Anti-Markovnikov
Hydroamination of Alkenes
2020/11/11
Literature Seminar
Hiroyasu Nakao

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Contents
1. Introduction
2. Hydroamination with secondary amines

3. Hydroamination with primary amines
4. Hydroamination with ammonia
5. Summary2

Introduction
Amine synthesis

C-N bond formation are widely studied.
3

Introduction
Hydroamination

4

Introduction
Challenges with hydroamination

5

Introduction
Regioselectivity

M. Utsunomiya, J. F. Hartwig, et al, J. Am. Chem. Soc. 2003, 125, 19, 5608–5609.

At this time, Anti-Markovnikov hydroamination of olefins wasnamed as one of 10 challenges for homogeneous catalysts.
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Introduction

Shaolin. Z, et al. J. Am. Chem. Soc. 2013, 135, 42, 15746–15749.
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Aminium Radical Cation (ARC)

8J. M. Ganley, R. R. Knowles, et al. ACS Catal. 2020, 10, 20, 11712–11738.

Back Electron Transfer (BET)

Problem‐BET vs the forward reactions of the aminium radical cation.
The rate of BET can be modulated through carefulmanipulation of the ligand architecture of the catalyst.
9J. M. Ganley, R. R. Knowles, et al. ACS Catal. 2020, 10, 20, 11712–11738.

Secondary Alkyl Amines✔Atom economy✔Mild condition✔Regioselectivity
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A. J. Musacchio, R. R. Knowles, et al. Science. 2017, 355, 727-730.

Proposed Mechanism
this thiyl radical(E1/2 = +0.07 V vs Fc+/Fc in MeCN)

piperidine(Ep/2 = +0.56 V vs Fc+/Fc in MeCN)[Ir(dF(Me)ppy)2(dtbbpy)]PF6(E1/2(Ir(III)*/Ir(II)) = +0.59 V vs Fc+/Fc in MeCN)

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J. M. Ganley, R. R. Knowles, et al. ACS Catal. 2020, 10, 20, 11712–11738.

Optimization

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A. J. Musacchio, R. R. Knowles, et al. Science. 2017, 355, 727-730.

Substrate Scope

13A. J. Musacchio, R. R. Knowles, et al. Science. 2017, 355, 727-730.

Substrate Scope

14A. J. Musacchio, R. R. Knowles, et al. Science. 2017, 355, 727-730.

The differences of Ir catalysts

Why did the reaction stop under [Ir-3]cat
condition?
15J. M. Ganley, R. R. Knowles, et al. ACS Catal. 2020, 10, 20, 11712–11738.

BET vs C-N bond formation

Knowles hypothesized that the divergent outcomes for cyclic and acyclic amines may arise
from differences in the kinetic competition between BET and C–N bond formation for therespective photocatalysts and ARCs.

[Ir-2]catalyst
BET vs C-N bond formation[Ir-3]catalyst
BET > C-N bond formation
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J. M. Ganley, R. R. Knowles, et al. ACS Catal. 2020, 10, 20, 11712–11738.

Primary Alkyl Amine
Next, Knowles proposed…

Kinetic framework may enable the development of a method forhydroamination with primary amines that avoids overalkylation

But it was unclear whether the primary ARC would undergo productive C–N bond formation.
Challenging with primary amines17Primary Alkyl Amine
Anti-Markovnikov Hydroamination of unactivated Alkenes with Primary Alkyl Amines

18J. M. Ganley, R. R. Knowles, et al. J. Am. Chem. Soc. 2019, 141, 42, 16590–16594.

Optimization

a Optimization reactions were performed
on a 0.2 mmol scale and run for 24 h.
b 1·HCl used instead of 1.
c 1·HCl used with 1 equiv LiOH.
d 0 mol% Ir photocatalyst B.
e No irradiation.

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J. M. Ganley, R. R. Knowles, et al. J. Am. Chem. Soc. 2019, 141, 42, 16590–16594.

Substrate scope20

BET vs C-N formation
Stern-Volmer equationSecondary amine product also quenches the excited state of the photocatalyst
even more efficiently than the primary amine starting materials

Using BET process limit the reaction channels available to an otherwise
kinetically competent radical intermediate.
21J. M. Ganley, R. R. Knowles, et al. J. Am. Chem. Soc. 2019, 141, 42, 16590–16594.

Hydroamination of Alkenes with Ammonia
Recently achievement
Anti-Markovnikov Hydroamination of Alkenes with Aqueous Ammonia
by Metal-Loaded Titanium Oxide Photocatalyst✔regioselectivity✔synthesis of primary amine✔mild condition

22Soyeong. P, et al. J. Am. Chem. Soc. 2020, 142, 29, 12708–12714.

Optimization

g water was used instead of MeCN

Acetonitlile was crucial to make the liquid phase homogenous.

23Soyeong. P, et al. J. Am. Chem. Soc. 2020, 142, 29, 12708–12714.

Loaded Metals(A), alkene conversion, and selectivity to amine(B) with the M(0.1)/TiO2 photocatalysts (M = Pt,Au, and Pd) in the same reaction time, 3 h.
the reaction time was controlled as follows: 95
min for Pt(0.1)/TiO2, 180 min for Au(0.1)/TiO2,
and 110 min for Pd(0.1)/TiO2, respectively (C, D).

3hAu-loaded photocatalyst
highest regioselectivity
Pt- and Pd-loaded photocatalyst
high reaction rate even for byproduct formation

180
min95
min

110
min
24Soyeong. P, et al. J. Am. Chem. Soc. 2020, 142, 29, 12708–12714.

Substrate scope

entry
12
3
4
5
6
7
8
9alkenes
1a1b1c1d1e1f1g
1h
1itime (h)
18
18
1215
9
9
9
9
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conversion
99.9
99.9
>99.9
98.1
98.3
99.9
>99.9
>99.9
98.1

yield of amines (%)
92.7 (88.9)
91.5
74.544.8
41.7
68.3
92.0
95.8
43.5

selectivity fo amines (%)
92.7
91.5
74.5
44.8
42.5
69.6
92.0
95.8
44.4

regioselectivity (%)
97.9
99.6
>99.9
97.0
97.3
98.1
72.3

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Soyeong. P, et al. J. Am. Chem. Soc. 2020, 142, 29, 12708–12714.

Overalkylation
The experiment about overreaction

The photocatalyst can predominantly activate notamines but ammonia, and the amide radical does
not react with amines.

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Soyeong. P, et al. J. Am. Chem. Soc. 2020, 142, 29, 12708–12714.

Thermodynamic stability

thermodynamic stability
Anti-Markovnikov products < Markovnikov products

Why were anti-Markovnikov products obtained despite
thermodynamic instability of the anti-Markovnikov products?
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Soyeong. P, et al. J. Am. Chem. Soc. 2020, 142, 29, 12708–12714.

Regioselectivity
Markovnikov productPossibly an alkene molecule is directly
photoexcited to form an excited complex withammonia.

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Soyeong. P, et al. J. Am. Chem. Soc. 2020, 142, 29, 12708–12714.

Amide radical generation process

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H. Yuzawa, et al. J. Phys. Chem. C 2012, 116, 6, 4126–4136.

Amide radical generation process
Amide radical generation process

ESR spectra of the TiO2(A/R) sample
adsorbing ammonia before
photoirradiation (a)under photoirradiation (b)the Pt(0.1)/TiO2(A/R) sample
adsorbing ammonia before
photoirradiation (c)under photoirradiation (d).

✔Amide radical is produced
from NH3.
✔Pt plays a role of restricting
reduction of Ti4+.
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H. Yuzawa, et al. J. Phys. Chem. C 2012, 116, 6, 4126–4136.

Summary・Anti-Markovnikov hydroamination of secondary and primary amines isaccomplished by using different Ir photocatalyst.
・Using BET process limit the reaction channels available to an otherwise
kinetically competent radical intermediate.
・Hydroamination with ammonia is accomplished by using metal-loaded titaniumoxide.

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