrate scopeMPA

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X. Guo et al. Angew. Chem. Int. Ed. 2018, 57, 2469-2473

Proposed mechanism

without AscH2 : no product formation at all• the inefficient reductive quenching of 3MLCT-excited [Ru(bpy)3]2+ by MPA• the reversible nature of the HAT between MPA and α-amino alkyl radicals
X. Guo et al. Angew. Chem. Int. Ed. 2018, 57, 2469-2473

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Mechanistic study

X. Guo et al. Angew. Chem. Int. Ed. 2018, 57, 2469-2473

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kinetic isotope effect studies

low H/D KIE (2.3)→ relatively low vibrational frequency of S-H bondlarge KIE (11.5)→ significant contribution of proton tunneling
X. Guo et al. Angew. Chem. Int. Ed. 2018, 57, 2469-2473

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DFT calculation

X. Guo et al. Angew. Chem. Int. Ed. 2018, 57, 2469-2473

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Summary
photoredox synthesis of amines :••••

visible light
HAT (thiol, silane)
photocatalyst (Ir, Ru)stereocontrol

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