Organometallic Chemistry in Industry E-Book

• Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 534

Veröffentlichungsjahr: 2020

Beschreibung

Showcases the important role of organometallic chemistry in industrial applications and includes practical examples and case studies

This comprehensive book takes a practical approach to how organometallic chemistry is being used in industrial applications. It uniquely offers numerous, real-world examples and case studies that aid working R&D researchers as well as Ph.D. and postdoc students preparing to ace interviews in order to enter the workforce. Edited by two world-leading and established industrial chemists, the book covers flow chemistry (catalytic and non-catalytic organometallic chemistry), various cross-coupling reactions (C-C, C-N, and C-B) in classical batch chemistry, conjugate addition reactions, metathesis, and C-H arylation and achiral hydrogenation reactions.

Beginning with an overview of the many industrial milestones within the field over the years, Organometallic Chemistry in Industry: A Practical Approach provides chapters covering: the design, development, and execution of a continuous flow enabled API manufacturing route; continuous manufacturing as an enabling technology for low temperature organometallic chemistry; the development of a nickel-catalyzed enantioselective Mizoroki-Heck coupling; and the development of iron-catalyzed Kumada cross-coupling for the large scale production of Aliskiren intermediates. The book also examines aspects of homogeneous hydrogenation from industrial research; the latest industrial uses of olefin metathesis; and more.

-Includes rare industrial case studies difficult to find in current literature
-Helps readers successfully carry out their own reactions
-Covers topics like flow chemistry, cross-coupling reactions, and dehydrative decarbonylation
-Features a foreword by Nobel Laureate R. H. Grubbs
-A perfect resource for every R&D researcher in industry
-Useful for PhD students and postdocs: excellent preparation for a job interview

Organometallic Chemistry in Industry: A Practical Approach is an excellent resource for all chemists, including those working in the pharmaceutical industry and organometallics.

Leseprobe

Table of Contents

Cover

Foreword

Prof. Grubbs Biography

1 Industrial Milestones in Organometallic Chemistry

1.1 Definition of Organometallic and Metal–Organic Compounds

1.2 Industrial Process Considerations

1.3 Brief Notes on the Historical Development of Organometallic Chemistry for Organic Synthesis Applications Pertaining to the Contents of this Book

1.4 Conclusion and Outlook

Biography

References

2 Design, Development, and Execution of a Continuous‐flow‐Enabled API Manufacturing Route

2.1 Continuous‐flow‐Enabled Synthetic Strategy

2.2 Design and Scale‐up of Chan–Lam Coupling

2.3 Design and Scale‐up of a Buchwald–Hartwig Cross‐coupling

2.4 Impurity Control

2.5 Conclusions

Biography

References

3 Continuous Manufacturing as an Enabling Technology for Low‐Temperature Organometallic Chemistry

3.1 Introduction

3.2 Organo‐Li and Mg Processes in Flow Mode

3.3 Continuous Flow Technology

3.4 Development of a Flow Process

3.5 Literature Examples: Flow Processes on Multi 100 g Scale

3.6 Conclusion and Future Prospects

Biography

References

4 Development of a Nickel‐Catalyzed Enantioselective Mizoroki–Heck Coupling

4.1 Introduction

4.2 Development of a Nickel‐Catalyzed Heck Cyclization to Generate Oxindoles with Quaternary Stereogenic Centers

4.3 Development of First Enantioselective Nickel‐Catalyzed Heck Coupling

4.4 Conclusions

Biography

References

5 Development of Iron‐Catalyzed Kumada Cross‐coupling for the Large‐Scale Production of Aliskiren Intermediate

5.1 Introduction

5.2 Optimization of Grade and Equivalents of Mg Metal

5.3 Optimization of Equivalents of 1,2‐Dibromoethane

5.4 Effect of Solvent Concentration on Preparation of Grignard Reagent and Kumada–Corriu Coupling

5.5 Effect of Alkyl Chloride 3 Addition Time on the Grignard Reagent Preparation

5.6 Stability of Grignard Reagent at 0–5 °C

5.7 Iron‐Catalyzed Cross‐coupling Reaction

5.8 Optimization of Equivalents of NMP and Fe(acac)3

5.9 Optimization of Equivalents of Substrate 4 and Its Rate of Addition

5.10 Execution at Pilot Scale and Scale‐up Issues

5.11 Agitated Thin Film Evaporator (ATFE) for Purification of 2

5.12 Conclusion

Acknowledgments

Biography

References

Notes

6 Development and Scale‐Up of a Palladium‐Catalyzed Intramolecular Direct Arylation in the Commercial Synthesis of Beclabuvir

6.1 Introduction

6.2 KOAc/DMAc Process

6.3 TMAOAc/DMF Process

6.4 TMAOAc/DMAc Process

6.5 Conclusion

Biography

References

7 Ruthenium‐Catalyzed C—H Activated C—C/N/O Bond Formation Reactions for the Practical Synthesis of Heterocycles and Pharmaceutical Agents

7.1 Introduction

7.2 C–H Activation Followed by CC Bond Formation

7.3 Alkyl/Acyl/Alkenyl Substitution on Heterocycles

7.4 C–H Activation Followed by CO/N Bond Formation: Heterocycle Synthesis

7.5 Conclusion

Biography

References

8 Cross‐couplings in Water – A Better Way to Assemble New Bonds

8.1 Introduction

8.2 Transition Metal Catalysis in Organic Solvents vs Micellar Catalysis

8.3 Highly Valuable Reactions in Water

8.4 Conclusions

Biography

References

9 Aspects of Homogeneous Hydrogenation from Industrial Research

9.1 Homogeneous Hydrogenation: A Brief Introduction

9.2 Catalyst Selection by Effective Screening Approaches

9.3 Considerations for Reaction Scale‐up

9.4 Notes on Additive Effects

9.5 A Novel Approach to Aliskiren Using Asymmetric Hydrogenation as a Key Step

9.6 Efficient Chemoselective Aldehyde Hydrogenation

9.7 Closing Remarks/Summary

Biography

References

10 Latest Industrial Uses of Olefin Metathesis

10.1 Introduction

10.2 General Information

10.3 Industrial Uses

10.4 Reaction Considerations

10.5 Troubleshooting

10.6 Conclusion

Biography

References

Note

11 Dehydrative Decarbonylation

11.1 Introduction

11.2 Use of Sacrificial Anhydride and Catalytic Mechanism

11.3 Rh‐, Pd‐, and Ir‐Catalysis

11.4 Milder Temperatures

11.5 Nickel and Iron Catalysis

11.6 Ester Decarbonylation

11.7 Synthetic Utility: α‐Vinyl Carbonyl Compounds

11.8 Conclusions and Future Prospects

Biography

References

Index

End User License Agreement

List of Tables

Chapter 2

Table 2.1 Thresholds for impurities in a drug substance.

Table 2.2 Summary of screening conditions for the oxidative coupling of

1

and

2

.

Table 2.3 Comparison of aqueous wash sequences for workup.

Table 2.4 Characterization of vertical pipes‐in‐series reactor sizes.

Table 2.5 Summary of screening conditions for the formation of

6

.

Table 2.6 Initial development of NaTMT for Pd removal.

Table 2.7 Results for the scale‐up batches of step 9.

Table 2.8 Thresholds for residual Cu and Pd in a drug substance adapted from ICH...

Table 2.9 Solubility of compounds 3, 4, and 1 in 40 : 60 ethanol:water.

Table 2.10 Relative rejection rate for some impurities observed in step 9.

Chapter 3

Table 3.1 Flash chemistry: functional group tolerance.

Chapter 4

Table 4.1 Optimization of the reducing agent.

Table 4.2 Robustness screening test.

Table 4.3 Control experiments to probe the mechanism of the reaction.

Chapter 6

Table 6.1 Factors and ranges used in the cyclization reaction DoE.

Table 6.2 Experiments and results for the DoE of the cyclization of aryl bromide

Table 6.3 Fractional factorial DoE analysis for the cyclization reaction DoE.

Table 6.4 Summary of the impact of cyclization process parameters on impurity fo...

Table 6.5 Verification data for cyclization process parameters.

Table 6.6 Experiments and results for the palladium loading study.

Table 6.7 Results for the reduced Pd loading at pilot scale.

Table 6.8 Effect of water on relative amounts of Des‐Br

7

and C–H

8

.

Table 6.9 Effect of L/M ratio on amount of phosphonium

9

.

Table 6.10 In‐process level of Me ester

10

at pilot scale.

Table 6.11 Removal of palladium throughout the process.

Table 6.12 Average cake properties of dried

2

.

Chapter 7

Table 7.1 Different condition to switch between pyran and lactone synthesis.

Table 7.2 Synthesis of substituted furans in different condition.

Chapter 8

Table 8.1 Effect of reaction medium on the outcome.

Chapter 11

Table 11.1 Effect of anhydride additive on TON and selectivity.

Table 11.2 Protocol with portionwise addition of anhydride.

List of Illustrations

Chapter 1

Scheme 1.1 Oxidative addition and reductive elimination.

Scheme 1.2 Carbometalation as a key step toward the synthesis of Tamoxifen

TM

.

Scheme 1.3 Hydroalumination of alkynes.

Scheme 1.4 a) β‐hydride elimination is exploited in the Shell higher olefin pr...

Scheme 1.5 Organometallic substitution reaction exemplified by Vaska's complex...

Scheme 1.6 Carbon–hydrogen bond activation exemplified by the total synthesis ...

Scheme 1.7 Cyclometalation exemplified by the oxidative additions of Rh into a...

Scheme 1.8 Migratory insertion exemplified by a step in the Cativa process.

Scheme 1.9 Nucleophilic abstraction illustrated by hydrogen abstraction using

Scheme 1.10 Electron transfer illustrated by one step in the photocatalytic Ps...

Figure 1.1 Victor Grignard.

Scheme 1.11 Simplified catalytic cycles for cross‐coupling reactions.

Scheme 1.12 Iridium‐catalysed direct borylation in Pfizer's synthesis of a nic...

Scheme 1.13 The application of asymmetric hydrogenation in the syntheses of

L

‐...

Scheme 1.14 Wittig olefination.

Scheme 1.15 General catalytic cycle for Metathesis reactions.

Chapter 2

Scheme 2.1 Final steps conducted under GMP for the scale‐up of API

6⋅HX

.

Scheme 2.2 Synthetic route used for campaign 1.

Scheme 2.3 Some retrosynthetic approaches to 6.

Scheme 2.4 Cyclopropylhydrazine condensation to test the viability of SR2.

Scheme 2.5 Model ullmann couplings evaluated for SR3.

Scheme 2.6 Cu‐catalyzed Chan–Lam coupling to the desired isomer,

3

.

Figure 2.1 Reaction kinetics for the conversion of

1

–

3

using Cu(OAc)

2

/bipy/myr...

Figure 2.2 Pipes‐in‐series reactor design schematic.

Figure 2.3 Setup of vapor‐liquid pipes‐in‐series reactor.

Figure 2.4 Online HPLC data trend for continuous run with 12 hours

τ

at 7...

Figure 2.5 Reaction kinetics in the 75 ml pipes‐in‐series reactor compared to ...

Figure 2.6 Reaction kinetics plots of temperature effect on conversion.

Figure 2.7 The effect of O

2

equivalents on conversion.

Figure 2.8 LOC data for THF/DMSO (50/50) under 100

–

200 psi at 80

–

2...

Scheme 2.7 Optimized conditions for Cu‐catalyzed Chan–Lam coupling to prepare

Figure 2.9 Reaction rate comparison for the 75 ml and 2 l reactors.

Figure 2.10 Reaction kinetics in 21 pipes in series reaction run with 3 equiv ...

Figure 2.11 Steady state profiles for reactions run in 21 reactor using (a) 6 ...

Figure 2.12 Steady state profile for manufacturing scale (2001) reaction.

Scheme 2.8 Buchwald–Hartwig amination conditions from campaign 1.

Scheme 2.9 Optimized reaction conditions for the formation of

6

.

Scheme 2.10 Some impurities observed in step 8.

Scheme 2.11 Some impurities observed in step 9.

Figure 2.13 Spiking studies for some impurities observed in step 9.

Chapter 3

Scheme 3.1 Metalation/quench sequence.

Figure 3.1 Timescales for flow and batch operation. SM = starting material; E

+

...

Figure 3.2 Possible temperature profiles: (a) accurate (quasi‐isothermal) temp...

Scheme 3.2 Metalation of

ortho

‐bromo‐aryl benzyl ethers under flow conditions:...

Scheme 3.3 Selectivity control gained by different residence times: outpacing ...

Scheme 3.4 Selectivity of the addition of phenyl lithium to diethyl oxalates i...

Figure 3.3 Schematic for a low temperature hardware setup.

Figure 3.4 Hot spots for clogging.

Scheme 3.5 Major side reactions when organometallic reagents are used.

Scheme 3.6 Diastereoselective Mannich‐type addition.

Key words

: diastereoselec...

Scheme 3.7 Reaction sequence toward a regulatory starting material using CSTRs...

Scheme 3.8 Synthesis of difluorobenzaldehyde and difluorotoluene in continuous...

Scheme 3.9 Metalation sequence toward bromomethyltrifluoroborate.

Key words

: B...

Scheme 3.10 Two‐step reaction sequence toward boronic acids.

Kew words

: Br/Li ...

Scheme 3.11 Multi‐step sequence toward a sulfonamide‐substituted benzoxazole.

Chapter 4

Scheme 4.1 The Mizoroki–Heck coupling.

Scheme 4.2 Selected applications of Mizoroki–Heck couplings at Albemarle and P...

Scheme 4.3 Challenges of nickel‐catalyzed Heck couplings.

Scheme 4.4 Types of reaction conditions for nickel‐catalyzed Heck couplings.

Scheme 4.5 Enantioselective nickel‐catalyzed classical couplings.

Figure 4.1 3,3

‐

Disubstituted oxindoles in natural products and synthetic...

Scheme 4.6 Palladium‐catalyzed intramolecular Mizoroki–Heck reaction.

Scheme 4.7 Precedents on nickel‐catalyzed Mizoroki–Heck cyclizations.

Scheme 4.8 Catalytic cycle and challenges associated with a nickel‐catalyzed e...

Scheme 4.9 Ligand screening.

Scheme 4.10 Impact of the aryl electrophile and alkene geometry.

Scheme 4.11 Scope of the nickel‐catalyzed Mizoroki–Heck cyclization.

Figure 4.2 Limitations of the methodology.

Scheme 4.12 Radical‐clock to probe the presence of organic radical.

Scheme 4.13 The proposed catalytic cycle for Ni‐catalyzed intramolecular Mizor...

Scheme 4.14 Optimal chiral ligands identified after library screening.

Scheme 4.15 Impact of alkene geometry.

Scheme 4.16 Reaction conditions promoting the neutral or cationic pathway.

Scheme 4.17 Synthesis of the QuinoxP*•NiCl

2

complex.

Scheme 4.18 Study of the scope of the enantioselective nickel‐catalyzed Mizoro...

Scheme 4.19 Energetic profiles for oxidative addition and insertion steps of M...

Figure 4.3 Geometries of the stereodetermining oxidative addition transition s...

Scheme 4.20 Proposed stereoselection mechanism for the

E

and

Z

isomers.

Chapter 5

Figure 5.1 Retrosynthetic analysis of Aliskiren.

Figure 5.2 Effect of Mg equivalence on purity of 2 (%).

Figure 5.3 Effect of DBE equivalents on Grignard and coupling reaction.

Figure 5.4 Proposed mechanism for formation of impurities.

Figure 5.5 Effect of THF concentration on the Grignard reagent and coupling re...

Figure 5.6 Effect of Grignard stirring time on conversion of

2

.

Figure 5.7 Kumada–Corriu cross‐coupling reaction and mechanistic understanding...

Figure 5.8 Study of Fe(acac)

3

and NMP equivalents.

Figure 5.9 Study of four equivalence.

Figure 5.10 Model study for coupling reaction.

Figure 5.11 Purity trend for 10 large scale batches.

Figure 5.12 Reagents and conditions: (i)

N‐Bromosuccinimide

(

NBS

), 42.5%...

Figure 5.13 ATFE purification purity trend (before/after) of 10 large‐scale ba...

Chapter 6

Scheme 6.1 Endgame of the commercial synthesis of HCV NS5B inhibitor beclabuvi...

Scheme 6.2 Palladium‐catalyzed intramolecular direct arylation of aryl bromide...

Scheme 6.3 Four‐step telescope sequence to prepare aryl bromide disodium salt

Figure 6.1 Top performing ligands in the palladium‐catalyzed cyclization of

1

.

Scheme 6.4 KOAc/DMAc process of final intermediate

2

.

Scheme 6.5 TMAOAc/DMF process of final intermediate

2

.

Figure 6.2 Main impurities formed in the cyclization of aryl bromide

1

with TMA...

Scheme 6.6 Potential hydrolyses of aryl bromide

1

during crystallization.

Scheme 6.7 Palladium‐catalyzed debromination of

1

with stoichiometric sodium f...

Figure 6.3 Revised charge order to mitigate the effect of residual NaOH on des...

Figure 6.4 Hydrolysis of DMF and DMAc with NaOH.

Figure 6.5 Impact of spiked NaOH on the level of

7

in DMF vs DMAc cyclization ...

Scheme 6.8 Commercial process for the synthesis of final intermediate

2

from a...

Figure 6.6 Reagent charge order for the cyclization reaction of the commercial...

Figure 6.7 Impact of oxygen on impurity profile and residual palladium content...

Figure 6.8 Impact of temperature and hold time post‐reaction age on the format...

Figure 6.9 Proposed catalytic cycle for the cyclization of

1

to

2

and formatio...

Figure 6.10 Solubility impact of added EtOH to the Acidification phase split.

Figure 6.11 Solubility of

2

with respect to DMAc (l/kg) in EtOH (target 7.0 l/...

Figure 6.12 Solubility of

2

as a function of temperature.

Figure 6.13 Desaturation of

2

over 16 hours during the crystallization.

Chapter 7

Scheme 7.1 Conventional cross‐coupling vs. direct arylation.

Scheme 7.2 CH arylation of heterocycles.

Figure 7.1 Angiotensin(II) receptor antagonists (ARBs).

Figure 7.2 Biphenyl core of angiotensin(II) receptor antagonists (ARBs).

Scheme 7.3 Model for Ru‐catalyzed angiotensin(II) receptor antagonists (ARBs) ...

Scheme 7.4 Seki's method for Ru‐catalyzed synthesis of selected angiotensin(II...

Scheme 7.5 Ruthenium‐catalyzed synthesis of irbesartan.

Scheme 7.6 Ackermann's method for Ru‐catalyzed synthesis of selected angiotens...

Scheme 7.7 Retrosynthetic analysis of synthesis of anacetrapib.

Scheme 7.8 CH activated carbon‐carbon coupling for the synthesis of anacetrap...

Figure 7.3 [Ru

2

Cl

2

(

p

‐cymene)(HCOO)

3

]Na (sodium η‐6‐

p

‐cymene dichloro dirutheni...

Scheme 7.9 CH arylation using ruthenium formato complex MCAT‐53

TM

.

Scheme 7.10 Application of ruthenium formato complex MCAT‐53

TM

toward anacetra...

Scheme 7.11 Examples – Alkylation of nonaromatic moieties.

Scheme 7.12 Example – Acylation of benzoquinoline.

Scheme 7.13 Synthesis of dihydrofurans.

Scheme 7.14 Example – Annulation of alkynol.

Scheme 7.15 Synthesis of narbosine B.

Scheme 7.16 Synthesis of omarigliptin.

Scheme 7.17 Synthesis of N‐containing carbocyles.

Scheme 7.18 Synthesis of isocoumarins using electrolysis.

Scheme 7.19 Synthesis of substituted phthalides.

Scheme 7.20 Synthesis of substituted indoles.

Scheme 7.21 Synthesis of dihydro‐isoquinolones.

Scheme 7.22 Synthesis of isoquinolones from benzamides.

Scheme 7.23 Synthesis of isoquinolines from keto oximes.

Scheme 7.24 Synthesis of isocoumarin and α‐pyrone.

Chapter 8

Figure 8.1 Pictorial overview of micellar catalysis.

Figure 8.2 Exchange of amphiphiles between micelles.

Figure 8.3 Structures of commonly used nonionic amphiphiles.

Figure 8.4 Demicellization at higher temperature.

Figure 8.5 Effect of the reactant on the micellar size and distribution.

Figure 8.6 Expansion of micelle size upon addition of cosolvent.

Figure 8.7 Co‐solvent technique when a reaction mixture contains volatile subs...

Figure 8.8 General sequence of addition. Notably, uniform and effective stirri...

Figure 8.9 Catalyst and micelle association.

Scheme 8.1 Suzuki–Miyaura couplings in the micelles of PTS.

Scheme 8.2 Coupling of allylic ethers assisted by micelles of PTS.

Scheme 8.3 Suzuki–Miyaura couplings – no use of organic solvents at any stage.

Scheme 8.4 Nano‐nickel technology for cross‐couplings.

Scheme 8.5 Selective Suzuki–Miyaura couplings using copper and ppm levels of p...

Scheme 8.6 HandaPhos technology for cross‐couplings with ppm palladium.

Scheme 8.7 Iron ppm palladium technology for cross‐couplings.

Scheme 8.8 Micelle‐enabled couplings of unactivated (iso)quinoline systems.

Scheme 8.9 Micellar Heck couplings.

Scheme 8.10 Micelle‐assisted Negishi couplings.

Scheme 8.11 Advancements in the micellar Negishi couplings.

Scheme 8.12 C–H activations in micellar media.

Scheme 8.13 C–H activation of benzoic acids.

Scheme 8.14 Synthesis of cinnamate esters via micellar catalysis.

Scheme 8.15 C–H arylation of heterocycles.

Scheme 8.16 Aminations in micellar media.

Scheme 8.17 A broader scope of micellar aminations.

Scheme 8.18 Borylation at room temperature.

Scheme 8.19 Arylation of nitroalkane in micellar media.

Scheme 8.20 Micellar catalysis adopted by Novartis Pharmaceuticals – compariso...

Figure 8.10 Effect of reaction medium on the cost reduction.

Scheme 8.21 Use of micellar media for the synthesis of bioactive molecule (by ...

Scheme 8.22 Highly challenging Suzuki–Miyaura coupling accomplished in the mic...

Chapter 9

Figure 9.1 Asymmetric Ir‐catalyzed imine hydrogenation in the (S)‐metolachlor ...

Figure 9.2 Asymmetric hydrogenation of a cyclic imine en route to solifenacin.

Figure 9.3 Asymmetric hydrogenation of a complex olefin substrate.

Figure 9.4 A Cat 24 reaction vessel used for small‐scale catalyst screening ex...

Figure 9.5 A Biotage Endeavour used for screening of reaction conditions and o...

Figure 9.6 Stand‐alone autoclaves used for preliminary reaction scale‐up.

Figure 9.7 Efficient Rh‐catalyzed asymmetric hydrogenation of an unsaturated c...

Figure 9.8 Rh‐catalyzed asymmetric hydrogenation of a pyridine‐substituted ena...

Figure 9.9 Asymmetric hydrogenation using a rhodium catalyst with ammonium chl...

Figure 9.10 Asymmetric hydrogenation of an enone with zinc triflate as an addi...

Figure 9.11 Ru‐catalyzed asymmetric hydrogenation of a pyridyl ketone in the p...

Figure 9.12 Ru‐catalyzed asymmetric hydrogenation of a dehydro beta‐amino acid...

Figure 9.13 An alternative Ru‐BINAP‐based catalytic system using NaBr as an ad...

Figure 9.14 Rh‐catalyzed asymmetric hydrogenation of an unsaturated acid for A...

Figure 9.15 Retrosynthesis of Aliskiren via Curtius rearrangement and asymmetr...

Figure 9.16 Rhodium‐Phanephos‐catalyzed asymmetric hydrogenation of synthetic ...

Figure 9.17 Rhodium‐Phanephos‐catalyzed asymmetric hydrogenation of unsaturate...

Figure 9.18 Rhodium‐Phanephos‐catalyzed asymmetric hydrogenation at lower cata...

Figure 9.19 Multifunctional ruthenium‐ampy catalysts from Prof. Baratta et. al...

Figure 9.20 Examples of solvent‐free conditions for chemoselective aldehyde hy...

Figure 9.21 Highly efficient and user‐friendly hydrogenation of benzaldehyde o...

Chapter 10

Figure 10.1 2005 Chemistry Nobel Prize Winners: Yves Chauvin, Robert H. Grubbs...

Figure 10.2 Popular molybdenum and tungsten catalysts.

Figure 10.3 Popular ruthenium catalysts.

Figure 10.4 Examples of pharmaceuticals that utilize metathesis for their synt...

Figure 10.5 Initial synthetic route of BILN‐2061. Conditions: (i)

5

(5 mol %) ...

Figure 10.6 Improved route for BILN‐2061. Conditions

:

(i)

9

(0.1 mol%), PhMe (...

Figure 10.7 (a) Process for hydrogenated metathesized soybean oil. (b) Soywax ...

Figure 10.8 Synthesis of peach twig borer pheromone.

Figure 10.9 General scheme for ethenolysis of seed oils.

Figure 10.10 Differences in ethenolysis and alkenolysis

Figure 10.11 Mechanistic pathway for a‐olefins.

Figure 10.12 General polymerization scheme of DCPD.

Figure 10.13 Formation of

cis

‐catalyst.

Figure 10.14 Effect of ligands on ruthenium metathesis catalyst reactivity.

Figure 10.15 Ruthenium catalysts.

Figure 10.16 Example of the “Boc effect” in macrocycle synthesis.

Figure 10.17 Application reference guide, Umicore naming (material naming).

Figure 10.18 Examples of chelators used to remove ruthenium.

Chapter 11

Scheme 11.1 Representative examples of carboxylic acids derived from Biomass.

Scheme 11.2 Dehydrative decarbonylation of carboxylic acids.

Figure 11.1 Proposed mechanism for transition‐metal dehydrative decarbonylatio...

Scheme 11.3 Rhodium catalyzed decarbonylation of stearic acid.

Scheme 11.4 Pd‐ and Rh‐catalyzed dehydrative decarbonylation of fatty acids.

Scheme 11.5 Pd‐ and Ir‐catalyzed dehydrative decarbonylations.

Scheme 11.6 PdCl

2

(PPh

3

)

2

/XantPhos catalyzed dehydrative decarbonylation.

Scheme 11.7 Well‐defined palladium precatalysts in dehydrative decarbonylation...

Scheme 11.8 Fe‐catalyzed decarbonylation.

Scheme 11.9 Ni‐catalyzed dehydrative decarbonylation by Tolman group.

Scheme 11.10 Decarbonylation of esters.

Scheme 11.11 Synthesis of α‐vinyl carbonyl compounds featuring a quaternary st...

Guide

Cover

Table of Contents

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Organometallic Chemistry in Industry

A Practical Approach

With a Foreword by Robert H. Grubbs

Edited by

Thomas J. Colacot

Carin C.C. Johansson Seechurn

Copyright

Editors

Thomas J. Colacot

Millipore Sigma (division of Merck

KGaA, Darmstadt, Germany)

6000 N Teutonia Avenue

Milwaukee, WI 53209

USA

Carin C.C. Johansson Seechurn

Johnson Matthey Plc

28 Cambridge Science Park

Milton Road, Cambridge CB4 0FP

United Kingdom

All books published by Wiley‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.:

applied for

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Foreword

In the late 1960s and through the 1970s, organometallic chemistry emerged from being a subfield of inorganic chemistry, where the interest was in boding and structure, to a field in its own right with chemists trained in inorganic or organic chemistry. The organic chemists brought reactivity to the field and helped to move organometallic chemistry into catalysis. The pioneering work of Collman, Vaska, and Halpern among others defined the basic mechanisms of the field and provided the basis for the application of this new field in organic transformations and organic synthesis. Now, most pharmaceuticals and natural product syntheses involve one, if not more, catalytic steps. The study of asymmetric hydrogenation and the ligands and mechanisms that controlled these processes paved the way for the discovery of a wide array of asymmetric processes. The structural flexibility of homogeneous catalysts and the wide array of ligands now available have resulted in most catalytic processes now being capable of producing products in high asymmetric purity. Heterogeneous catalysts, although they are generally favored for ease of processing, do not provide the flexibility required for more precise transformations. The rise of homogeneous catalysts has required the development of processes and methods that allow homogeneous catalysts to be exploited in practical large‐scale processes.

Colacot (Millipore Sigma, a business of Merck KGaA) and Seechurn (Johnson Matthey), the editors of this book, have addressed these issues. After authoring the first chapter, which provides the historical background for the development of homogeneous catalysts and the basic mechanisms, they have chosen an outstanding group of authors to provide specific information about the practical aspects of the conversion of laboratory‐scale reactions into real processes. Most of the processes are demonstrated by real examples. Themes of the chapters emphasize new developments in the pharmaceutical industry processes such as flow and continuous processes and the development of catalysts based on earth‐abundant metals.

Chapters 2 and 3 discuss the advantages of continuous flow process. For example, the safe use of oxygen with organic solvents can be mitigated by the use of flow systems, and efficient processes can be developed for homogeneous reactions on scale. Particularly interesting is the use of the Buchwald–Hartwig reaction in a flow system with the efficient removal of the residual palladium catalysts. The second of the two chapters describes the methods for the use of low‐temperature processes in the production of materials on a large scale, which involve reactive and environmentally sensitive reagents. These two chapters provide a detailed update on flow processes with the goal of increasing the use of flow processes in homogeneous processes. These processes regain some of the advantages that were traditional with heterogeneous catalysts while maintaining the selectivity of homogeneous processes. In a related process development, Chapter 8 describes the use of another “nanoreactor”: micelles in water. In this chapter, the developments of traditional homogeneous cross‐coupling reactions such as Heck and Suzuki–Miyaura in aqueous environments using a micelle environment are described. Carrying out the reactions in nanoreactors – micelles – results in interesting new selectivity and reactivity. From a process chemist's perspective, micelle‐enabled processes can offer benefits such as the replacement of toxic organic solvents, reduced PMI value, improved reaction yields, high purity of API with reduced metal contents, and high cost efficiency.

As processes are scaled, the costs of the metal and ligands become more important. Chapters 4 and 5 describe the development of processes that are traditionally carried out using precious metals by rather employing either nickel or iron. These successful examples will encourage further development of efficient selective catalysts based on earth‐abundant metals. In spite of potential costs, palladium catalysts have been shown to have a wide array of activities and selectivities. Chapter 6 demonstrates an outstanding example of the use of palladium in the commercial synthesis of beclabuvir utilizing the selectivity of palladium catalysts. Although, earth‐abundant metals can take the place of palladium in a number of reactions, or rather complement Pd, the efficiency and selectivity of many palladium catalysts will ensure that it continues to be used in the pharmaceutical and fine chemical industry for many years to come.

Chapters 7, 9, and 10 cover specific reactions in process chemistry. The chapter on homogeneous hydrogenation provides a guide to the use of asymmetric hydrogenation in the synthesis of complex structures on a commercial scale. Asymmetric hydrogenation is one of the oldest and most used asymmetric processes in synthesis. This up‐to‐date guide provides the highlights of this field and helps to simplify the vast literature. In contrast, CH activation in complex synthesis is one of the newer areas of emphasis. For a number of years, there has been the recognition of the value of being able to functionalize CH bonds directly, although C–H activation has not risen up like the cross‐coupling reactions for industrial process. Therefore, the editors were conscientious enough to add a chapter on this topic. As is demonstrated in Chapter 7, this promise is now being realized as demonstrated by the use of a CH activation process in the synthesis of important compounds such as Merck's anacetrapib, sartans, etc. Olefin metathesis has been an important topic in academic synthesis for several decades; Phillips provides examples where this background of reactivity is now being translated into key structures for the pharmaceutical industry. He provides particularly good coverage of the important topics such as catalyst stability and removal that are required for the use of a homogeneous catalyst in a larger process.

The last chapter takes homogeneous catalysts outside of the applications in the pharmaceutical industry to the conversion of biomass‐derived materials into chemical feedstocks. As many biomass sources are solids, a soluble catalyst is particularly suited for such applications. Although they focus on the conversion of carboxylic acids into olefins, the techniques and strategies would apply to many other such processes and can be developed for potential applications in industry.

It is particularly pleasing to see the evolution of organometallic chemistry into catalysts for extremely useful organic transformations. The basic principle and reaction mechanisms that were developed in the early decades of the area are now the basis for major processes that open the efficient synthesis of an amazing array of new chemical structures that have revolutionized how present‐day bioactive materials are designed and prepared. Colacot and Seechurn have used their broad experience in new catalyst development, organic synthesis, and process chemistry involving homogeneous catalysts to assemble an outstanding team of authors from all over the world to highlight the important developments required to fulfill the promise of catalysis in organic synthesis for the twenty‐first century. This is a very timely book for both academia and industry chemists and engineers to understand how academic concepts are translated into industries with a wide variety of important molecules as depicted in the cover of the book.

Robert Howard Grubbs

Division of Chemistry and Chemical Engineering

California Institute of Technology, Pasadena, CA 91125 USA

[phone], [e-mail]

Prof. Grubbs Biography

B.A. and M.S. Chemistry, University of Florida, Gainesville, Florida, 1963 and 1965. Ph.D., Chemistry, Columbia University, New York, 1968. NIH Postdoctoral Fellow, Chemistry, Stanford University, 1968‐69. He is the Victor and Elizabeth Atkins Professor of Chemistry at the California Institute of Technology, Pasadena, California, USA, and a faculty member since 1978. He was a faculty member at Michigan State University from 1969 to 1978.

The Grubbs group discovers new catalysts and studies their fundamental chemistry and applications. For example, a family of catalysts for the interconversion of olefins, the olefin metathesis reaction, has been discovered in the Grubbs laboratory. In addition to their broad usage in academic research, these catalysts are now used commercially. Other projects involve the design and synthesis of materials for use in medical applications. He has also been involved in the translation of technology through the founding of five companies.

His awards have included the Nobel Prize in Chemistry (2005) and 10 ACS National Awards. He was elected to the National Academy of Sciences (1989), Fellow of the American Academy of Arts and Sciences (1994), the Honorary Fellowship of the Royal Society of Chemistry (2006), Fellow of National Academy of Inventors, National Academy of Engineering (2015), and Foreign Member of the Chinese Academy of Sciences (2014) and of Great Britains's Royal Society (2017). He has 655+ publications and 160+ patents based on his research.

1Industrial Milestones in Organometallic Chemistry

Ben M. Gardner1, Carin C.C. Johansson Seechurn2, and Thomas J. Colacot3

1Cambridge Display Technology Ltd, Unit 12 Cardinal Park, Cardinal Way, Godmanchester, PE29 2XG, UK

2Johnson Matthey, 28 Cambridge Science Park, Milton Road, Cambridge, CB4 0FP, UK

3Millipore Sigma (A Business of Merck KGAa Darmstadt, Germany), 6000N Teutonia Avenue, Milwaukee, WI 53209, USA

1.1 Definition of Organometallic and Metal–Organic Compounds

Organometallic compounds can be defined as compounds that contain at least one chemical bond between a carbon atom of an organic moiety and a metal. The metal can be alkaline, alkaline earth, transition metal, lanthanide, or a metalloid such as boron, silicon, and phosphorus. Therefore, metal–phosphine complexes are also often included in this category, although they do not contain a typical metal–carbon bond – they are more commonly referred to as “metal–organic compounds.” For the purposes of this book, applications of both organometallic and metal–organic compounds are discussed on the basis of “organometallic chemistry.”

1.1.1 Applications and Key Reactivity

The three major types of applications of organometallic compounds in industry are in the areas of electronics, polymers, and organic synthesis. In organic synthesis, the organometallic compounds are used as either catalysts or stoichiometric reagents.

1.1.1.1 Electronic Applications

For electronic applications typically, the organometallic complex is subjected to chemical vapor deposition (CVD) to form an appropriate thin layer or subjected to organometallic chemical vapor deposition (OMCVD) where the deposition ultimately occurs via a chemical reaction at the substrate surface to produce a high‐quality material. The production of thin films of semiconductor materials is used, for example, for LED applications via metal–organic vapor‐phase epitaxy (MOVPE) where volatile organometallic Me3E (E = Ga, In, Al, and Sb) compounds are used as precursors. They react with ultrapure gaseous hydrides in a specialized reactor to form the semiconducting product as a crystalline wafer [1–23].

1.1.1.2 Polymers

Another major application for organometallic complexes is in the polymer industry. Three common types of polymers produced via catalysis are particularly noteworthy. Polysiloxanes, also known as silicone, are polymers made up of repeating units of siloxane [4]. They have widespread application in a large number of different fields ranging from cookware to construction materials (e.g. GE silicone), medicine, and toys. Pt‐based catalysts are commonly applied in the silicone industry for the production of a variety of products [5]. A milestone in the history of organometallic chemistry in the industry was the discovery of the Ziegler–Natta catalyst and its application in polymerization reactions [6]. Ziegler and Natta were awarded the Nobel Prize for their work in this field in 1963 [7]. Another area that has been recognized for its importance is olefin metathesis for which a Nobel Prize has been awarded to Grubbs, Schrock, and Chauvin. This has been applied to synthesize polymers via ROMP (ring‐opening metathesis polymerization) [8].

1.1.1.3 Organic Synthesis

The focus of this book, however, is on the exploitation of organometallic compounds for organic synthesis, relevant to industry applications. One of the major applications in organic synthesis is catalysis.

In cases where the organometallic compound is used as a catalyst, for example in a process involving cross coupling, a precatalyst should be able to get activated to the active catalytic species to bind with the organic substrate(s), do the transformation, and release the product such that the active catalytic species returns to its original state in the catalytic cycle. During the organic transformation, the concentration of the catalyst can decrease with time because of poisoning. The efficacy and efficiency of the catalyst depend on how fast and how long it can retain its original activity. The turnover numbers (TONs) and turnover frequencies (TOF) are usually used to describe the activity of a catalyst. Organic chemists have started using organometallic compounds as catalysts to develop more efficient and practical processes [9–12].

The reactivity of organometallic complexes toward various reagents is the reason behind the widespread use of organometallic compounds as catalysts for a variety of organic transformations. The most important types of organometallic reactions are oxidative addition, reductive elimination, carbometalation, hydrometalation, β‐hydride elimination, organometallic substitution reaction, carbon–hydrogen bond activation, cyclometalation, migratory insertion, nucleophilic abstraction, and electron transfer. In the following paragraphs, we will provide a brief overview of the basic theory with some selected applications.

Oxidative addition involves the breakage of a bond between two atoms X–Y. Splitting of H2 with the formation of two new metal–H bonds is an example of an oxidative addition process (Scheme 1.1). Reductive elimination is the reverse of this process. In an oxidative addition process, the oxidation state of the metal is increased by 2, whereas in reductive elimination, oxidation state of the metal is decreased by 2. Both steps are crucial for metal‐catalyzed cross‐coupling reactions, as the first and the last steps of the catalytic cycle. Several factors can affect these two steps. The structure of the ligand (phosphine or other molecules coordinated with the metal), the coordination number of the metal in the complex, and the way in which the complex is activated to the catalytic species in the catalytic cycle, etc., can be modified and tailored to get the best outcome for a particular reaction [13]. The oxidative addition of H2 onto Vaska's complex (Scheme 1.1) is a crucial step in metal‐catalyzed hydrogenation reactions. The application of this methodology to industrially relevant molecules is further discussed in Section 1.3.3.

Scheme 1.1 Oxidative addition and reductive elimination.

Carbometalation involves, as the name suggests, the simultaneous formation of a carbon–metal and a CC bond. This is most commonly used to form a stoichiometric metal‐containing reagent, such as the reaction between ethyllithium and bis‐phenylacetylene in the synthesis of TamoxifenTM, a breast cancer drug (Scheme 1.2) [14].

Scheme 1.2 Carbometalation as a key step toward the synthesis of TamoxifenTM.

Hydrometalation is similar to carbometalation, where, instead of a CC bond, a CH bond is formed alongside the carbon–metal bond. One such example is hydroalumination, where DIBAL (i‐Bu2AlH) is added across an alkyne (Scheme 1.3) [15]. This, similar to carbometalation, is most commonly a stoichiometric transformation with the aim of preparing an organometallic reagent that can be used as a reactant for subsequent desired transformations.

Scheme 1.3 Hydroalumination of alkynes.

β‐Hydrogen elimination, technically the reverse of hydrometalation, can in some cases result in the formation of undesired side products. In other cases, it is a “blessing” as the preferred reaction pathway. In Shell higher olefin process (SHOP), for the oligomerization to occur, a final β‐hydrogen elimination reaction is performed to release the substrate from the catalyst (Scheme 1.4a) [16]. In the cross‐coupling reaction between an aryl halide and an organometallic reagent containing β‐hydrogens, this reaction can form the undesired alkene side products, hence detrimental. This is the reason why sp2–sp3 coupling and sp3–sp3 coupling become very challenging even today. However, a few success stories of these types of cross‐coupling reactions have been reported, such as sp2–sp3 Negishi reaction for the synthesis of LX2761, a diabetes drug by Lexicon Pharmaceuticals (Scheme 1.4b) [17].

Scheme 1.4 a) β‐hydride elimination is exploited in the Shell higher olefin process (SHOP). b) sp2−sp3 cross-coupling in the synthesis of a diabetes drug.

Organometallic substitution reactions can occur either via an associative or a dissociative substitution mechanism. This can be compared to SN1 and SN2 substitution mechanisms in organic chemistry. The overall outcome in either case is an exchange of a ligand on the organometallic complex. Scheme 1.5 illustrates an associative substitution mechanism to exchange Cl for X on Vaska's complex. This complex does not have any significant references to being employed in industry as a catalyst, but studies of its reactivity has been vital in providing the conceptual framework for homogeneous catalysis [18].

Scheme 1.5 Organometallic substitution reaction exemplified by Vaska's complex.

Source: Wilkins 1991 [24]. Reproduced with permission of John Wiley & Sons.

One of the reactions that has become increasingly exploited, particularly to complement the cross‐coupling chemistry, is C–H activation. This is where the metal gets inserted into a CH bond of the substrate. There are many different pathways for this to happen; it can be promoted and directed to the site of choice by using a directing group, such as the amide exemplified in Scheme 1.6. Iridium‐catalyzed direct borylation reactions can also be considered as a type of C–H functionalization reaction. This type of reactions is further discussed in Section 1.3.2.1.

Scheme 1.6 Carbon–hydrogen bond activation exemplified by the total synthesis of calothrixin B, which possesses various biological activities such as anti‐malarial and anti‐cance.

Source: Ramkumar and Nagarajan 2013 [25]. Reproduced with permission of American Chemical Society.

In cyclometalation reaction, the strain of certain motifs is often exploited to insert the metal into CC bonds. One example is the Rh‐catalyzed insertion into cyclopropanes to form metallacyclobutanes (Scheme 1.7). This has been applied in the total synthesis of (±)‐β‐cuparenone [19]. Metallacyclobutanes also form a very crucial part of the metathesis olefination mechanism, as deduced by Chauvin [20].

Scheme 1.7 Cyclometalation exemplified by the oxidative additions of Rh into a cyclopropane moiety.

Migratory insertion is crucial for any carbonylation reaction and is illustrated in Scheme 1.8 by a step in the iridium‐catalyzed Cativa process, where methanol is converted into acetic acid [21]. The migration involves the insertion of one ligand (CO) into the metalC bond (Ir‐Me). The reverse reaction, decarbonylation of aldehydes to form an alkane with the release of CO, is also a reaction known to be catalyzed by Rh complexes [22], such as Wilkinson's catalyst [23]. Migratory insertion is not restricted to CO alone but can also occur with SO2, CO2, and, most importantly, alkenes. The insertion of an alkene into an MC bond is the key step in any oligo‐ or polymerization reaction, such as the Ziegler–Natta process [26].

Scheme 1.8 Migratory insertion exemplified by a step in the Cativa process.

Nucleophilic abstraction is a process when a ligand is fully or partly removed from the metal by the action of a nucleophile. In Scheme 1.9, the action of n‐BuLi on a chromium‐coordinated benzene ligand results in hydrogen abstraction [27]. Basically, the chemical reactivity of the ligand is altered when coordinated with a metal. This alters the reactivity of the ligated compound and may result in reactions that are not possible to carry out with the same non‐ligated substrate.

Scheme 1.9 Nucleophilic abstraction illustrated by hydrogen abstraction using n‐BuLi.

Scheme 1.10 Electron transfer illustrated by one step in the photocatalytic Pschorr reaction to form phenanthrene.

Another important organometallic reaction to be discussed is electron transfer. The ability of certain organometallic complexes to initiate electron transfer reactions in combination with a visible light source has made some transformations possible that cannot be achieved using conventional chemistry. This is illustrated in Scheme 1.10 with one step in the photocatalytic Pschorr reaction using Ru(bpy)32+ as the photoredox catalyst [28,29]. The phenanthrene formed can be further used for various purposes, such as in the manufacture of dyes, pharmaceuticals, etc. [30]. The potential of metal‐catalyzed electron transfer reactions forms the basis for a new area in organic synthesis with lot of potentials [31].

Exploitation of the wide variety of “organometallic reactivity” has made the field of organometallics one of the most applied areas in process chemistry with particular importance to the pharmaceutical, agrochemical, polymer, and fine chemical industries.

1.2 Industrial Process Considerations

Organometallic compounds are routinely prepared and used as stoichiometric reagents or catalysts for a range of synthetic processes on a multikilogram scale or even a ton scale.

In order to operate a commercially viable industrial chemical process, a reliable chemical synthesis route is needed as well as an understanding of how a process will behave during the scale up by taking into consideration factors such as heat and mass transfer, mixing, particle size, and filterability, etc. Air, moisture, and thermal sensitivity of some of the organometallic complexes or their intermediates needs to be addressed with proper handling techniques including inert conditions to achieve the maximum process efficiency and process safety. In addition, incorporation of environmental impact of the process is also very important, where exposure of chemicals and solvents and waste generation need to be minimized.

It is important to have a scalable chemical process, usually optimized on a bench scale to produce milligram to gram and then transferred to the pilot plant, typically to a kilogram scale. During this transfer, typically, one needs to readjust the rate of reagent addition to manage the exotherm, rate of agitation, rate of heating, degassing cycles, reaction time, etc. Identifying the optimal catalyst with the minimal loading especially when one uses platinum group metals (PGMs) in conjunction with expensive ligands is also important. Even for a well‐known organic transformation such as a Pd‐catalyzed cross‐coupling, the process will not be economical if the reaction is poorly optimized, considering metal loss, purification of the products, and waste disposal. A proper understanding of the thermodynamics and kinetics is also important.

Experience in using DOE coupled with a “knowledge‐based” process approach can accelerate the process development. It is important to involve both chemists and chemical engineers during the scale‐up and process optimization, considering the equipment design, safety, raw material selection, etc. Even if the precatalyst is not sensitive to air, one has to conduct the reactions under inert conditions as the “active catalytic species” in the cycle might be sensitive to air. This can not only minimize the by‐product formation but also increase the life cycle of the catalyst and hence the TONs and TOFs.

The kinetic control of an organometallic process can be another important factor. One example is low‐temperature reactions involving organolithium reagents, where it is essential to avoid significant decomposition of thermally sensitive species, thermal promotion of undesired side reactions, and control the reactivity of exothermic processes.

Treatment of waste streams from organometallic processes must be considered carefully as they may contain precious metal or even other transition metal residues originating from the decomposition of the organometallic compounds. Apart from the well‐documented environmental impact of PGM compounds, finely divided PGM particles, if allowed to dry out, pose a significant fire hazard. Because of the significant environmental hazards associated with heavy metal residues, predominantly arising from their persistence in the biosphere via bioaccumulation, generation of this type of waste stream on production scale should be avoided wherever possible, with environmental regulations strictly controlling the level of any emissions. Some common catalyst precursor complexes release harmful side products when activated or substituted. For instance, [Pd(COD)(Cl)2] releases 1,5‐cyclooctadiene (COD) in the presence of phosphines, which, among its other chemical hazards, has a pungent odor even in low concentrations. Therefore, extreme care must be taken when dealing with process waste that contains it. Similarly, many of the metal carbonyl compounds can generate CO gas, which needs to be properly vented. Some of these carbonyl‐based compounds undergo sublimation as well.

1.3 Brief Notes on the Historical Development of Organometallic Chemistry for Organic Synthesis Applications Pertaining to the Contents of this Book

Most organometallic processes have evolved and developed from seminal discoveries in the late 1800s or early 1900s. In some cases, it is easier to pinpoint the exact seminal reports, whereas in other cases, this task is not so easy. Sabatier's report of nickel‐catalyzed hydrogenation can easily be identified as the discovery of metal‐catalyzed hydrogenation reactions [32], for which he got the Nobel Prize in Chemistry in 1912. For the cross‐coupling area, its origin is slightly more difficult to deduce precisely although our 2012 review articles and book provide a much better understanding of the area [9,10,13,33,34]. One could argue that it dates back to 1912 Nobel laureate Victor Grignard's discovery of RMgX reagents, where Grignard shared the Nobel Prize with Sabatier. Although both technologies (Grignard in 1912 and cross‐coupling in 2010) got Nobel Prizes, the former is considered to be a “breakthrough innovation,” whereas the latter is called “incremental innovation.” The impact of cross‐coupling in chemical processes shows its significance by being awarded the Nobel Prize, in comparison to many competing technologies.

In this section, we will briefly go through the origins of a few prominent areas within organometallic chemistry and how they relate to the current industrial applications with respect to the topics covered by the chapters in this book.

1.3.1 Synthesis of Stoichiometric Organometallic Reagents

1.3.1.1 Conventional Batch Synthesis

Arguably, the most important stoichiometric organometallic reagents are organolithium compounds, RLi. The studies of these reagents were pioneered by Karl Ziegler, Georg Wittig, and Henry Gilman [35]. Their relatively straightforward preparation, high basicity, and wide array of functionality provide convenient access to useful synthetic routes such as metalation, deprotonation, carbolithiation, and transfer or exchange of the nucleophilic organic fragment R−.

In 1899, by substituting Mg for Zn in alkylation reactions, Philippe Barbier's student Victor Grignard (Figure 1.1) developed the RMgX alkylating agents that bear his name to this day. Being a less sensitive but more potent source of alkyl anions than their Zn‐based counterparts, Grignard showed how they can efficiently alkylate carbonyl compounds, a discovery that proved to have huge impact in synthetic chemistry and earned him a Nobel Prize in 1912 [36].

Figure 1.1 Victor Grignard.

Source: https://commons.wikimedia.org/w/index.php?curid=545837. Licensed under CC BY 3.0.

Today, Victor Grignard is remembered as the father of organometallic chemistry. Organomagnesium compounds represent very useful alternatives to their lithium counterparts, exemplified by the widespread use of Grignard reagents, RMgX, for efficient alkylations and arylations. These reagents are now produced in multiton quantities. Organocalcium compounds are more reactive alkyl sources than Grignard reagents, but their applications are limited because of the increased difficulty of their preparation and the thermal instability they exhibit. Organocalcium compounds have also shown promise as hydroamination catalysts. In comparison to organolithium and organomagnesium, organoaluminum compounds, R3Al reagents, are generally far less effective stoichiometric reagents but do add to alkenes and alkynes with high regio‐ and stereoselectivity via carboalumination. Importantly, however, they have found particular use as a vital component of the heterogeneous Ziegler–Natta polymerization process for the industrial‐scale production of polyethylene and polypropylene. Aluminum alkyls are also widely utilized for group III–V chemistry for the production of electronic materials via CVD.

1.3.1.2 Organometallics in Flow

Industrial‐scale organic synthesis for fine chemical applications, such as natural products or active pharmaceutical ingredients (APIs), and organometallic syntheses have traditionally been conducted in batch using large‐volume (>100 l) reactors. In continuous flow processes, small amounts of reagent solutions are continuously pumped along a flowing stream to mix at a specific junction with resonance time to react them together to yield the product, which is being purified under the flow conditions and collected. In some cases, a cascade approach has been considered where multiple reagents have been mixed sequentially rather than performing reactions in different batch reactors. Industries have been using this technique for the manufacture of petrochemicals and bulk chemicals as this approach has proven to be not only most economical but also produce good‐quality products consistently. The recent interest in flow chemistry in academia for the synthesis of more complex organic compounds has increased efforts to apply this rapidly burgeoning technology both in fine chemical and pharmaceutical industries. The advantages that flow processes can bring in a commercial context relative to batch production are shorter reaction times, greater temperature control, rapid optimization, shorter path length for photochemical reactions, and improved process safety. Chapter 2, authored by Joseph Martinelli of Eli Lilly, presents the design, development, and implementation of an API manufacturing route under continuous flow conditions to showcase the application of this technology in organic synthesis. Chapter 3 details the lithiation and borylation chemistry under flow, as developed by Joerg Sedelmeier and Andreas Hafner at Novartis. This chapter provides a snapshot of how this technology can also be applied for the synthesis of organometallic reagents.

1.3.2 Cross‐coupling Reactions

Several years after Grignard's discovery of RMgX reagents, in 1941, Kharasch undertook the first systematic investigation of transition‐metal‐catalyzed sp2–sp2 carbon coupling, detailing the observation of homocoupling of Grignard reagents [37,38]. Subsequent research from his group led to the earliest report of a cross‐coupling reaction, where a cobalt‐based catalyst was used to couple vinyl bromide with an aryl Grignard reagent [39]. This made him to be the father of cross‐coupling reactions.

The metal catalysts in question are also organometallic complexes that mediate the coupling of two different hydrocarbon fragments for organic synthesis purposes in the fine chemical, agrochemical, and pharmaceutical industries. A simplified catalytic cycle is shown in Scheme 1.11. Many of the key reactivity steps that are characteristic for organometallic complexes are a prerequisite for these reactions to take place. Initial oxidative addition is followed by transmetalation (organometallic substitution) and finally reductive elimination to form the desired product and regenerate the catalyst. Each of these steps has been the subject of a number of studies to try and understand the exact nature of their mechanism. For Suzuki–Miyaura reactions, the transmetalation step has been the focus of attention of several research groups. The Denmark, Lloyd‐Jones, and Hartwig groups have independently studied this step of the catalytic cycle for these types of cross‐coupling reactions [40–42]. In Sonogashira reactions (sp–sp2 bond formation), a Cu cocatalyst is commonly employed [43]. In many recent refinements of this reaction, however, the need for a cocatalyst has been circumvented by, for example, a careful choice of Pd catalyst and reaction conditions [44–46]. The mechanism of the Heck reaction differs from the other named cross‐coupling reactions in that a β‐hydrogen elimination is crucial for the formation of the final product.

Scheme 1.11 Simplified catalytic cycles for cross‐coupling reactions.

Many pioneers have played a role in the development of this area and lent their names to the reactions they have discovered. The importance of cross‐coupling to the field of chemistry was ultimately recognized in 2010 by awarding the Nobel Prize to Richard F. Heck, Ei‐ichi Negishi, and Akira Suzuki for their research efforts in palladium‐catalyzed cross‐couplings in organic synthesis [9,10,13,35,36]. Cross‐coupling is an example where incremental innovation is of equal importance to the breakthrough discovery, significant enough even for the award of the Nobel Prize.

Following from an earlier work by Fujiwara, in 1969, Richard Heck published the first examples of cross‐coupling using stoichiometric palladium(II). Building on a separate work by Mizoroki, he proposed the first Pd(0)‐mediated catalytic cycle for the cross‐coupling of iodobenzene and styrene, opening the door for an explosion of discoveries in Pd‐catalyzed cross‐coupling chemistry. The traditional Mizoroki–Heck reaction forms a substituted alkene via cross‐coupling of an unsaturated halide or pseudo‐halide with an alkene under Pd catalysis and is frequently employed for C–C coupling in industrial settings. The Heck mechanism can also be accessed using nickel to mediate the catalysis. Under certain conditions, this brings advantages relative to the palladium version, such as higher activity. This is thought to be because of lower energy barriers to crucial steps in the catalytic cycle and greater selectivity to the desired product because of the greater efficiency of undesirable β‐hydride elimination for Pd vs Ni. One example of successful implementation and scale‐up of a nickel‐catalyzed Mizoroki–Heck reaction at BI is discussed in detail in Chapter 4 by Jean‐Nicolas Desrosiers and Chris H. Senanayake. This chapter is also relevant in terms of the emerging area of the use of base metal instead of precious metal catalysis.

The Suzuki–Miyaura reaction, where a boronic acid/ester is coupled to a halide or pseudo‐halide precursor under palladium‐mediated catalysis, is the most common C–C coupling reaction in industry. Suzuki couplings are advantageous at a large scale because of the mild reaction conditions, the commercially available and relative environmentally benign boronic acid/ester starting materials, and the comparative ease of disposal of boron‐containing by‐products compared to processes using other organometallic reagents.

The Kumada cross‐coupling reaction utilizes a Grignard reagent and an organic halide as precursors and classically operates under palladium or nickel catalysis. Although demonstrated to be a largely efficient CC bond formation strategy, Kumada couplings can be problematic in large‐scale synthesis because of the high reactivity of Grignard reagents, which exhibit limited functional group tolerance. However, there is a new trend where palladium catalysts are substituted for those containing iron, advantages of which include lower cost of the metal because of higher earth abundance and lower toxicity. Although still relatively new, the iron‐catalyzed Kumada coupling represents a rapidly growing area of organometallic synthesis with great industrial potential, which is discussed in Chapter 5, authored by Rakeshwar Bandichhor of Dr Reddy's Laboratories. Similar to the nickel‐catalyzed Mizoroki–Heck reaction detailed in Chapter 4, Chapter 5 provides another example of the industrial trend in switching from precious metal to earth‐abundant metal catalysis.

Overall, the breadth of catalytic cross‐coupling reactions has found significant application in the field of organic synthesis for the production of pharmaceutically and agriculturally relevant molecules, often employed in several steps as part of a multistep synthesis. Under carefully optimized conditions, these catalysts typically offer advantages over stoichiometric alternatives such as high selectivity, mild reaction conditions, functional group tolerance, low loadings, and avoidance of protecting groups. In cases where the metal‐catalyzed cross‐coupling reaction takes place in the end game of a total synthesis, it is important to determine the levels of residual metal in the final API. There are well‐defined limits for each metal and how much a drug can legally contain [47]. In general, homogeneous cross‐coupling catalysts cannot be recycled, although the metal itself can be recovered from the waste stream.

1.3.2.1 CH Bond Activation

In 1983, Robert Bergman and William Graham independently detail the first transition‐metal‐mediated intermolecular C–H activation of alkanes by oxidative addition by pentamethylcyclopentadienyl–iridium(I) complexes [48,49]. This opened up the possibility of carrying out cross‐coupling reactions where only one cross‐coupling partner, or in rarer cases, neither of the two cross‐coupling partners, is pre‐functionalized as an aryl (pseudo)halide or an organometallic reagent. Noteworthy efforts within this field have been reported by the research groups of Keith Fagnou and coworkers [50], Melanie Sanford and coworkers [51], Christina White and coworkers [52], and Jin‐Quan Yu and coworkers [53]. One class of reaction that falls under the C–H activation category is direct arylation of aromatics or heterocycles. In this type of chemistry, the heterocycle is nonfunctionalized and the successful reaction relies on the inherent nucleophilicity of the substrate or inherent acidity of certain CH bonds in the molecule in order to achieve regioselectivity. Another breakthrough discovery in this area is the iridium/bipyridine‐catalyzed direct borylation, first reported by Hartwig and coworkers [54]. This methodology was recently employed by Pfizer to form a nicotine analog (Scheme 1.12) [55].

Scheme 1.12 Iridium‐catalysed direct borylation in Pfizer's synthesis of a nicotine analog.