Innovative Catalyst Design for

Palladium Catalyzed Cross-

Coupling Reactions

Chandramouli Reddy U.
Outline

1. Introduction
2. Ligand Design
3. Buchwald Precatalysts
3a. 1st Generation
3b. 2nd Generation
3c. 3rd Generation
3d. 4th Generation
4. Summary
Introduction: Evaluation of Ligands

PtBu2
PPh2 NHMe
P Fe P i i
PPh2 Pr Pr Pd OMs
L
i
Pr

Evaluation of Ligands

• Ligands have a distinct influence on the catalytic performance

• Suitable ligands showing higher reactivity and selectivity and has been a field of
enormous activity over the last two decades

• P(t-Bu)3 is found to be a remarkably active ligand

• Mono-dentate biaryldialkylphosphine ligands greatly enhanced the scope of

cross-coupling reactions

Organometallics, 2015, 34, 5497–5508

Ligand Design: The Era of Modern Cross-Coupling

• Osborn performed a systematic study of steric and

electronic properties of ligand
• Significant catalytic activity observed only with the ligand
basicity having pKa ˃ 6.5 & cone angle (Θ) must exceed
160 °
Steric and stertoelectronic evaluation of phosphine
ligands

Bulky and electron-rich ligand scalfolds

High reactivity of Pd/P(t-Bu)3 (ligand 3) in Suzuki-
Miyaura coupling of aryl chlorides Organometallics, 2015, 34, 5497–5508

© Aurigene Discovery Technologies Limited. 4

Ligand Design: Dialkylbiaryl Phosphine Ligands

OMe

MeO PCy2
i i PCy2
Pr Pr
i
PrO OiPr

i
Pr

BrettPhos RuPhos

1º Amines/Anilines 2º Amines/Anilines

Key dialkylbiaryl phosphine ligands for amination

OMe

MeO PCy2
i i PCy2
Pr Pr i
PrO OiPr

SO3- Na+
SO3- Na+

XPhos-SO3Na SPhos-SO3Na

Water soluble phosphine ligands

Important dialkybiaryl phosphine ligands for amination

© Aurigene Discovery Technologies Limited. 5

Ligand Design: Structural Features of Ligands

R: Substituent fixes conformation R1: Electron-rich groups accelerate rate of oxidative addition
Enhances rate of reductive elimination Steric bulky groups promotes reductive elimination
and also promotes formation of [L1Pd0]

R
R1
P
R1
R2 R2

: Lower aryl ring retards oxidation by O2

R2: Large substituents increases stability R3 Allows stablizing Pd-arene interactions
by preventing cyclometalation Acclerates reductive elimination
Large Substituents on ring promotes [L1Pd0]

R3: When not equal to H, usually for easy of synthesis

Structural features of dialkylbiryl phosphine ligands

Mechanism of the Buchwald-Hartwig Amination Reaction

Reductive Oxidatve
elimination addition

-Hydried Amine Pd-halide

elimination Deprotonation bonding dimers

Mechanism of the Buchwald-Hartwig Coupling

Potential Issues in Buchwald-Hartwig Amination Reactions

- Protodemetallation
- Pd-halide dimers (Ar-I)
- β-Hydried elimination

© Aurigene Discovery Technologies Limited. 7

Palladacyclic Precatalysts: Historical Context

Hermann and Beller palladacycle (1995)

Heck coupling of 4-bromobenzaldehyde and n-butyl acrylate with 1

• Superior reactive over its precursor
• TONs as high as 200,000
• First potential palladacyclic precatalyst

Shaw (1998) Buchwald (2003) Blaser & Studer (2002) Bedford (2001)

Representative palladacycles utilized in Pd cross-coupling reactions

© Aurigene Discovery Technologies Limited. 8

1st Generation: Effect of Palladium Source in Amination Reaction

H
Cl N
0.1% Pd/L Ph
+ PhNH2
base MeO NaOtBu, dioxane MeO
NH2 L Pd(0) 80 ºC, 35 min
Pd -HX.Base
Cl L indoline active Pd(0) species

First Geneartion

- Formation of the active LPd(0) species is easy

- Catalyst is very active, oxidative addition took
place even at -40 °C
- Used in a variety of cross coupling reactions
Effect of Pd Source on the cross-coupling reaction using Pd and XPhos

NH2
Pd
Cl
P
i
Pr

i
i
Pr Pr
Superior reactivity of G1 BrettPhos over its precursor

XPhos Pd G1

J. Am. Chem. Soc. 2008, 130, 6686–6687

1st Generation: C-N Bond Forming Reactions at or Below RT

C-N Bond-forming reactions using ArCl at or below room temperature

• Aryl chlorides coupled with amine even at -10 °C

• Unstable functional groups at high temperature can coupled efficiently
• Unactivated aryl chloride can undergo oxidative addition to SPhosPd(0) at temperatures as low as -40 °C.

J. Am. Chem. Soc. 2008, 130, 6686–6687

© Aurigene Discovery Technologies Limited. 10

1st Generation: Coupling of 1° Amines using BrettPhos Ligand

• High levels of chemo selectivity for the arylation of a

primary amine over a secondary amine
• More conformational rigidity of the biaryl backbone (3-
& 6-OMe) and steric effect prevented the diarylation

BrettPhos (1), Pd G1 BrettPhos (6)

Selectivity of Primary Amines Over Secondary Amines

• Electron-rich and electron-deficient aryl

mesylates coupled with anilines in excellent
yields
• Several functional groups were well tolerated on
both the aniline and aryl mesylates

BrettPhos (1), Pd G1 BrettPhos (6)

Formation of Diarylamines Using Aryl Mesylates Chem. Sci., 2011, 2, 57
Nature Protocols, 2, 2881 – 2887

© Aurigene Discovery Technologies Limited. 11

1st Generation: Coupling of 2° Amines using RuPhos

Pd-catalyzed amination of functionalized aryl chlorides and 2º amines

Chem. Sci., 2011, 2, 57

Nature Protocols, 2, 2881 – 2887

© Aurigene Discovery Technologies Limited. 12

Buchwald 1st Generation Precatalyst: Introduction

90 - 95% 90%
Ligand = XPhos

Preparation of Pd G1 precatalyst and its mode of activation

The key features of Pd G1-precatalysts:

- Quantitative generation of the active LPd(0) catalyst species
- Highly efficient catalyst
- Utilized under mild reaction conditions
- Short reaction times
- Low catalyst loadings

J. Am. Chem. Soc. 2008, 130, 6686–6687

Buchwald 2nd Generation Precatalyst

Parent aliphatic amine is replaced by the

more reactive 2-aminobiphenyl (lower pKa)

Synthesis of Pd G2 precatalyst

The key features of Pd G2-precatalysts:

- Air stable
- Highly efficient
- Utilized under reaction mild conditions
- Short reaction times
- Low catalyst loadings

Mode of activation

i
Pr
base, RT NH2 i
Pr
NH2 P
L Pd(0) Pd
Pd L -HCl.Base Cl
kinitically active i
Cl - carbazole Pr
12-electron Pd(0) species

XPhos Pd G2
J. Am. Chem. Soc. 2010, 132, 14073-14075
Pd G2 XPhos: Suzuki Coupling of Heterocyclic and Polyfluoro Boronic Acids

Coupling of polyfluoroboronic acids with aryl halides and triflates

Coupling of heterocyclic boronic acids with aryl halides

J. Am. Chem. Soc. 2010, 132, 14073–14075

© Aurigene Discovery Technologies Limited. 15

Buchwald 3rd Generation: Introduction

Synthesis of Pd G3 precatalysts

The key features of Pd G3-precatalysts:

- Quantitative generation of the active Pd(0) catalyst
- Accommodates a broader ligand scope
- Compatible with the BrettPhos family, and extremely bulky t-Bu phosphines
- Increased stability in solution, compared to G1 and G2 precatalysts

Chem. Sci., 2013, 4, 916-920

3rd Generation: Screening of Ligands and Palladium Source

• XPhos ligand is the effective in these SMC

• µ-OMs-dimer is more effective for SMC

X Pd NH2
2

Screening of Ligands and Palladium Sources for the

Suzuki-Miyaura Coupling of an Unstable Boronic Acid
Chem. Sci., 2013, 4, 916-920
3rd Generation: tBuXphos Pd G3 Precatalyst Applications

• Cyanide source, potassium cyanide is a

nontoxic food additive

• Tolerated a wide range of functional groups

(−OH, −NH2, −CO2Et) and N−H heterocycles

Use of G3-XPhos precatalyst in cyanation of heterocyclic halides

Use of G3-tBuXPhos precatalyst in -arylation of acetate esters

ACS Catal. 2015, 5, 1386−1396

3rd Generation: Selective Monoarylation of Aryl Halides

Use of G3-precatalyst in arylation of 1º nitrogen nucleophiles (amides and ammonia)

• Me3(OMe)XPhos or AdBrettPhos, showed high selectivity toward the monoarylation of ammonia

• More conformational rigidity of the biaryl backbone (3- and 6-Me or OMe) and steric effect prevented the
diarylation

• High chemoselectivity, observed toward amides versus alcohol and N−H azoles.

ACS Catal. 2015, 5, 1386−1396

3rd Generation: C-O bond Forming Reaction

Use of G3-tBuBrettPhos precatalyst in C-O cross-coupling

• Primary alkyl alcohols coupled with aryl halides without any side product derived from β-hydride elimination

• The bulky RockPhos played a critical role in promoting the reductive elimination than the competing β-hydride
elimination

ACS Catal. 2015, 5, 1386−1396

Buchwald 4th Generation Precatalyst

Mode of Activation

NHR base
NR + L Pd(0)
Pd L -HX.Base
X kinitically active
12-electron Pd(0) species
R = Ph, Me

• Substitution at the nitrogen center prevents the presence of traces of

aminobiphenyls that contain a free −NH2 group from contaminating
cross-coupling products

• These precatalysts produce N-substituted carbazoles upon activation,

which cannot consume starting materials
4th Generation: Arylation of α-Branched Secondary Amines

• Less electron-rich biaryl phosphine ligand increased the rate

of reductive elimination

• Less electron-rich biaryl phosphine ligand also increased the

rate of transmetalation

• Hindered cyclic/acyclic secondary amines were well tolerated

Palladium catalyzed arylation of -branched 2º amines

Angew. Chem. Int. Ed. 2015, 54, 8259 –8262

Precatalyst Outlines
Summary of Buchwald Precatalysts

NH2
NH2 Pd L
Pd
Cl L Cl

First Geneartion Second Geneartion

- Compatible with bulky Ligands - Simple one pot preparation

- 3-step preparation - Pd(OAc)2 as Pd Source
- Unstable intermediates - Not compatible with bulkier ligands
- Short life in solution - Poor Solubility and short life in solution

NH2 NHR
Pd L Pd L

OMs OMs

Third Geneartion Forth Geneartion

- Simple preparation with stable isolable intermediate - Generate N-Substituted Carbolzole

- Compatible with bulky ligands - Avoids 2-aminobiphenyl
- Effective in C-N and C-C bond forming reaction - Compatable with a range of ligands
- Can be prepared in-situ - Effective in C-N and C-C
- Long solution life (more than a month)
- Generate 2-aminobiphenyl byproduct
Precatalyst Capsules: Glove-box free Coupling of 2-pyridylzinc with
ArX

• Capsule catalysts are bench-top stable and air- and

moisture resistant
• Encapsulated with the basic 2-pyridylzinc dioxanate
with base-activated palladium precatalyst
• Capsules contains pre-measured quantities of catalyst
and reagent

Wax capsules for the Pd-catalysed Negishi

cross-coupling of 2-pyridylzinc dioxanate.

Nature 524, 208-211

Precatalyst Capsules: Fluorination of Arylbromides

• Effectively fluorinated both aryl and heteroaryl

bromides

Wax capsules for the glove-box-free Pd-catalysed nucleophilic

fluorination of aryl bromides.

Nature 524, 208-211

© Aurigene Discovery Technologies Limited. 25

Conclusion

 Ligands having bulky, electron rich alkyl groups (tBu3P, PCy3, PAd2Alk) are highly
efficient for the cross-coupling reactions

 Buchwald dialkylbiarylphosphine ligands are one the most efficient catalyst for
various amination reactions

 Buchwald preformed palladium catalysts generates highly active LPd(0) specie

than the traditional palladium source

 Third generation methanesulfonate precatalysts are readily activated, and

incorporate the broadest range of ligands

 Precatalysts are very efficient for various cross-coupling reactions such as Buchwald-
Hartwig amination, Suzuki-Miyaura, Heck-Mizoroki etc.
© Aurigene Discovery Technologies Limited. 27