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Mechanism of the Week

Scheme 1: Mechanism of the Week

CO2Me
S Yb(OTf)3 (20 mol%)
CO2Me +
CO2Me H 2N NH2 DCE, 90ºC NH2
Ph S
1 eq. 2 eq. Ph 80% yield

Chem. Commun., 2019, 55, 1580-1583

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Proposed Mechanism

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Formal group insertion into aryl C-
N bonds through an aromaticity
destruction-reconstruction process
Nature Communication, 2018, 9, 1-7
Group Literature Meeting: 2/16/2019
Presented by Anae Bain

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Goal of paper
“We report an aromaticity deconstruction-reconstruction process that selectivity
inserts a trimethylenemethane group into the aryl carbon-nitrogen bonds in
anilines concomitant with a functionalization of the benzylic carbon-hydrogen
bond”

X FG
Transition Metal
X waste

NH2 1. Aniline Activation FG


2. Transition Metal
Nitrogen Waste

Functional Group
Insertion
NH2 FG NH2

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TriMethylMethane
Only known as Pd complex!

What is it ? Triplet Ground Singlet State


State

OAc

Pd(0)
TMS OAc TMS
-OAc Pd Pd
How does it work?
OAc OAc

Pd(0) Pd(0)
c TMS TMS OAc TMS
-OAc Pd -OAc Pd Pd Pd

What does it do? EWG TMS OAc


EWG

transition metal

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TriMethylMethane
O
O TMS OAc
cycloadditions! transition metal

Pd

Pd
Synthetic formal [3+2]

APPLICATION
Pd(OAc)2 O
(iPrO)3P MeO2C O HO
AcO TMS + O O
O H O

H
MeO2C HO
(+)- Brefeldin A

NC HO
Ph H OH
N Pd/L* N N
+ TMS
Ph
NO2 NC OAc N NO2
O N
Ph H 2N H
Ph O
Jogyamycin

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Reaction Optimization
1. PhIO (1 eq), MeOH, 25ºC, 5 min
2. Catalyst A(10 mol%), 2 (1.1 eq)
Ts Solvent A MeO
HN NH
Me 3. Catalyst B (12 mol %), Solvent B Me Ts

TMS OAc

Entry Catalyst A Solvent A Catalyst B Solvent B % Yield

1 Pd(PPh3)4 THF TsOH-H2O THF 2

15 Pd(PPh3)4 Toluene Cu(OTf)2 DCE 7

23 Pd(PPh3)4 Toluene Fe(acac) DCE 0

20 Pd(PPh3)4 Toluene Pd(PPh3)4 DCE 0

25 Pd(PPh3)4 Toluene In(Otf)3 DCE 5

28 Pd(PPh3)4 Dixoane Bi(OTf)3 DCE 13

46 Pd(PPh3)4 AcOEt Bi(OTf)3 MeOH 68

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Scheme and Mechanism

1. PhIO (1 eq), MeOH, 25ºC, 5 min


2. Pd(PPh3)4 (10 mol%), 2 (1.1 eq)
Ts AcOEt, reflux, 1 h MeO
HN NH
Me 3. Bi(OTf)3 (12 mol %), MeOH, 25ºC, 12 h Me Ts

TMS OAc

Ts Me
HN NH
Me PROPOSED MECHANISM MeO Ts

Dearomatization 1.Rearomatization, MeOH


MeOH 2. Rearrangement

Pd-TMM Bi(III)
MeO Ts Cycloaddition MeO
N Me
H N N
Bi(III)
Me Me Ts Ts

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Benzylic Cation Trapping
1. PhIO (1 eq), MeOH, 25ºC, 5 min
2. Pd(PPh3)4 (10 mol%), 2 (1.1 eq)
Ts AcOEt, reflux, 1 h Nuc
Me HN NH
3. Bi(OTf)3 (12 mol %), solvent, 25ºC, 12 h H Ts

TMS OAc

HO
NH
H 2O*
Scheme: Benzylic Carbocation Formation H Ts
Nuc Ph
56%

Me Me
N Me C O
Ts
Bi(III) OH
HN Ts O
Bi(OTf)3
O
Me NH
H Ts
Ph
55%

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*H2O/Acetone (1:10) Mixture
Substrate Scope

MeO MeO
NH NH NH
MeO
H Ts H Ts H Ts
F Ph

0% H 83% 55%

MeO MeO MeO


NH NH NH
H Ts H Ts H Ts

73% Ph 70% 70% S


OMe

Et
Me MeO
Me NH NH
Me Ts H Ts
OMe Et
71% 45%

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Synthetic Utility
MeO
NH
Ts

Ts
NTs N
MeO MeO
I

Aziridination O Pyrole Formation


MeO
NH
Ts
Epoxidation

MeO Ph
Au(PPh3)Cl (5 mol%)
NH AgNTf2 (5mol %) HN Ts
Ts
H2O (5 eq.) MeO
ClCH2Cl, rt, 12 h OH

Ph

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Overview/Criticisms

1. Dearomatization
Ts 2.Trimethylenemethane [3+2] Cycloadditon MeO
HN
3. Rearomtization/ Rearrangement NH
Me
Me Ts

• Insertion products are good precursors through simple conversions

• Overall modest yields for procedures

• Ideal optimization would facilitate one-pot protocol

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