Catalytic Functionalization of Allylic Substrates by Palladium Pincer Complexes

Nicklas Selander

©Nicklas Selander, Stockholm 2010 ISBN 978-91-7447-090-1 Printed in Sweden by E-Print, Stockholm 2010 Distributor: Department of Organic Chemistry

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Abstract

This thesis is based on the development of novel catalytic reactions for the synthesis and application of organometallic reagents. The main focus is di-rected towards organoboronate derivatives. We developed an efficient pro-cedure for converting allylic alcohols to the corresponding allylboronates using palladium pincer complexes as catalysts. The reactions were per-formed under mild conditions with high selectivity, allowing further one-pot transformations. Using this approach, a variety of stereodefined homoallylic alcohols and amino acid derivatives were synthesized via trapping of the in situ generated allylboronate derivatives with an appropriate electrophile. The synthetic scope of these types of multi-component reactions is broad as many different substrate allylic alcohols may be used together with various electrophiles. Several aspects of these reactions were studied, including dif-ferent reagents, catalysts and electrophiles.

Furthermore, we studied the possibility to use oxidizing reagents as an es-sential component in the functionalization of olefins. Two main strategies were utilized for these catalytic methods using palladium pincer complexes. The functional group was either transferred from the oxidizing reagent, or introduced via an oxidation-transmetallation route. We propose that both methods involve palladium(IV) intermediates thus expanding both the coor-dination sphere of palladium and the synthetic scope of pincer complex ca-talysis.

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List of Publications

This thesis is based on the following papers, which will be referred to by Roman numerals:

I. Direct Boronation of Allyl Alcohols with Diboronic Acid Us-

ing Palladium Pincer-Complex Catalysis. A Remarkably Fac-ile Allylic Displacement of the Hydroxy Group under Mild Reaction Conditions V. J. Olsson, S. Sebelius, N. Selander, and K. J. Szabó J. Am. Chem. Soc. 2006, 128, 4588-4589

II. Strategies for Fine-Tuning the Catalytic Activity of Pincer-Complexes J. Aydin, N. Selander, and K. J. Szabó Tetrahedron Lett. 2006, 47, 8999-9001

III. Direct Synthesis of Functionalized Allylic Boronic Esters from Allylic Alcohols and Inexpensive Reagents and Catalysts G. Dutheuil, N. Selander, K. J. Szabó, and V. K. Aggarwal Synthesis 2008, 2293-2297

IV. Highly Selective and Robust Palladium-Catalysed Carbon-Carbon Coupling between Allyl Alcohols and Aldehydes via Transient Allylboronic Acids N. Selander, S. Sebelius, C. Estay, and K. J. Szabó Eur. J. Org. Chem. 2006, 4085-4087

V. Petasis Borono-Mannich Reaction and Allylation of Carbonyl Compounds via Transient Allyl Boronates Generated by Pal-ladium-Catalyzed Substitution of Allyl Alcohols. An Efficient One-Pot Route to Stereodefined α-Amino Acids and Homoal-lyl Alcohols N. Selander, A. Kipke, S. Sebelius, and K. J. Szabó J. Am. Chem. Soc. 2007, 129, 13723-13731

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VI. Performance of SCS Palladium Pincer Complexes in Boryla-tion of Allylic Alcohols. Control of the Regioselectivity in the One-Pot Borylation-Allylation Process N. Selander, and K. J. Szabó J. Org. Chem. 2009, 74, 5695-5698

VII. Single-Pot Triple Catalytic Transformations Based on Cou-pling of in situ Generated Allyl Boronates with in situ Hydro-lyzed Acetals N. Selander, and K. J. Szabó Chem. Commun. 2008, 3420-3422

VIII. Synthesis of Stereodefined Substituted Cycloalkenes by a One-Pot Catalytic Boronation-Allylation-Metathesis Se-quence N. Selander, and K. J. Szabó Adv. Synth. Catal. 2008, 350, 2045-2051

IX. Pincer Complex-Catalyzed Redox Coupling of Alkenes with Iodonium Salts via Presumed Palladium(IV) Intermediates J. Aydin, J. M. Larsson, N. Selander, and K. J. Szabó Org. Lett. 2009, 11, 2852-2854

X. Catalytic Allylic C-H Acetoxylation and Benzoyloxylation via Suggested (η3-Allyl)palladium(IV) Intermediates L. T. Pilarski, N. Selander, D. Böse, and K. J. Szabó Org. Lett. 2009, 11, 5518-5521

XI. Selective C-H Borylation of Alkenes by Palladium Pincer Complex Catalyzed Oxidative Functionalization N. Selander, B. Willy, and K. J. Szabó Angew. Chem. Int. Ed. 2010, DOI: 10.1002/anie.201000690

Reprints were made with kind permission from the publishers.

Related papers by the author not submitted as part of this thesis: XII. Catalytic Performance of Symmetrical and Unsymmetrical

Sulfur-Containing Pincer Complexes: Synthesis and Tandem Catalytic Activity of the First PCS-Pincer Palladium Complex M. Gagliardo, N. Selander, N. C. Mehendale, G. van Koten, R. J. M. Klein Gebbink, and K. J. Szabó Chem. Eur. J. 2008, 14, 4800-4809

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XIII. Efficient Synthesis of α-Amino Acids via Organoboronate Re-agents N. Selander, and K. J. Szabó In Asymmetric Synthesis and Application of α-Amino Acids; V. A. Soloshonok, and K. Izawa, Eds.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009, p.190-202

XIV. Synthesis and Transformation of Organoboronates and Stan-nanes by Pincer-Complex Catalysts N. Selander, and K. J. Szabó Dalton. Trans. 2009, 6267-6279

XV. [2,6-Bis[(phenylseleno-κSe)methyl]phenyl-κC]chloropalladium N. Selander, and K. J. Szabó In e-EROS Encyclopedia of Reagents for Organic Synthesis; L. A. Paquette, P. Fuchs, D. Crich, and G. A. Molander, Eds.; Wiley: Chichester, 2009

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Contents

Abstract .........................................................................................................v

List of Publications .................................................................................... vii

Abbreviations............................................................................................. xiii

1. Introduction .............................................................................................1 1.1 Palladium Pincer Complexes ..............................................................................1

1.1.1 Nomenclature and Properties ...................................................................2 1.1.2 Synthesis of Palladium Pincer Complexes..............................................3

1.2 Allylic Organometallic Reagents ........................................................................4 1.2.1 Allylboronic Reagents .................................................................................4 1.2.2 Allylation Reactions with Allylic Boron Reagents ..................................5 1.2.3 Synthesis of Allylic Boronates...................................................................7

1.3 Aim of this Thesis .................................................................................................9

2. Synthesis of Allylic Boronates by Palladium-Catalyzed Substitution Reactions (Papers I-III)....................................................10

2.1. Palladium Pincer Complex-Catalyzed Borylation of Allylic Alcohols .......10 2.1.1 Selectivity and Substituent Effects ........................................................11 2.1.2 Solvent Effects – Methanol as Co-solvent............................................13 2.1.3 Activation of the Hydroxy Group............................................................13

2.2 Fine-Tuning the Catalytic Activity of the Pincer Complex..........................15 2.2.1 Synthesis and Characterization of Methoxy-Substituted Pincer Complexes .............................................................................................................16 2.2.2 Methoxy-Substituted Pincer Complexes in Catalytic Arylation of Vinyl Epoxide and Borylation of Cinnamyl Alcohol........................................16

2.3 Synthesis of Allylic Boronates from Allylic Alcohols and Readily Available Reagents and Catalysts ............................................................................................18 2.4 Comparison of Borylation Reaction Conditions ............................................20 2.5 Proposed Mechanism of the Borylation Reaction.........................................21

3. Development of One-Pot Reactions Based on Palladium-Catalyzed Borylation of Allylic Alcohols (Papers IV-VIII) .................23

3.1 One-Pot Allylation of Aldehydes ......................................................................24 3.1.1 Control of the Regioselectivity in the One-Pot Borylation-Allylation Process....................................................................................................................27

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3.2 One-Pot Allylation of Ketones ..........................................................................30 3.3 Synthesis of α-Amino Acids via Borylation of Allylic Alcohols...................31 3.4 Coupling of Catalytically Generated Allylboronates with in situ Hydrolyzed Acetals ....................................................................................................34 3.5 Stereoselective Synthesis of Cycloalkenes by a One-Pot Borylation-Allylation-Metathesis Sequence ..............................................................................36 3.6 Summary of the One-Pot Transformations...................................................38

4. Palladium-Catalyzed Functionalization of Alkenes Under Oxidative Conditions (Papers IX-XI) .....................................................39

4.1 Pincer Complex-Catalyzed Redox Coupling of Alkenes with Iodonium Salts..............................................................................................................................40

4.1.1 Proposed Mechanism for the Palladium-Catalyzed Arylation of Alkenes ...................................................................................................................42

4.2 Allylic C-H Functionalization via Suggested Palladium(IV) Intermediates.......................................................................................................................................44

4.2.1 Mechanistic Aspects of the Palladium-Catalyzed Acetoxylation and Benzoyloxylation Reactions................................................................................46

4.3 C-H Borylation of Alkenes by Palladium Pincer Complex-Catalyzed Oxidative Functionalization......................................................................................49

4.3.1 Proposed Mechanism ................................................................................52

5. General Conclusions and Outlook .....................................................54

Acknowledgements ...................................................................................55

References ..................................................................................................56

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Abbreviations

The abbreviations are used in agreement with standards of the subject.a Only non-standard and unconventional abbreviations that appear in the thesis are listed here. B2pin2 Bis(pinacolato)diboron BQ 1,4-Benzoquinone L. A. Lewis acid p-TsOH para-Toluenesulfonic acid pin Pinacolato RCM Ring closing metathesis TFA Trifluoroacetate

aThe ACS Style Guide, 3rd ed.; American Chemical Society: Washington, DC, 2006

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1. Introduction

The development of highly selective and efficient transition metal catalysts is of fundamental importance in modern organic chemistry.1-5 Palladium complexes have played a vital role in this process, offering a wide array of catalytic transformations.3-7 A key property of an ideal transition metal cata-lyst is a well-defined metal-ligand bonding, giving the possibility to predict and fine-tune the catalytic activity. One of the strategies to achieve this is to use so called “pincer complexes”.8-18 This thesis is focused on catalytic ap-plications of palladium pincer complexes in selective organic transforma-tions. The major objective is the synthesis of organoboron compounds and the development of various one-pot transformations based on catalytic gen-eration of these species.

1.1 Palladium Pincer Complexes Palladacycles19-23 are amongst the most important types of organopalladium compounds. A special subclass of these compounds are the so-called pincer complexes 18-18 (Figure 1).

Figure 1. Schematic representation of palladium pincer complexes (1) and their most common structural motif (1a)

Since the first reports by Shaw in the 1970s,8 a plethora of different transi-tion metal pincer complexes has been synthesized and studied in multifari-ous catalytic applications.8-18 Palladium pincer complexes have been used as catalysts in a range of diverse organic transformations, including Heck24-38 and Suzuki39-44 couplings, the aldol reaction45-53 and Michael additions.46,54-56 In the Szabó group, several novel methods were developed for the synthesis and transformations of organometallic reagents using palladium pincer com-plexes.13,52,57-72

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The structural diversity of palladium pincer complexes is great. Common to all of them is a tridentate ligand coordinating to palladium in a meridional fashion, to create two palladacyclic rings. Usually, the pincer ligand is based on an anionic aromatic backbone (as in 1a), with the general formula [2,6-(ECH2)2C6H3]

- (Figure 1).

1.1.1 Nomenclature and Properties A practical way of classifying the pincer ligands is based on the three atoms coordinating to the metal center, abbreviated to EYE. In most cases, E repre-sents a neutral two-electron donor and Y an anionic carbon of the pincer backbone. Figure 2 shows a selection of palladium pincer complexes used as catalysts in this thesis. According to the classification above, these species are referred to as SeCSe-73, SCS-52, NCN-74 and PCP-39 palladium pincer complexes, respectively (1b-e).

PhSe SePhPd

Cl

1b

MeS SMePd+

NCMe

1c

Me2N NMe2Pd

Br

1d

O O

Ph2P PPh2Pd

OCOCF3

1e

BF4-

Figure 2. Selected pincer complexes used as catalysts for work described in this thesis

This structural framework offers unique possibilities to affect the catalytic properties of palladium by altering the side-arm donors, the ligand backbone and/or the counter-ion of the complex. The main reason for this intrinsic possibility of fine-tuning the reactivity is the rigid tridentate coordination of the pincer ligand. Moreover, the meridional pincer ligand is co-planar with the active site for catalysis, ensuring that the steric and electronic properties of the pincer ligand are efficiently transferred to the palladium. The pincer architecture also accounts for many other highly desired properties in cata-lytic transformations.9-18 As a consequence of the firm tridentate coordina-tion mode, the palladium pincer complexes show a high thermal stability. In addition, most of them are stable to moisture and air, resulting in easy han-dling and high durability under catalysis. The pincer ligand is also crucial for the selectivity of the catalysis. The oxidation state of palladium is largely restricted to +II. Thus, only one free coordination site is available for cataly-sis, preventing the formation of undesirable side-products arising from ligand exchange processes. On reduction to Pd(0), the geometry of the pincer complex is altered. This usually leads to decomposition of the complex35 although it has been shown that the pincer architecture can be regenerated using mild oxidants.75

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An emerging field in catalysis is the development of reactions involving palladium(IV) species.76-98 Canty85 and van Koten77 have shown that oxida-tion of palladium pincer complexes with hypervalent iodine reagents can give access to Pd(IV) pincer complexes. Catalytic applications of this con-cept are presented in Chapter 4, expanding both the coordination sphere of palladium and thus the synthetic scope of catalysis.

1.1.2 Synthesis of Palladium Pincer Complexes The most common way to synthesize palladium pincer complexes is to in-troduce the palladium to a preformed pincer proligand, the synthesis of which is usually based on straightforward functional group conversions. However, sophisticated ligand design is an important part of pincer chemis-try. For example, asymmetric catalysis can be achieved using chiral pincer ligands.45-47,54,66,69,99 Furthermore, unsymmetrical pincer complexes17,100 with two different donor atoms (EYE´) have shown to possess interesting cata-lytic properties. The ligand can also be attached to dendrimers101,102 or solid supports,26,103-106 representing valuable contributions to environmentally be-nign and sustainable catalysis. The metallation can be done in at least three different ways: a) via trans-metallation from another organometallic compound107 or b) via an oxidative addition to an aryl-halogen bond74 or c) via C-H activation8 /transcyclometallation108 (Scheme 1).

Scheme 1. Different methods for palladation of pincer ligands

A representative example of a synthesis via path c is given in Scheme 13, Chapter 2. An innovative alternative route relies on final assembly of the pincer structure after the formation of a ligand-palladium Ar-Pd bond.55,109,110

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1.2 Allylic Organometallic Reagents The fundamental importance of C-C bond forming reactions in organic chemistry has been a driving force for the development of allylic or-ganometallic reagents.111-116 Many different allylic metal reagents (5) have been explored as carbanion equivalents in allylation reactions. Their addi-tions to aldehyde (6), ketone and imine (7) electrophiles provide a valuable route to homoallylic alcohols (8) and amines (9), respectively (Scheme 2).

Scheme 2. Allylation of aldehydes or imines using allylic organometallic reagents

These C-C bond forming reactions are complementary to the aldol reaction since the homoallylic alcohol can be converted to the corresponding aldol product. In addition, the introduction of a double bond offers an important synthetic handle for further transformations. Whilst a wide array of allylic organometallic reagents has been utilized with different levels of selectivity, the main focus of this thesis is directed towards the synthesis and applica-tions of allylic boron reagents.

1.2.1 Allylboronic Reagents Several attractive properties of allylboronates account for their high recogni-tion in organic synthesis.111-122 The high diastereoselectivity in the coupling reactions with aldehydes is predictable and often superior to other allylic organometallic reagents.111-116 Moreover, the allylboronates are non-toxic and fairly stable towards oxidation and metallotropic rearrangement reac-tions. Three different types of allylic boron compounds are explored in this thesis; allylic boronic acids (10a), allylic boronic esters (10b) and allylic trifluoroborates (10c). The major advantage of these species over the corre-sponding boranes (10d) is their much higher stability123 (Figure 3).

Figure 3. Different types of allylboronic reagents

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The reactivity of the allylic boron compounds has been studied by Brown,123 and attributed to substituent effects. Crucial for the stability towards rear-rangements and oxidation are the oxygen atoms, decreasing the electro-philicity of boron by donation (nπ-pπ) of electrons into the unoccupied pπ-orbital of boron. The pinacol allylboronic esters (10b) are more stable than the corresponding boronic acids (10a), and can be purified by column chro-matography. Although the allylic boronic acids are not stable under solvent-free conditions,62,124 they can easily be transformed into the corresponding air- and moisture stable potassium trifluoro(allyl)borates125-131 (10c).

1.2.2 Allylation Reactions with Allylic Boron Reagents The high diastereoselectivity in the coupling of allylic boronates with alde-hydes is the result of an internal Lewis acid type activation of the aldehyde functionality by the empty pπ-orbital of boron. The diastereospecific addition proceeds via a compact six-membered (Zimmerman-Traxler type) transition state (11), where the geometry of the double bond determines the diastereo-selectivity132,133 (Scheme 3).

Scheme 3. Allylation of aldehydes via type I and type II mechanisms

Allylboronates add to aldehydes by a “type I”134 (11) mechanism with high diastereoselectivity. Thus, E-allylboronate gives the anti product, and Z-allylboronate gives the syn isomer of 8.135,136 In contrast, allylic silanes and stannanes require an external Lewis acid activation via an open transition state 12 (type II),134 reducing the diastereoselectivity and predictability. Although allylboronates activate the aldehyde internally via transition state 11, added Lewis or Brønsted acids may accelerate the reaction.118,119,137-145 It was shown that Lewis acids interact with the lone-pairs of the boronate oxy-gen (13) and thereby render the boron atom more electron deficient146 (Fig-ure 4). Chiral Brønsted acids142-145 were found to give moderate to high lev-els of enantioselectivity in the allylation of aldehydes. Alternatively, chiral-ity can be induced by chiral diol-based boronates.124,133,139,147-150

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Figure 4. Proposed Lewis acid activation in the allylation of aldehydes

Allylation of imine electrophiles with allylic boronates and borates is a vi-able route to homoallylic amines.64,150-163 Perhaps the most elegant and syn-thetically powerful development in this field is based on in situ generation of imines. Petasis and coworkers164-168 have shown that organoboronic acids (14) add to imines, formed in situ from various amines (15) and glyoxylic acid (16) to give unnatural α-amino acid derivatives (17). Virtually all types of organoboronates undergo the Petasis Borono-Mannich reaction, including vinyl-164,165,169-171, aryl-166 and allylboronates155-157 (Scheme 4). An asymmet-ric version of the Petasis reaction has been developed by Schaus and co-workers.171

Scheme 4. General scheme for the Petasis Borono-Mannich reaction

It was also demonstrated that palladium pincer complexes are excellent cata-lysts in electrophilic allylation of imines (7) using allyl borate 18.64,67,69 The reaction was proposed to proceed via a transmetallation to pincer complex 1e followed by allylation of the imine, to give homoallylic amines (9). The tri-dentate coordination of the pincer ligand proved to be crucial for the forma-tion of the nucleophilic η1-allyl palladium intermediate 19. Thereby, homo-coupling products from reductive elimination of bis-allyl palladium com-plexes172-174 could be avoided (Scheme 5).

Scheme 5. Palladium pincer-catalyzed allylation of imines using trifluoroborates

Allylation of ketones with allylic boronates is generally much slower than the allylation of aldehydes, and the selectivity is highly dependent on the relative size of the ketone substituents. Chelating groups such as amines in the α-position to the ketone functionality were shown to enhance the reactiv-ity.175 Furthermore, asymmetric allylation of ketones, using chiral phospho-

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rus-based ligands176 or diols177-180 have been reported. The allylation of ke-tones can also be catalyzed by indium reagents. Kobayashi and co-workers developed a mild InI-catalyzed allylboration reaction of ketones181 and N-acylhydrazones.161-163

1.2.3 Synthesis of Allylic Boronates Although several methods for the synthesis of allylic boronates can be found in the literature, only some of the relevant procedures are shown below. These methods can be categorized as direct and indirect routes to the allylic boronates.117 The direct methods are based on various coupling reactions where the boronate group is introduced to the substrate. Examples of this strategy include transmetallation reactions123,133,135,136,147 and transition metal-catalyzed couplings.62,68,153,182-193 In contrast, the indirect methods are instead based on rearrangements or functionalizations of an existing organoboronate to construct the allylic system. Simple allylic boronates such as allyl- and crotylboronate can be prepared readily by addition of reactive allylic organometallic reagents 20 such as allylic lithium, Grignard or potassium reagents to trialkoxyborates (21).123,133,135,136,147 When substituted allylic reagents are applied, the stereo- and regioselectivity is sometimes decreased. A mixture of products 22 and 23 is usually obtained due to metallotropic rearrangement of the precursor (Scheme 6).

Scheme 6. Synthesis of allylboronates using highly reactive allylic metal reagents

However, the harsh conditions and the stereochemical instability132 associ-ated with this type of reagent limits the synthetic scope. A more versatile strategy for the synthesis of functionalized allylboronates is the use of transi-tion metal-catalyzed transformations.62,68,153,182-193 Miyaura and co-workers182 have shown that allylic acetates (24) can be borylated in a palladium-catalyzed substitution reaction using bis(pinacolato)diboron (26) to yield functionalized allylic boronic esters 27 (Scheme 7).

Scheme 7. Palladium-catalyzed substitution of allylic acetates

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A drawback of this process is the formation of varying amounts of dimer 28, resulting from transmetallation of the product to the mono-allyl palladium intermediate 25 followed by reductive allyl-allyl coupling. Notably, in the presence of an electrophile this by-product was not observed.153,184 Another way to circumvent the formation of 28 is to reduce the number of available coordination sites on palladium. The Szabó group has developed several catalytic methods for the synthesis of various allylic organometallic reagents using palladium pincer complexes. It was shown that stannanes, silanes, selenides and boronates could be obtained from the corresponding dimetal reagent and allyl precursor.13,18,194 For example, allylic acetates 24, vinyl cyclopropanes 29 and aziridines 30 were borylated under mild conditions using tetrahydroxydiboron (31).62 The initial allylboronic acids 32 were treated with aqueous KHF2 and isolated as the corresponding potassium trifluoroborates 33 (Scheme 8).

Scheme 8. Palladium pincer complex-catalyzed synthesis of allylborates

Another method for the synthesis of allylic boronates via allylic substitution reactions is based on copper(I) catalysis. Sawamura and Ito189-191 have dem-onstrated that allylic carbonates 34 can be transformed into branched allyl-boronates 36 under mild catalytic conditions. Using the chiral ligand 35, optically active allylboronates were prepared (Scheme 9).

Scheme 9. Asymmetric borylation of alyllic carbonates using copper

An interesting approach for the synthesis of organoboronates is based on catalytic C-H bond activation.117,195,196 Although alkyl-, aryl- and alkenyl-boronates can be obtained from simple precursors, the biggest challenge in this field is the selective activation of one C-H bond over others. In most

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cases, ruthenium, rhodium or iridium complexes have been used as catalysts. For example, an iridium-catalyzed C-H borylation of olefins was developed in the Szabó group.197-199 Both vinylic (39) and allylic boronates (40) were generated and used in further one-pot coupling reactions. Interestingly, the addition of 38 shifted the product distribution from 39 to 40 (Scheme 10).

Scheme 10. Iridium-catalyzed C-H borylation of olefins

1.3 Aim of this Thesis The focus of this thesis is directed towards the development of novel palla-dium-catalyzed reactions. Palladium pincer complexes were chosen as cata-lysts due to their inherent rigidity and tunability. The main efforts are made in the development of selective borylation methods starting from easily ac-cessible precursors. These protocols are also explored in various one-pot reactions to construct stereodefined coupling products. Another important aim is to extend the scope of palladium pincer catalysis by the use of hyper-valent iodine reagents as oxidants. The putative involvement of palla-dium(IV) species is studied in the oxidative functionalization of olefinic substrates.

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2. Synthesis of Allylic Boronates by Palladium-Catalyzed Substitution Reactions (Papers I-III)

As mentioned in the introduction (section 1.2.1), allylboronates are impor-tant synthetic intermediates in organic synthesis. However, many of the ex-isting protocols require either harsh conditions or rather exotic precursors. Thus, the functional group tolerance is sometimes low, and the poor avail-ability of the starting materials limits the synthetic scope. Therefore, devel-opment of selective methods to prepare functionalized allylboronates from easily accessible starting materials is highly important. Allylic alcohols are one of the most attractive and readily available substrates that undergo palla-dium-catalyzed allylic displacement reactions.3,115,200-207 Unfortunately, the hydroxy group is one of the most reluctant leaving group in substitution reactions; and therefore the application of harsh reaction conditions, use of Lewis acids or other additives is required in these processes.200-207 Such con-ditions preclude the efficient synthesis of sensitive allylic metal derivatives, such as allylic boronates. This chapter addresses the development of novel methods for the synthesis of allylic boron compounds using allylic alcohols as starting materials.

2.1. Palladium Pincer Complex-Catalyzed Borylation of Allylic Alcohols A method for borylation of allylic acetates and other allylic precursors using palladium pincer complexes was previously developed in the Szabó group62 (Scheme 8). Inspired by these results, we studied the possibility of using allylic alcohols as substrates instead of allylic acetates. Initial studies showed that under the same reaction conditions as used for allylic acetates, the con-versions of the allylic alcohols were low. However, by changing the solvent from DMSO to a mixture of DMSO and methanol, we observed a significant increase of the conversion. The scope of this reaction proved to be broad, as a range of allylic alcohols (41) was borylated under mild reaction conditions using tetrahydroxydiboron (31) and palladium catalyst 1b73 in DMSO/methanol. As the initial allylboronic acid products (42) easily de-

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compose under solvent-free conditions,62,124 they were converted to the cor-responding potassium trifluoro(allyl)borates (43) with aqueous KHF2 before isolation (Scheme 11).

Scheme 11. Direct borylation of functionalized allylic alcohols

This method can be used for regio- and stereoselective synthesis of a variety of functionalized trifluoroborates 43 which are useful precursors in organic synthesis.125-131 The mild reaction conditions and the highly selective pincer catalyst 1b ensure high isolated yields of the borate products. The transient allylboronic acids (42) were fully characterized by 1H NMR before conver-sion into the corresponding borates (43). Alternatively, the allylboronic acids can be generated in situ and used in subsequent Suzuki-Miyaura couplings68 or one-pot allylation reactions (see Chapter 3). Commonly used palladium(0) sources, such as Pd2(dba)3 and Pd(PPh3)4, were found to be inefficient as catalysts in these transformations.

2.1.1 Selectivity and Substituent Effects The borylation of allylic alcohols proceeded with excellent regio- and stereoselectivity; only one isomer of the products was observed (Scheme 11, Table 1). Starting from acyclic allylic alcohols, only the linear E-substituted allylic borates were obtained regardless of the regioisomer or double bond geometry of the starting material. Thus, the isomeric allylic alcohols 41a and 41b gave the same regioisomer 43a (entries 1 and 2, Table 1). Similarly, the branched alcohol 41c and the linear alcohol 41d provided the linear allylbo-rates 43b and 43c, respectively (entries 3 and 4, Table 1). Tertiary and cyclic allylic alcohols were also converted to the corresponding borates in excellent yields (entries 5, 6, 9 and 10, Table 1). Allylic substitution in the presence of hydroxy or benzyloxy substituents led to an increased reactivity, as the reaction could be performed at lower temperatures (entries 7-9, Table 1). Decreasing the temperature was also necessary in order to obviate the competing hydroxy-boronate elimination of 42g and 42h leading to 1,3 dienes. The acyclic cis-substituted allylic alco-hols 41g and 41h furnished the trans-substituted products with excellent

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selectivity. Borylation of 41h gave the mono-borylated product 43g exclu-sively, offering the possibility for desymmetrization of allylic diols.

Table 1. Palladium pincer complex-catalyzed synthesis of allylic boratesa

aUnless otherwise stated, the reactions of 31 (1.2 equiv) and the corresponding substrates 41

(0.15 mmol) were conducted in the presence of 1b (5 mol%) in a 1:1 mixture of DMSO and

MeOH. After the indicated reaction times, aqueous KHF2 was added. bIsolated yield (%). cMeOH was used as solvent. dA mixture of DMSO and water was used as solvent. ep-Toluenesulfonic acid 2.5 mol% (entry 11) or 5 mol% (entry 10) was used as co-catalyst.

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Interestingly, cyclic diol 41i provided the 1,2-substituted borate 43h as a single diastereomer, indicating that the reaction is both regio- and stereose-lective. The substitution pattern of 43h clearly shows that the reaction pro-ceeds with allylic rearrangement and with anti-substitution, suggesting a directing effect of the other hydroxy group. Formation of this regioisomer is particularly interesting, since usual palladium-catalyzed reactions via allyl-palladium complexes bearing electron-withdrawing substituents usually gives the 1,4-substituted regioisomer.3,208-210 The borylation reaction was considerably slower with ester-substituted allylic alcohols (entries 10 and 11, Table 1). However, we found that addi-tion of catalytic amounts (3-5 mol%) of p-toluenesulfonic acid (p-TsOH) accelerated the conversion of 41j and 41k. This additive had no negative influence on the regio- and stereoselectivity of the reaction as product 43i was obtained as a single diastereomer.

2.1.2 Solvent Effects – Methanol as Co-solvent The inclusion of methanol as a co-solvent was crucial for the efficient bory-lation of allylic alcohols. When the reaction was performed in neat DMSO, only 5-20% conversion of the allylic alcohol was observed. Nevertheless, catalyst 1b is poorly soluble in methanol alone and therefore, only the most reactive substrates (such as 41h) could be borylated efficiently without DMSO. Neat methanol gave a higher isolated yield of product 43g compared to a DMSO/methanol mixture by reducing the competing elimination reac-tion. For allylic alcohol 41i though, a mixture of DMSO and water proved to be more efficient to preclude the formation of the corresponding 1,3-diene via elimination processes.

2.1.3 Activation of the Hydroxy Group In order to gain more insight into the activation of the hydroxy group we monitored the borylation of cinnamyl alcohol (41a) and cinnamyl acetate (24a)62 by 1H NMR. The reactions were performed under identical condi-tions and the conversion into cinnamylboronic acid (42a) was determined at regular time intervals. Furthermore, the effect of a catalytic amount of p-TsOH was also studied (Figure 5). Surprisingly, under the same reaction conditions, cinnamyl alcohol 41a was borylated much faster than the corresponding acetate 24a. Thus, allylic alcohol 41a was converted quantitatively to 42a in 8 hours, while its acetate derivative 24a was still present in the reaction mixture after 11 hours. Addi-tion of 5 mol% of p-TsOH had a remarkable effect on the rate of the reac-tion, as the borylation of 41a was complete in just 2 hours. Only 5 % de-composition of allylboronic acid 42a was observed after an additional 9 hours.

13

10 122

t [hours]

50

100

0 4 6 8

OH

41a31

B

42a

Ph[1b]cat

OH

OH

Ph

OH

41a31

+ p-TsOH

Ph[1b]cat

OAc

24a31

Ph[1b]cat

Figure 5. Borylation of 24a and 41a at 55 oC in DMSO-d6/MeOH-d4

The ‘S-shaped’ curve obtained for cinnamyl alcohol (•) suggests that the reaction requires an induction period. A reasonable explanation could be an activation of the allylic alcohol since the results above clearly indicate that the hydroxy group is converted to an excellent leaving group which is easier to displace than the acetate group. Tamaru reported that allylic alcohols could be activated for displacement by BEt3.

203,206,207 Similarily, the dibo-ronic reagent could act as a Lewis acid, interacting with the free electron-pairs of the oxygen. However, the boronic acids are far weaker Lewis acids than alkylboranes. Therefore we proposed another type of activation based on esterification of the diboronic acid 31 with alcohol 41 (Scheme 12).

Scheme 12. Proposed activation of the allylic alcohols

14

This process is facilitated by methanol transfering the proton from the alco-hol in a six-membered transition state (44) to form boronic acid ester 45. By this type of esterification, the hydroxy group is converted to a better leaving group and moreover, the B-B bond is weakened by the coordination of a water molecule. The catalytic amount of p-TsOH can be envisioned to cata-lyze the ester formation.

2.2 Fine-Tuning the Catalytic Activity of the Pincer Complex As pointed out in Chapter 1, the tridentate coordination of the pincer ligand gives the opportunity to affect the catalytic activity of the metal center by rational ligand design. Thus, when the pincer complex is the active catalyst in a reaction, electronic properties of the ligand are expected to be transmit-ted to the metal. In the borylation reaction presented above, the selenium-based pincer complex 1b proved to be a competent catalyst. Previously in the group, the same catalyst was studied in ring opening of vinyl expoxides and aziridines with organoboronic acids65 and also in the borylation of allylic acetates, vinyl cyclopropanes and aziridines.62 It was concluded that the cata-lytic activity of the pincer complex can be increased in several catalytic transformations by increasing the electron density on palladium.62,65 These studies inspired us to prepare a few analogues (1f-h) of 1b to investigate the electronic effects of electron donating methoxy-substituents upon the cata-lytic activity of the complex (Figure 6).

Figure 6. Structures of the parent catalyst 1b and its methoxy-substituted analogues

15

The methoxy-substituents were placed in the para-position with respect to the palladium carbon bond (1f) or on the selenium side-arms (1g). Expecting a co-operative effect between backbone and side-arm methoxy-substitution, we also prepared complex 1h. The catalytic properties of these new com-plexes were explored in the borylation of cinnamyl alcohol and in the phenylation of a vinyl epoxide.

2.2.1 Synthesis and Characterization of Methoxy-Substituted Pincer Complexes Pincer complexes 1f-h were synthesized by a slightly modified version of the procedure reported by Yao and co-workers.73 Dibromoxylene derivatives 46a-b were reacted with the appropriate diselenide (47a or 47b) to obtain pro-ligands 48a-c, which underwent a transcyclopalladation reaction108 with palladacycle 49 to give complexes 1f-h in good to excellent yields (Scheme 13).

Br Br

RSe

2

NaBH4

R'

Se Se

R' R'

R

AcOH

46a R = H46b R = OMe

47a R = H47b R' = OMe

48a R = OMe, R' = H48b R = H, R´= OMe48c R = R' = OMe

491f-h

Yield: 70-96%

2Pd

N

Cl

Scheme 13. Synthesis of methoxy-substituted pincer complexes

Characterization of the complexes by 77Se NMR spectroscopy revealed an interesting trend. The 77Se NMR shift values obtained for the parent catalyst 1b61 (427.1 and 424.9 ppm) and 1f (427.1 and 425.7 ppm) were almost iden-tical, while methoxy-substitution in the side-arms led to an increased shield-ing of the selenium nuclei (1g, 420.5 and 419.3 ppm; 1h, 420.7 and 419.1 ppm). Thus, only methoxy-substitution on the side-arms affects the electron-density of the selenium atoms. The two 77Se NMR shift values obtained for each one of complexes 1b,f-h are a consequence of the presence of two di-astereomeric forms of each of the complexes (about 1:1 ratio).

2.2.2 Methoxy-Substituted Pincer Complexes in Catalytic Arylation of Vinyl Epoxide and Borylation of Cinnamyl Alcohol First, we investigated the effects of the methoxy-substitution in the catalytic ring opening of vinyl epoxide 50 with phenylboronic acid (51) (Scheme 14). This reaction was previously developed in the group and mechanistic inves-

16

tigations by us and by the van Koten group211 indicated that the arylboronic acid transmetallates to the pincer catalyst followed by a nucleophilic substi-tution reaction.65

Scheme 14. Palladium pincer complex-catalyzed phenylation of vinyl epoxide 50

The progress of the reaction (formation of 52) was monitored by 1H NMR spectroscopy (Figure 7).

Figure 7. Phenylation of 50 at 25 oC in THF-d8/D2O using catalysts 1b and 1f-h

Under the applied reaction conditions, complete conversion of 50 to 52 re-quired about 10 hours using the parent catalyst 1b. A methoxy-substituent on the aryl backbone of the pincer complex (1f) led to a significant acceleration rate of the reaction that was complete in 2-3 hours. Interestingly, methoxy-substitution on the side-arms of the catalyst led to a weak deactivating effect. Complex 1g proved to be slightly less reactive than the parent complex 1b, and the trimethoxy-substituted catalyst 1h was less efficient than the mono-methoxy complex 1f. Subsequently, we studied the borylation of cinnamyl alcohol 41a with diboronic acid 31 in the presence of catalytic amounts of 1b, f or h (Table 1, entry 1 and Scheme 15).

Ph OH Ph B(OH)2

41a 42a

[1b, 1f or 1h]cat

DMSO/MeOHB

OH

OHB

HO

HO

31

+

Scheme 15. Palladium pincer complex-catalyzed borylation of allylic alcohol 41a

The reaction was completed in about 8 hours using the parent catalyst 1b. Similar to the catalytic phenylation of 50, the borylation reaction was accel-erated using para-methoxy complex 1f. Although the acceleration of the

17

borylation reaction was less pronounced than in the phenylation reaction (Figure 7), full conversion into boronic acid 42a was observed after 4-5 hours with catalyst 1f. The methoxy-substituents on the side-arms did not affect the rate of borylation very much, as the reaction with catalysts 1f and 1h showed comparable rates (Figure 8).

Figure 8. Borylation of 41a at 55 oC in DMSO-d6/MeOH-d4

Interestingly, the same trends are observed in the phenylation reaction (cf. Figure 7 and 8) which could indicate that the borylation reaction operates via a similar mechanism (transmetallation-nucleophilic substitution). The above results clearly show that the catalytic activity of pincer complex 1b can be fine-tuned by judicious substitution of the complexes. Although the 77Se NMR shift values indicated an increased electron density on the selenium atoms by methoxy-substituents on the side-arms (1g and 1h) these complexes did not display a higher activity than 1b and 1f, respectively. Instead, the most efficient fine-tuning of the catalytic activity of the pincer complexes was achieved by para-substitution of the aromatic ring. These results are in line with previous studies of platinum pincer complexes from van Koten and co-workers.212

2.3 Synthesis of Allylic Boronates from Allylic Alcohols and Readily Available Reagents and Catalysts A major drawback with the borylation reaction presented above is the poor availability of tetrahydroxydiboron (31). Therefore we explored the possibil-ity of using cheap and readily accessible bis(pinacolato)diboron (B2pin2) (26) as the borylating reagent. Moreover, this reagent enables the opportu-nity to isolate the products as the corresponding pinacol esters instead of converting the boronic acids into potassium trifluoroborates (cf. Scheme 11). The convenient use of bis(pinacolato)diboron in one-pot borylation reactions will be discussed in Chapter 3. In collaboration with the Aggarwal group

18

(University of Bristol, UK), we developed a novel method for borylation of allylic alcohols with B2pin2 (26) and catalyst 49. This palladacycle can be readily prepared213 or obtained from commercial sources. The pinacol boro-nate products 53 were isolated by silica gel column chromatography without any significant decomposition (Scheme 16, Table 2).

BO

OB

O

O

26

+OH

41

R

2

[49]catBpin

53

R[p-TsOH]cat

DMSO/MeOH

Pd

N

Cl

Scheme 16. Palladium-catalyzed borylation of allylic alcohols with B2pin2 (26)

A catalytic amount (5 mol%) of p-TsOH is an essential component of this reaction; the reaction did not proceed without p-TsOH, whilst higher load-ings resulted in extensive decomposition of the products.

Table 2. Representative entries of palladium-catalyzed synthesis of allylboronatesa

aUnless otherwise stated, the reactions of 26 (2.0 equiv) and the corresponding substrates 41

(0.5 mmol) were conducted in the presence of 49 (2.5 mol%) and 5 mol% p-TsOH at 50 oC

for 14 hours in a 1:1 mixture of DMSO and MeOH. bIsolated yield (%). c3.0 equiv of 26 was

used. dProduct obtained as a 93:7 ratio of E:Z isomers. eThe reaction was performed on 25

mmol scale.

19

The borylation reaction was effective for a range of allylic alcohols includ-ing primary, secondary and tertiary as well as functionalized allylic alcohols. The same high selectivity for linear E-substituted products was observed as in the borylation with palladium pincer complex 1b (cf. Table 1). However, geranylboronate 53b was obtained in a 93:7 ratio of E:Z isomers. The bory-lation of geraniol (41l) was scaled up to 25 mmol giving comparable yields (entry 3, Table 2). By increasing the stoichiometry of B2pin2 (26) to 3.0 equivalents, the yields were improved (entries 1-3, Table 2). The reaction tolerates substrates with ester groups and vinyl silane functionality, indicat-ing a broad synthetic scope.

2.4 Comparison of Borylation Reaction Conditions To summarize the above findings, the borylation of allylic alcohols was found to be efficient with pincer complex 1b and palladacycle 49 with two different diboronic reagents (26 and 31). Furthermore, addition of a catalytic amount of p-TsOH was found to promote the borylation reaction. In order to compare the different methods, we monitored the progress of the catalytic reactions by 1H NMR under eight different reaction conditions (Scheme 17).

BO

OB

O

O

26

+OH

41a

Ph[1b]cat or [49]cat

Bpin

53a

Ph

([p-TsOH]cat)DMSO/MeOH B(OH)2

42a

PhBOH

OHB

HO

HO

31

oror

PhSe SePhPd

Cl

2

49

Pd

N

Cl

1b

Conditions:ABCDEFGH

Catalyst:49491b1b491b491b

Diboron:3126313131262626

p-TsOH:yyynnynn

Scheme 17. Borylation of cinnamyl alcohol using different reaction conditions

The rate of 1b- and 49-catalyzed formation of cinnamyl boronic acid (42a, using 31) and cinnamyl boronate (53a, using 26) in the presence or absence of 5 mol% p-TsOH was plotted against time (Figure 9).

20

Figure 9. Competitive borylation of 41a at 55 oC in DMSO-d6/MeOH-d4 under conditions A-H

As Figure 9 shows, the fastest borylation was observed when catalyst 49 was used with diboron reagent 31 in the presence of 5 mol% p-TsOH (conditions A). The same reaction using 26 instead of 31 was the next fastest (conditions B). No reaction occurred at all in the absence of p-TsOH with B2pin2 (condi-tions G and H). Thus, it can be concluded that: (1) Acid promotes the reac-tion since all corresponding reactions without acid are slower. (2) Reactions with diboron reagent 31 are in all cases faster than the corresponding reac-tion with 26. (3) Catalyst 49 is generally faster than pincer complex 1b, ex-cept under conditions D and E where the two reactions proceed with compa-rable rates.

2.5 Proposed Mechanism of the Borylation Reaction Although the in-depth mechanistic details are not fully understood, a plausi-ble mechanism can be envisioned based on the above findings and previous studies.60,62,63,214 As discussed in Chapter 2.1.3, the first step of the borylation reaction is an activation of the hydroxy group by (partial) formation of a boronic acid ester (54) with the allylic alcohol (41). This esterification converts the hydroxy group to a better leaving group and facilitates the cleavage of the diboronic reagent. Previous studies in the Szabó group60,63 on the stannylation of allylic and propargylic substrates showed that the catalytic cycle is initiated by transmetallation of hexamethylditin (tin analogue of 26/31). Thereafter, the nucleophilic palladium stannyl species reacts with the substrate in a substitu-tion reaction. By analogy with the stannylation reaction, we propose that the borylation proceeds in a similar manner. Accordingly, the catalytic cycle is

21

initiated by transmetallation of the diboronic reagent to obtain palladium boryl intermediate 55. The boryl group is then transferred to the activated allylic alcohol 56 by a SN2/SN2´type mechanism to furnish the allylic boro-nate 42 or 53 (Scheme 18).

Scheme 18. Proposed mechanism for the borylation reaction

The high regioselectivity of the process can be explained by a nucleophilic attack at the less hindered position at the allylic alcohol (SN2 vs. SN2´). As shown in Chapter 2.2.2, an electron-rich palladium pincer complex catalyzes the borylation reaction at a higher reaction rate. This is consistent with a reaction mechanism proceeding via a nucleophilic substitution pathway. Moreover, an electron-rich catalyst prevents transmetallation of the allylbo-ronic products which may then be isolated in high yields. In summary, a novel method for the borylation of allylic alcohols was devel-oped. The reaction proceeds with high regio- and stereoselectivity using palladium pincer complex 1b or palladacycle 49. These protocols give ac-cess to a variety of functionalized allylic borates and boronates from readily available precursors under mild reaction conditions.

22

3. Development of One-Pot Reactions Based on Palladium-Catalyzed Borylation of Allylic Alcohols (Papers IV-VIII)

Allylic boron compounds are highly selective and efficient allylating re-agents in their reactions with carbonyl compounds such as aldehydes, ke-tones and imines (Chapter 1). Because of the high significance of allylbo-ronic reagents, their availability and ease of synthesis is of fundamental im-portance. Ideally, the synthetic methods for preparation of allylic boronates need to be highly regio- and stereoselective and tolerate a range of functional groups. Moreover, the functionalized allylboronates have to be stable enough for isolation, and yet sufficiently reactive in the desired allylation reaction. The development of transition metal-catalyzed methods62,68,153,182-193 has cer-tainly increased the availability of functionalized allylic boron compounds. However, due to their relatively low stability, isolation and purification often becomes a major issue. For example, allylboronic acids are more reactive as allylating reagents than the corresponding esters;123,156 unfortunately the allyboronic acids are known to decompose rapidly under solvent-free condi-tions.62,124 An attractive approach to obviate purification problems is the development of one-pot procedures, in which the transient allylboronic re-agents are not isolated but instead used directly in further transforma-tions.68,150,153,187,215 The development of effective multi-component reactions where several reaction steps are performed in the same reaction vessel is an important area in organic chemistry.216,217 Although the reactive intermedi-ates need not be isolated, the reaction conditions have to be carefully de-signed to ensure compatibility between the reagents in order to prevent for-mation of undesired side-products. Based on the borylation method described in Chapter 2, we explored the possibility to generate allylic boronates in situ for one-pot allylation reac-tions. The palladium pincer complex-catalyzed borylation of allylic alcohols proved to be versatile for the preparation of functionalized allylboronates. The high selectivity in these reactions allowed us to integrate the borylation protocol with the allylation of aldehydes (57), ketones (58) and in situ gener-ated imines from 15 and 16 (Scheme 19).

23

Scheme 19. One-pot transformations of in situ generated allylic boron compounds

These one-pot reactions proceed via palladium-catalyzed generation of allyl-boronic acids 42 using bis(pinacolato)diboron (26) or diboronic acid (31) as borylation reagent. Boronic acid intermediates 42 were found to be compati-ble with the multi-component conditions and reacted smoothly with various electrophiles, providing homoallylic alcohols (59-60) and amines (61). The selectivity of the one-pot reactions is excellent; almost all products are formed as single regio- and stereoisomers.

3.1 One-Pot Allylation of Aldehydes Allylation of aldehydes using allylic alcohols is a highly attractive synthetic route to functionalized homoallylic alcohols. Allylic alcohols are one of the least expensive and most accessible allylating agents. However, an activation of the alcohol functionality is required prior to the allylation step. This prob-lem has partly been addressed by palladium-catalyzed substitution reac-tions3,112,115,116 where the hydroxy group is activated in situ by SnCl2,

201,218,219 BEt3,

203,206,220,221 Et2Zn222 or indium salts.223-225 Unfortunately these types of reagents reduce the functional group tolerance and moreover, the selectivity of the allylation step is often decreased. A more versatile strategy is to con-vert the allylic alcohols to the corresponding boronates with the method de-scribed in Chapter 2. The mild activation of the hydroxy group and the sub-sequent reaction conditions tolerate an array of functional groups. In addi-tion, the borylation conditions do not hamper the high selectivity of the ally-lation step in the one-pot reactions. In fact, all the presented coupling reactions of aldehydes with in situ generated allylboronates provided a single

24

diastereomer of the homoallylic products. The coupling between allylic al-cohols 41 and aldehydes 57 using diboron reagent 26 or 31 and catalysts 1b-c, was performed as an operationally simple one-pot procedure with all components present from the outset of the reaction (Scheme 19, Table 3). The excellent selectivity of the one-pot allylations is a direct consequence of the highly selective borylation (Chapter 2) and the subsequent coupling with the aldehydes. Primary and secondary, cyclic and acyclic alcohols all react with an excellent stereo- and regioselectivity to give the branched homoally-lic products in good to excellent yields. Starting from acyclic alcohols, the anti-substituted products were obtained as the reactions proceed via E-allylboronic acids (entries 1-5 and 7, Table 3). In contrast, with cyclic allylic alcohols (Z-substituted olefins) the new carbon-carbon bond forms with syn-diastereoselectivity (entries 8-11, Table 3). Furthermore, high regioselectiv-ity was observed in the coupling of tertiary allylic alcohols, creating a new quaternary carbon center in the homoallylic product 59d (entry 6, Table 3). As shown in Chapter 2, the transient allylboronic acids derived from the alcohols in Table 3 can be isolated and fully characterized. However, the dienylboronic acid obtained from allylic alcohol 41p was too unstable to be isolated. Nevertheless, in the presence of aldehyde 57a, the sensitive inter-mediate could react immediately after its formation and thus, the coupling product 59i could be isolated in a high yield. Although the coupling reactions can be carried out in the absence of p-TsOH, the reactions proceed much faster with catalytic amounts of p-TsOH (cf. entries 1 and 2, Table 3). In Chapter 2, it was mentioned that the acid promotes the borylation reaction and studies by Hall have shown that the rate of the allylation step could be enhanced dramatically with added Brønsted acids.140-145 This type of activation may be particularly important for allylation of deactivated aldehydes with sterically hindered allylboro-nates. Most of the one-pot borylation-allylation reactions in Table 3 were per-formed with diboronic acid 31. However, the poor commercial availability of 31 is a limiting factor and therefore we investigated the possibility of re-placing it with commercially available bis(pinacolato)diboron 26. Unfortu-nately, the borylation step is slower with 26 than with diboronic acid 31, and also the allylation reaction is slower with pinacol esters of the intermediate allylboronic species. Initial optimization studies showed that the addition of 8.0 equiv of water and 20 mol% p-TsOH to the reactions performed with 26 gave yields comparable with those obtained with 31. However, longer reac-tion times and/or higher temperatures were required (cf. entries 1 and 3; 8 and 9, Table 3). Probably, under the applied conditions, bis(pinacolato)-diboron 26 is (partially) hydrolyzed in situ to 31 as we could detect released pinacol by NMR spectroscopy. The ratio between released and boron bound pinacol was constant (1:3) during the process, indicating that the hydrolysis is an equilibrium.

25

Table 3. Allylation of aldehydes via transient allylboronates, representative entriesa

aIn a typical reaction 41 (0.15 mmol), 26 or 31 (1.2 equiv) and 57 (1.2 equiv) were dissolved

in a DMSO/MeOH mixture in the presence of catalytic amounts of 1b or 1c and p-TsOH

(each 5 mol%). bWhen 26 was used, 8.0 equiv of water and 20 mol% of p-TsOH were used. cCatalyst. dTemperature/time [°C]/[h]. eIsolated yield (%). fWithout p-TsOH.

26

In order to shorten the reaction time in the coupling of 41j with aldehydes, catalyst 1c was used instead of 1b. The borylation of alcohol 41j was found to be slow (Chapter 2). In addition, using bis(pinacolato)diboron 26 in the one-pot borylation-allylation procedure led to a further slowdown. However, the SCS-based catalyst 1c reduced the reaction time from 48 hours to only 6 hours in the reaction between 41j and 57a with diboron reagent 26 (cf. en-tries 9 and 10, Table 3).

3.1.1 Control of the Regioselectivity in the One-Pot Borylation-Allylation Process SCS-palladium pincer complex 1c displayed a high catalytic activity in the above described reaction. We found that the one-pot borylation-allylation reactions with 1c could be performed in chloroform or a mixture of chloro-form and methanol. Different regioisomers of the products were formed depending on which solvent the one-pot reaction was performed in. When a mixture of MeOH/CHCl3 (1:1) was used, the usual branched homoallylic alcohols 59 were obtained (as with DMSO/MeOH, Table 3). However, se-lective formation of the corresponding linear isomers 62 was observed in neat CHCl3 (Scheme 20).

OH

41

R1

[1c]cat

[p-TsOH]cat

+

BO

OB

O

O

26

CHCl3/MeOH(1:1)

R2-CHO 57CHCl3

R1

OH

R2

59

OH

R2

62

R1

Scheme 20. One-pot borylation-allylation with complex 1c

The method can be used for synthesis of certain homoallylic alcohols with a high level of regiocontrol. In the presence of methanol, the branched prod-ucts were obtained from both aromatic and aliphatic aldehydes (entries 1 and 3, Table 4). In contrast, chloroform furnished the corresponding linear iso-mers 62a and 62b using the same starting materials. Nitrobenzaldehyde 57d gave the branched homoallylic product 59k independent of which solvent was used (entry 5, Table 4).

27

Table 4. Allylation of aldehydes with allylic alcohols under various conditionsa

aIn a typical reaction 41 (0.15 mmol), 26 (1.2 equiv) and 57 (1.2 equiv) were dissolved in the

indicated solvent in the presence of 1c and p-TsOH (each 5 mol%). bTemperature/time

[°C]/[h]. cIsolated yield (%). d2.0 equiv 57c. e3.0 equiv 57c and 10 mol% p-TsOH

Moreover, the borylation step could be performed without addition of p-TsOH using SCS-complex 1c and bis(pinacolato)diboron 26. Thus, cin-namylboronate 53a and borate 43a was obtained from 41a under neutral conditions without any additives (Scheme 21).

Scheme 21. Borylation of cinnamyl alcohol under neutral conditions

In order to understand the regioselectivity of the one-pot borylation-allylation in chloroform, we monitored the reaction of cinnamyl alcohol (41a) and benzaldehyde (57a) with 1H NMR spectroscopy. The relative con-

28

centrations (Cx/C0(57a)) of different species x were measured over time (Fig-ure 10).

Ph

O

57aPh

OH

Ph59a

Ph OH

41a

OH

Ph

62a

Ph

+

x

-20 64 8 1210

0

0.5

Rel

ativ

eC

onc

entr

atio

n(C

x/C

57a)

1.0

-

+

xx

x

xx

x xx x x x x x x x x x x x x x x x

+ + + + + + + + + + + + + + + + + + + + + +

t [hours]

26

[1c]cat

57a

41a

Bpin

53a

Ph

53a

59a

62a

+

Figure 10. Monitoring the reaction components in the one-pot borylation-allylation with 1c in CDCl3 at 50 oC

Initially, the concentration of reactants 41a and 57a decreased, and forma-tion of the branched product 59a was observed. Interestingly, the amount of allylboronate 53a was very low for the entire reaction, indicating that the in situ formed 53a reacted immediately with 57a. The concentration of the branched product 59a passed a maximum value after 4 hours. After about 2 hours the linear product 62a appeared, and then its amount increased stead-ily. Obviously, the formation of linear product 62a took place at the expense of the branched product 59a and thus we proposed a mechanism involving a rearrangement step (Scheme 22). The initial product from the allylation step between 53 and 57 is boronate ester 63 which hydrolyzes to the branched homoallylic alcohol 59 in the presence of protic solvents. When the reaction is conducted in neat chloro-form, acetal 64 may form from intermediate 63 and excess aldehyde 57. According to studies by Ramachandran,226 Nokami227 and Loh,228 this proc-ess takes place particularly easily with boronates in the presence of Lewis-acid catalysts. In our case, the cationic pincer complex 1c or p-TsOH is be-lieved to assist in the formation of 64 which subsequently forms 2-oxonia intermediate 65. After a [3,3]-sigmatropic rearrangement to 66, acetal 67 is obtained. The driving force of this proposed rearrangement route is probably

29

the higher thermodynamic stability of linear acetal 67 compared to the branched acetal 64. Hydrolysis of 67 liberates aldehyde 57 and furnishes the linear homoallylic alcohol 62.

Scheme 22. Proposed mechanism for the formation of branched 59 and linear 62 products

3.2 One-Pot Allylation of Ketones The allylation of ketones using allylboronates usually requires an activation of one of the reactants.175-181 Recently, Kobayashi and co-workers161-163,181 reported an excellent way to activate allylboronates with a catalytic amount of InI. We found that this strategy could also be used for the activation of allylboronic acids generated in situ from allylic alcohols 41. The reaction was carried out similarly to the one-pot allylation of aldehydes, except that the ketone 58 and InI (20 mol%) was added after completion of the boryla-tion step in order to prevent catalyst deactivation (Scheme 23). The regioselectivity of the reaction was excellent, giving the branched allylic isomers 60a-b with a new quaternary carbon center as the only regioi-somers. However, the diastereoselectivity was lower than that observed in the allylation of aldehydes; the one-pot borylation-allylation of ketone 58a gave a 9:1 ratio of the two diastereomers of 60a.

30

58a

Ph

OH

Ph

60aYield: 72%

[1b]cat

[p-TsOH]cat

DMSO/MeOH

50 oC, 16 h

+B2(OH)4

31Ph OH

41a

O

Ph

[InI]cat

50 oC, 16 h

58b

C5H11

OH

60bYield: 86%

[1b]cat

[p-TsOH]cat

DMSO/MeOH

50 oC, 16 h

+B2(OH)4

31[InI]cat

50 oC, 16 h

OH

C5H11

41c

O

Scheme 23. One-pot allylation of ketones using in situ generated allylboronates

3.3 Synthesis of α-Amino Acids via Borylation of Allylic Alcohols The addition of various organoboronates to in situ generated imines was pioneered by Petasis and co-workers164-168 and has found many synthetic applications.155-157,169-171 However, previously reported applications of allylic boronates155-157 were performed with isolated boronates. The poor availabil-ity of functionalized allylboronates inspired us to develop a one-pot proce-dure based on palladium-catalyzed borylation of allylic alcohols followed by allylation of in situ generated imines. Thereby, the three-component Petasis Borono-Mannich reaction is extended to a four-component coupling reaction via in situ generated allylboronates. The synthesis of α-amino acid deriva-tives 61 from allylic alcohols 41 was performed as a sequential one-pot reac-tion since amine 15 inhibits the palladium-catalyzed borylation. Thus, after the borylation of 41 was completed, the transient allylboronic acids 42 were coupled with imines 69 generated in situ from amines 15 and glyoxylic acid 16 (Scheme 24).

Scheme 24. One-pot synthesis of α-amino acids via palladium-catalyzed borylation

31

The structural diversity of the homoallylic amino acids 61 is a function of the various substituents in the allylic alcohol precursors. The substrate scope is fairly broad as primary, secondary and tertiary alcohols performed equally well. Furthermore, ester and benzyloxy groups are tolerated, giving access to densely functionalized amino acid derivatives. In the four-component cou-pling reactions we observed a regio- and stereoselectivity equivalent to the analogous coupling of allylic alcohols and aldehydes. The α-amino acid de-rivatives 61 were formed as single regio- and stereoisomers from readily available alcohols and amines. Accordingly, the presented reactions provide an easy access to stereodefined analogues and homologues of natural amino acids, such as phenylalanine (61a-b), isoleucine (61c-d), valine (61e), serine (61f), glutamic acid (61g) and pyroglutamic acid (61h) (Table 5). We found that the one-pot reactions worked best with primary benzhydryl 15a and aryl amines 15b-c to avoid allylic rearrangement of the products. According to Kobayashi and co-workers,157 branched homoallylic α-amino acids with unprotected amino groups showed a tendency for rearrangement to the corresponding linear isomers via an aza-Cope rearrangement. This process was found to be most extensive for products incorporating a quater-nary carbon center, such as 61e. However, formation of the linear isomer could be completely avoided using amine 15a (entry 6, Table 5). An interesting domino reaction was triggered using ester substituted allylic alcohol 41q. When the ethyl ester 41k was used, glutamic acid derivative 61g was isolated in a high yield (entry 8, Table 5). However, the correspond-ing methyl ester 41q underwent a spontaneous lactam formation, providing pyroglutamic acid derivative 61h (entry 9, Table 5). Similar to the coupling reactions of alcohols and aldehydes (Table 3), the one-pot borylation-Petasis reaction could also be performed with bis(pinacolato)diboron 26 instead of diboronic acid 31. The required modifi-cations of the reaction conditions (addition of 8 equiv of water and 20 mol% p-TsOH) did not influence the isolated yields (cf. entries 3-4, Table 5). Use of diboronic acid 31 (either directly or by in situ hydrolysis of 26) to gener-ate the transient allylboronic acids 42 is probably an important factor in en-suring high yields and efficiency in the Petasis reaction. Thadani and co-workers156 have shown that the analogous coupling reactions of (isolated) allylboronates with ammonia and aldehydes proceed more efficiently when allylboronic acids are used instead of allylboronic esters. The mechanistic aspects of the imine formation and the addition of or-ganoboronates in the Petasis Borono-Mannich reaction are yet not fully un-derstood. Although the mechanism has been studied for alkenylboro-nates,117,229-231 less is known about the addition of allylic boronates to in situ generated imines. Based on the regio- and stereoselectivity obtained in the one-pot borylation-Petasis reaction and previous studies from Kobayashi,155 we propose that the allylation of the in situ generated imines proceeds simi-larly to that of aldehydes, via a cyclic transition state (Scheme 3, Chapter 1).

32

Table 5. Petasis Borono-Mannich reaction with in situ generated allylboronatesa

1 31 40/161b 76

15a61a

COOH

HN

Ph

2 31 40/161b 78

15b 61b

3 31 50/161b 7515a

61c

4

H2N

Ph

Ph

Ph

Ph

25/16

25/16

25/8

PhNH2 COOH

NHPh

Ph

COOH

HN

C5H11

Ph

Ph

5

26 50/41c 7715a 61c25/16

6

31 50/161b 52

15c61d

25/8

COOH

HN

C5H11

H2N

OMe

OMe

7

31 50/161b 6015a

61e

25/24

COOH

HN Ph

Ph

8

31 40/81b 7715b61f

25/16 COOH

NHPh

BnO

9

31 50/161b 7815a

61g

25/16COOH

HN Ph

Ph

EtOOC

31 50/161b 8015a

61h

25/16

COOH

N Ph

PhO

Entry Alcohol Cat.c Cond.Ad Product YieldfAmine Diboronb

41a

Ph OH

41a

OH

C5H11

41c

41c

41c

OH

41e

OHBnO

41g

OH

EtOOC

41k

OH

MeOOC

41q

Cond.Be

aIn a typical reaction 41 (0.15 mmol) and 26 or 31 (1.2 equiv) were dissolved in a

DMSO/MeOH mixture in the presence of catalytic amounts of 1b or 1c and p-TsOH (each 5

mol%). After the allotted times (cond. A), 15 (2.0 equiv) was added followed by addition of

16 (1.5 equiv). The reaction was continued for the times and temperatures given under cond.

B. bWhen 26 was used, 8.0 equiv water and 20 mol% p-TsOH were used. cCatalyst. dTem-

perature/time [°C]/[h] for the borylation. eTemperature/time [°C]/[h] for the allylation. fIso-

lated yield (%). All products except 61h were isolated as the corresponding HCl salts.

33

3.4 Coupling of Catalytically Generated Allylboronates with in situ Hydrolyzed Acetals As a further extension of the synthetic scope in the one-pot borylation-allylation reactions, we studied the possibility to use in situ hydrolyzed acet-als as electrophiles. This approach is particularly useful when the acetals are more stable or easier to access than the corresponding aldehydes. We found that the coupling of catalytically generated allylboronates with aldehydes from in situ hydrolyzed acetals could be performed as a one-pot process. Various allylic substrates (24, 29 or 41) were borylated using catalyst 1b or 1c and diboronic reagent 26 or 31 in the presence of water, p-TsOH and acetals 70, giving functionalized homoallylic alcohols 59 in good to excel-lent yields (Scheme 25).

Scheme 25. Allylation of in situ hydrolyzed acetals with catalytically generated allylboronates

The reaction has a broad synthetic scope and a high functional group toler-ance. A range of novel stereodefined homoallylic alcohols were obtained using functionalized acetals that are easier to handle than their aldehyde counterparts. The protected amino aldehydes 70a-b reacted smoothly with the in situ generated allylboronates providing stereodefined amino alcohols 59l-m, p and r. Chloro-substituted acetal 70d was used to prepare chloro-hydrins such as 59o and 59s. Upon addition of base, 59o was converted to epoxide 71 in a one-pot sequence (entry 5, Table 6). Furthermore, a homolo-gation (including allylic rearrangement) of the substrate was achieved using dimethoxy methane 70e, which is easier to handle and less toxic than for-maldehyde (entry 7, Table 6). Although the majority of the reactions was performed as the above de-scribed one-pot procedure, a sequential approach had to be used in a few cases. Acrolein, formed by the hydrolysis of 70c inhibited the palladium-catalyzed borylation of 41a and therefore acetal 70c was added after comple-tion of the borylation step (entry 3, Table 6). Likewise, a sequential reaction had to be used for silyl substituted acetate 24b as it underwent rapid Peterson elimination even under mild acidic conditions. In this reaction, diboronic

34

acid 31 was used since bis(pinacolato)diboron 26 was inefficient under the neutral reaction conditions that had to be applied for the borylation step (en-try 8, Table 6).

Table 6. Representative entries of the allylation of in situ hydrolyzed acetalsa

3d 50/16

70c 59n

1b 81

70e

70d 59o

1b 78

1b5e,f 68

71

70/24

4e 70/24

1b2 89

70b 59m

70/24

1b 9270/241

70a 59l

1b 7459q

70/24

6 1c 7670a

59p

70/24

MeO

OMe OH

Ph

OMe

MeOCl Cl

OMe OH

PhO

Ph

EtONHTs NHTs

OEt

Ph

OH

EtO

TsN

TsN

OEt

Ph

OH

OH

Entry Acetal Cat Cond.b Product YieldcSubstrate

599

7

24b

8g 1c 7870a

59r

70/24

29

1c 70/2470d59s

OAcNHTs

OH

EtOOC COOEt Cl

OH

COOMe

OHH

NHTs

Ph OH

41a

COOMe

HO

41j

41l

OH

41a

41a

41a

70d41a

EtOOC

COOEt

OMe

Me3SiMe3Si

aUnless otherwise stated, the allylic substrate (0.15 mmol), 26 (1.2 equiv) and 70 (1.2 equiv)

were dissolved in a DMSO/MeOH/H2O mixture in the presence of catalytic amounts of 1b or

c (5 mol%) and p-TsOH (20 mol%). bTemperature/time [°C]/[h]. cIsolated yield (%). dSequen-

tial one-pot reaction was performed. e50 mol% p-TsOH was used. fAfter formation of 59o,

KOH was added. gDiboron reagent 31 and 20 mol% LiOAc was used in a sequential one-pot

reaction.

35

The reactions described above involve three individual reactions performed in concert. First, palladium pincer complexes 1b and 1c catalyze the boryla-tion of the allylic substrates. The transient allylboronic acids are then cou-pled with the in situ hydrolyzed acetals to form homoallylic alcohols. In these processes, p-TsOH catalyzes the borylation, allylation and also the hydrolysis of the acetals. The one-pot setup is important since the highly reactive and/or unstable aldehydes formed from the acetals do not accumu-late in the reaction mixture, but react immediately with the allylic boronates. The stereo- and regiodefined products obtained by this method can be used for the synthesis of biologically important compounds. For example, acetal 70b was used to construct amino alcohol 59m comprising two terminal ole-fins. After a ring-closing metathesis (RCM) reaction, the stereodefined azepine 72 was obtained using the Hoveyda-Grubbs232,233 catalyst 73 (Scheme 26). Azepine 72 is an analogue of potent glycosidase and kinase inhibitors.234-236

Scheme 26. Ring-closing metathesis of stereodefined amino alcohol 59m

3.5 Stereoselective Synthesis of Cycloalkenes by a One-Pot Borylation-Allylation-Metathesis Sequence Throughout this chapter (sections 3.1-3.4) it has been demonstrated that the palladium pincer complex-catalyzed borylation of allylic alcohols provides access to stereodefined homoallylic products via one-pot allylation of vari-ous electrophiles. By appropriate choice of the electrophiles, dienes such as 59m (Scheme 26) can be obtained from the processes. Instead of performing the RCM with isolated substrates, as in Scheme 26, we found that the one-pot borylation-allylation reactions can also be terminated with a RCM reac-tion. Thus, stereodefined dienes 59 were prepared in situ from allylic alco-hols 41 and unsaturated aldehyde 57e (or acetal 70c) via palladium-catalyzed borylation. Thereafter, a solution of Hoveyda-Grubbs catalyst 73 was added to the crude reaction mixture to obtain functionalized cycloalkenes 74 in high overall yields (Scheme 27).

36

Scheme 27. Ring-closing metathesis of in situ generated homoallylic alcohols

Both primary and secondary allylic alcohols can be used to give regio- and stereodefined substituted cycloalkenes (entries 1-4, Table 7). Also quater-nary alcohols such as 41s reacted smoothly in the one pot reaction, forming spirocyclic compound 74e (entry 5, Table 7). Another useful building block in natural product synthesis is lactone 74b237,238 which was obtained as a single diastereomer from alcohol 41q (entry 2, Table 7). Table 7. Synthesis of cycloalkenes by RCM, representative entriesa

OH

MeOOC

41q

OHBnO

41g

OH

41r

OH

41s

3c

5

4c,d

2

1

Entry Substrates Product Yieldb

OH

OBn

68

OH 78

63

OO

H

H

68

OH72

OH

O

MeO

OMe

74a57e

70c

57e

74b

57e

57e

41r

74c

74d

74e

aUnless otherwise stated, alcohol 41 (0.15 mmol), 26 (1.2 equiv) and 57e (2.0 equiv) were

dissolved in a DMSO/MeOH/H2O mixture in the presence of catalytic amounts of 1b or 1c (5

mol%) and p-TsOH (10 mol%). After stirring at 50 °C for 20 hours, a DCM solution of 73

was added and this mixture was refluxed for additional 20 hours. bIsolated yield (%). cRCM

was performed in only 2-4 hours. dAcetal 70c was added after 16 hours.

37

Borylation of 41r followed by allylation of 57e or 70c provided trienes 59t and 59u that underwent selective RCM reactions to cycloalkenes 74c and 74d respectively. Despite the possibility of forming other types of rings, 74c-d were obtained as single isomers in high overall yields, 78% and 63%, re-spectively (Scheme 28).

OH

OH

74c

74d

OH

41r

57e26

[1b]catOH

OH

[73]cat

42kB(OH)2

59t

59u

70c [73]cat

Scheme 28. Generation of stereodefined trienes and their ring closure transforma-tions

The presented method shows that the one-pot borylation-allylation reaction can be conjoined with a ring-closing metathesis reaction for stereoselective synthesis of small organic building blocks. Moreover, the robust Hoveyda-Grubbs catalyst 73 performed well in the presence of all other components in the one-pot, multi-step reactions.

3.6 Summary of the One-Pot Transformations In this Chapter several methods for the transformation of in situ generated allylboronates have been devised. A wide array of regio- and stereodefined products was obtained from one-pot allylation reactions of various electro-philes. The high level of compatibility between the palladium-catalyzed borylation and subsequent transformations resulted in a high functional group tolerance. The compatibility relies on three main factors: (a) the high selectivity of the pincer complex catalyst, which does not undergo further reactions with the allylboronic acids or other components; (b) the mild acti-vation of the allylic alcohols with diboron reagents 26 or 31, which avoids harsh reaction conditions; and (c) the high reactivity of the in situ formed allylboronic acids, which is accompanied by a fairly high stability to acid, water and air. Due to the high regio- and stereoselectivity both in the forma-tion of the allylboronates and in the following allylation reactions, the final products were obtained as single regio- and stereoisomers.

38

4. Palladium-Catalyzed Functionalization of Alkenes Under Oxidative Conditions (Papers IX-XI)

The development of catalytic transformations involving palladium(IV) in-termediates is an emerging field in organic chemistry.76-98 By replacement of the traditional Pd(0)/Pd(II) catalytic systems with a Pd(II)/Pd(IV) cycle, the synthetic scope of palladium catalysis can be broadened. This approach leads to new types of synthetically useful transformations that are not accessible with Pd(0)/Pd(II) catalytic cycles. The most important features of a Pd(II)/Pd(IV) cycle are: a) An increased reactivity of the reductive elimina-tion from Pd(IV) intermediates; b) an increased chemoselectivity for the oxidative addition to Pd(II) catalytic precursors; and c) the avoidance of unstable Pd(0) intermediates which often leads to catalyst deactivation or incompatibility with certain functional groups. However, the design of catalytic procedures aimed to proceed via Pd(IV) species is dependent on mild and selective oxidants for synthetically useful applications. This requirement is largely met by hypervalent iodine re-agents,88,90,239-242 which have successfully been used in a range of innovative catalytic reactions.76-98 Nevertheless, a potential limitation of using oxidizing reagents is the difficulty of finding compatible ligand systems. For example, phosphines are easily oxidized by hypervalent iodine reagents which might preclude their use for enantioinduction. Furthermore, an oxidation of palladium from oxidation state +II to +IV leads to an expansion of its coordination sphere. We reasoned that the well-defined metal-ligand bonding in palladium pincer complexes could be a use-ful tool in the development of palladium(IV) catalysis. Although the in-volvement of palladium(IV) intermediates in Heck couplings with pincer complexes is under debate,11,21,22,32,35,36 it has been demonstrated that NCN-palladium pincer complexes can be oxidized with hypervalent iodine re-agents. Both van Koten77 and Canty85 have shown that pincer complexes 1i and 1j, undergo stoichiometric oxidative addition to hypervalent iodine re-agents 75a and 75b to obtain Pd(IV) pincer complexes 1k and 1l (Scheme 29).

39

Scheme 29. Stoichiometric oxidation of NCN-Pd complexes

Inspired by these results, we decided to study the use of hypervalent iodine reagents in palladium-catalyzed functionalization of alkenes. In these reac-tions, palladium pincer complexes were used to explore the mechanistic aspects of the catalytic transformations. It turned out that two pathways for the functionalization of alkenes were feasible; the functional group was ei-ther transferred from the hypervalent iodine reagent via palladium, or intro-duced to the alkene via a proposed oxidation-transmetallation process.

4.1 Pincer Complex-Catalyzed Redox Coupling of Alkenes with Iodonium Salts We started our investigations by studying the Heck-type redox coupling24,243-

250 between diaryliodonium salts242,251 and functionalized alkenes. Palladium pincer complexes 1e and 1j showed a high catalytic activity in the reactions of various diaryliodonium salts 76 and alkenes 77 under mild conditions in the presence of NaHCO3 (Scheme 30, Table 8).

Scheme 30. Palladium-catalyzed arylation of alkenes using diaryliodonium salts

40

Table 8. Selected examples of arylation of functionalized alkenesa

94/93c1 14OAc OAc

PhOAc OAc

8

Entry Substrate Time[h] Product Yieldb

10

83

9

21 OAc

COOEt

Br

914 21

OAc

OAc

Br

11

1e

Cat.

1e

1e

98/90c3 2079

942 141e

916 20OAc

OAc

Ph

OAc

OAc1e

997 2279

9918

Ph

Br Br1e

95171j

76a

76c

76c

76b

76b

76a

76a

76a

76a

Ar2IX

77a 78a

77a 78a

77a 78a

77a

78b

77b 78d

77b 78d

77c 78e

77g 78i

77g 78i

MeCN

MeCN

THF

THF

MeCN

MeCN

MeCN

THF

THF

8916

Ph

OMe OMe1j 76a

77f 78h

THF

89

12

14SiMe2Ph SiMe2PhPh1j 76a

77d 78f

THF

74

13

141e 76e

77e 78g

THF

995 16

OAc

OAc

F

1e 76d77a

78c

THF

OAc

COOEt

Solvent

aUnless otherwise stated, alkene 77 (0.30 mmol), 76 (0.20 mmol) and NaHCO3 (0.20 mmol)

were dissolved in THF or MeCN in the presence of catalytic amounts of 1e or 1j or 79 (5

mol%). The reactions were stirred at 50 °C for indicated times. bIsolated yield (%). cIsolated

yield (%) in the presence of 150 equiv of Hg.

The reactions proceeded with high regio- and stereoselectivity, obtaining the functionalized products 78 as single isomers. The majority of the products have allylic acetate and/or aryl bromide functionalities which normally un-

41

dergo oxidative addition under classic Heck conditions. However, these functional groups were fully tolerated in the presented reactions and the products were isolated in good to excellent yields. A variety of terminal al-kenes were arylated, including those with bulky electron-donating substitu-ents e.g. 77d (Table 8). In order to investigate if Pd(0) species were involved in the catalysis, we performed the reaction in the presence of 150 equiv (per Pd) of elemental Hg (so called mercury drop test). The addition of mercury has been shown to terminate Heck reactions when PCP-palladium pincer complexes act as dis-pensers of active Pd(0) species but not as the true catalyst of the reac-tion.32,35,36 In the phenylation of alkene 77a, no catalyst poisoning was ob-served using the mercury drop test,252 providing the product 78a in excellent yield (entry 1, Table 8). Mercury itself did not show any catalytic activity in the reaction. Pd(OAc)2 (79) showed almost exactly the same activity in the reactions as pincer complex 1e (cf. entries 2 and 3, 6 and 7, Table 8). Addi-tion of mercury to the reaction catalyzed by 79 did not affect the reaction either (entry 3, Table 8). From a practical and cost point of view 79 is the catalyst of choice, but palladium pincer complexes can be useful in further developments and can also give important mechanistic insights. For exam-ple, in the above reactions, the 31P NMR spectrum of the crude reaction mix-ture indicated that the pincer structure of 1e was intact after full conversion of the substrates. This also suggests that Pd(0) species are not likely to be catalytic intermediates as it is known that the pincer architecture is not re-tained upon reduction to Pd(0).32,35,36

4.1.1 Proposed Mechanism for the Palladium-Catalyzed Arylation of Alkenes Based on the findings that the presented reaction tolerates allylic acetates and aryl bromides, the negative mercury drop test and that the pincer struc-ture was fully intact after the reaction, we propose a mechanism based on a Pd(II)/Pd(IV) redox cycle. Accordingly, the catalytic cycle with catalyst 1e is initiated by an oxidative addition with diaryliodonium salt 76 and the catalyst to give Pd(IV) interme-diate 80a. The next step is a carbopalladation to 80b, followed by a β-hydride elimination affording complex 80c. The hydride probably enters trans to the X-ligand instead of trans to the Pd-C(aryl) bond, as the latter would be destabilized by a trans hydride. Thereafter, 80c undergoes a depro-tonation by the base, regenerating the catalyst and furnishing the arylated product 78 (Scheme 31).

42

Scheme 31. Proposed Pd(II)/Pd(IV) catalytic cycle for the reaction of alkenes and iodonium salts

Unfortunately, we did not succeed in isolating or observing any aryl-Pd(IV) intermediates. DFT modeling showed253 that the activation barrier for the oxidation of palladium pincer complex 1m with diaryliodonium salt 76a is almost 13 kcal/mol higher in energy than the corresponding reaction with 75b (cf. Scheme 29, Canty85 and co-workers). Both reactions, obtaining Pd(IV) species 81a and 81b, are highly exothermic (Scheme 32).

Scheme 32. DFT modeling of the oxidation with hypervalent iodine reagents 75b and 76a (energies are given in kcal/mol)

The relatively high activation barrier for reaction with 76a, requiring an ele-vated reaction temperature, might explain the difficulty in observing aryl-Pd(IV) intermediates such as 80a or 81b. Under the applied reaction condi-tions, hypervalent iodine reagent 75b decomposed and therefore it could not be used in the presented functionalization of alkenes. In conclusion, a mild method for arylation of alkenes with diaryliodonium salts was presented. Several experimental findings suggest that the catalysis proceeds via a Pd(II)/Pd(IV) mechanism.

43

4.2 Allylic C-H Functionalization via Suggested Palladium(IV) Intermediates Acetoxylation of allylic C-H bonds using palladium catalysis is one of the most efficient methods for alkene functionalization.3,254-263 Many excellent procedures for preparation of allylic acetates have been reported in the last decades by Åkermark,256,257 Bäckvall,258,259 White260,261 and others.262,263 The majority of these reactions were performed in the presence of benzoquinone (BQ) which proved to be important both for the reoxidation of Pd(0) to Pd(II), as well as activation of the nucleophilic attack.264-266 However, a drawback with BQ is that it requires acidic reaction conditions because pro-tonation is involved in the redox process to generate hydroquinone. How-ever, acidic conditions lead to reduced nucleophilicity of the acetate. By replacing the traditional Pd(0)/Pd(II) catalytic cycle with a Pd(II)/Pd(IV) cycle,95-98 we postulated that the allylic C-H functionalization could be per-formed in the absence of BQ. Indeed, we found that hypervalent iodine re-agents 82 were efficient oxidants in the acetoxylation and benzoyloxylation of alkenes 77 using palladium catalyst 1d or 79. The reactions were per-formed in the presence of KOAc or LiOBz under mild conditions, obtaining products 83 in good yields (Scheme 33).

1d

PdMe2N NMe2

Br[1d or 79]cat

KOAc or LiOBz

AcOH or MeCN

40 oC, 18 h

+

8382a R = CH382b R = Ph

Pd(OAc)2

79

R1 R2 R1 R2

OCOR

PhI(OCOR)2

77

Scheme 33. Palladium-catalyzed acetoxylation and benzoyloxylation of alkenes using hypervalent iodine reagents

We found that pincer complex 1d and palladium acetate (79) were equally efficient in the acetoxylation of 77h (entries 1 and 2, Table 9). Therefore, most of the reactions were carried out with palladium acetate (79) as cata-lyst. However, we used pincer complex 1d for exploring some mechanistic aspects of the reaction (see Chapter 4.2.1). Most of the acetoxylation reactions were performed in acetic acid using 82a and KOAc. The acetoxylation of 77h also worked in acetonitrile, but with a slightly lower isolated yield (entry 3, Table 9). The catalytic benzoy-loxylation of 77h and 77i were conducted in a slightly basic reaction me-dium with 82b and LiOBz in acetonitrile (entries 4 and 6, Table 9). Both terminal alkene 77h and internal alkenes 77i-l worked well in the presented reaction. No isomerisation was observed using carboxylates 77h-j, which

44

was reported earlier using the classical Pd(0)/Pd(II) method.263 A single re-gio- and stereoisomer was obtained in all reactions in Table 9, except for the acetoxylation of 77k, which gave a 1:1 ratio of cis- and trans-83f (entry 8, Table 9). Acetoxylation of cyclohexene (77l) gave the allylic acetate 83g as a single regioisomer (entry 9, Table 9). Table 9. C-H functionalization of alkenes using hypervalent iodine reagentsa

Entry Substrate Product YieldbCat. PhI(OCOR)2 Solvent

591 79 82a

77h 83a

AcOHCOOMe AcO COOMe

602 1d 82a77h 83aAcOH

463 1d 82a77h 83aMeCN

644 79 82b77h

83b

MeCN BzO COOMe

625 79 82a

77i 83c

AcOHCOOMeCOOMe

OAc

616 79 82b77i

83d

MeCNCOOMe

OBz

7 70

8

79 82a

77j 83e

AcOHC5H11 COOMe

OAc

52c

9

79 82a

77k 83f

AcOHCNCN

OAc

6679 82a

77l83g

AcOH

OAc

COOMeC5H11

aAlkene 77 (0.30 mmol), oxidant 82 (0.60 mmol), catalyst 1d or 79 (5 mol%), and KOAc

(0.30 mmol) or LiOBz (0.30 mmol) were dissolved/suspended in the indicated solvent (1

mL), and the reaction mixture was stirred at 40 °C for 18 h. KOAc and LiOBz were used with

oxidants 82a and 82b, respectively. bIsolated yield (%). cCis and trans isomers formed in a

1:1 ratio.

45

4.2.1 Mechanistic Aspects of the Palladium-Catalyzed Acetoxylation and Benzoyloxylation Reactions Our mechanistic studies were mainly focused on the mechanism of the nu-cleophilic attack and the oxidation state of palladium in the presented reac-tions. Two different mechanisms were considered for the nucleophilic attack in the acetoxylation process.258,259 We supposed that the reaction can either proceed through a nucleophilic attack of an acetate on an (η3-allyl)palladium intermediate (such as 84) or via an acetoxy-palladation followed by a β-hydride elimination to give the acetoxylated product. In order to differentiate between these two mechanisms, we carried out the acetoxylation reaction with monodeuterated cyclohexene (77l-2d). Two dif-ferent (η3-allyl)palladium complexes, 84a and 84b are expected to form from this starting material. A nucleophilic attack at either of the terminal positions in these complexes would give rise to the acetoxylated products 83g-1d, 83g-2d, and 83g-3d, in an expected 1:2:1 ratio (Scheme 34).

Scheme 34. Nucleophilic attack on 84a and 84b affording a 1:2:1 statistical ratio of 83g-1d : 83g-2d : 83g-3d

Alternatively, two insertion complexes 85a and 85b may form in an acetoxy-palladation reaction. Subsequent β-hydride elimination would give the two allylic acetates 83g-1d : 83g-2d in an expected 1:1 ratio. Product 83g-3d is not expected to form from 85a or 85b (Scheme 35).

Scheme 35. β-hydride elimination from 85a and 85b affording a 1:1:0 statistical ratio of 83g-1d : 83g-2d : 83g-3d

In the acetoxylation reaction of monodeuterated cyclohexene (77l-2d) under standard conditions (entry 9, Table 9) we obtained the three monodeuterated products 83g-1d : 83g-2d : 83g-3d in a 1:2:1 ratio (determined by 2H NMR spectroscopy). This is the same distribution of the deuterated products as

46

expected from a nucleophilic attack on an (η3-allyl)palladium complex. Therefore, we conclude that the mechanism of the presented acetoxylation reactions most probably involves (η3-allyl)palladium intermediates (Scheme 36).

Scheme 36. Catalytic acetoxylation of 77l-2d under standard conditions obtaining a 1:2:1 ratio of 83g-1d : 83g-2d : 83g-3d

A further important mechanistic question concerns the oxidation state of palladium in the presented acetoxylation reaction. Previous studies by San-ford and co-workers82 have shown that benzoyloxy-based hypervalent iodine reagents can oxidize palladium(II) complexes to form stable palladium(IV) species. In addition, van Koten77 and Canty85 have reported stoichiometric oxidation of NCN-palladium pincer complexes with hypervalent iodine re-agents, and identified the obtained palladium(IV) complexes by 1H NMR spectroscopy (cf. Scheme 29). Similarly, we attempted to generate Pd(IV) intermediates starting from pincer complex 1d, which we found to be as active a catalyst in the presented acetoxylation reaction as 79. In our investi-gation, NCN complex 1d was reacted with oxidant 82a in CDCl3 and the progress of the reaction was monitored by 1H NMR spectroscopy (Scheme 37).

Scheme 37. Oxidation of the Pd(II) central atom of 1d. The 1H NMR shifts are given in ppm.

The signals for the CH2 and CH3 protons of the side-arms of 1d appear as singlets resonating at 4.04 and 3.01 ppm, respectively. This arises from the fast inversion of the nitrogen atoms of the side-arms, lending a time-averaged C2v symmetry to the complex. Upon addition of the oxidant 82a to a solution of NCN complex 1d, the color of the solution changed from pale yellow to amber. After five minutes at room temperature, new signals ap-peared in the 1H NMR spectrum. The singlet from the CH3 signals in 1d split up into two distinct singlets resonating at 2.88 and 3.24 ppm. In addition, two new doublets (2JH,H = 14 Hz) at 4.46 and 4.38 ppm appeared. Similar characteristic changes in the 1H NMR spectrum were reported by Canty85

47

from the reaction in Scheme 29. The observed changes in the 1H NMR spec-trum are consistent with an oxidation of the metal atom from Pd(II) to Pd(IV) and thus, an expansion of the coordination sphere of palladium. The change of the coordination state reduces the symmetry of the complex from C2v (1d) to Cs (86). These results strongly suggest that under the applied catalytic conditions the palladium atom of the catalyst is oxidized to Pd(IV) by the oxidant 82. Based on the findings from the reaction of deuterium labeled compound 77l-2d and the above NMR studies, we propose a mechanism for the C-H ace-toxylation reaction involving (η3-allyl)palladium(IV) intermediates. The initial step of the proposed catalytic cycle is an oxidation of the palladium catalyst to obtain Pd(IV) intermediate 87a. Thereafter, the coordination of alkene 77 affords complex 87b which is deprotonated, generating the sug-gested (η3-allyl)palladium(IV) intermediate 87c. The final step of the cata-lytic cycle is a reductive elimination which gives the product 83 and regen-erates the catalyst (Scheme 38).

Pd(II)X2L2

RCO2 Pd

O2CR

(IV)X2L2

R2R1

RCO2 Pd+

O2CR

(IV)XL2

R2R1

RCO2 Pd+

L

(IV)LX

82

L

77h-l

Oxidativeaddition

Alkenecoordination

Allylf ormation

Reductiveelimination

87a

87b

87c

PhI

RCOOH

X-

X-

83

R1 R2

OCOR

Scheme 38. Proposed catalytic cycle for the C-H acetoxylation/benzoyloxylation reaction

In contrast to the traditional Pd(0)/Pd(II) catalytic cycle that in most cases requires an activator such as BQ for reductive elimination or nucleophilic attack,264-266 no activator is needed in the final step. The driving force for the reductive elimination in the proposed mechanism is the reduction of Pd(IV) to Pd(II). Interestingly, the nucleophile of complex 87c does not necessarily

48

come from the oxidant 82. When the catalytic reaction of 77h and oxidant 82a (entry 3, Table 9) was repeated with LiOBz as an additive in place of KOAc, a mixture of 83a and 83b formed. This indicates that the carboxylate groups may undergo exchange either in the oxidant267 or in complexes 87a-c. Further developments based on this principle are presented in Chapter 4.3. In conclusion, a palladium-catalyzed C-H acetoxylation/benzoyloxylation of alkenes was developed using hypervalent iodine reagents. The reactions were performed under mild conditions obtaining functionalized alkenes with high regio- and stereoselectivity. Mechanistic studies are consistent with the reactions proceeding via a Pd(II)/Pd(IV) redox cycle and (η3-allyl)palladium intermediates.

4.3 C-H Borylation of Alkenes by Palladium Pincer Complex-Catalyzed Oxidative Functionalization The catalytic methods for the functionalization of alkenes presented so far in this chapter are all based on the introduction of a functional group from the hypervalent iodine reagent to the substrate. However, in the acetoxylation of alkenes presented above, we found that addition of LiOBz to an acetoxyla-tion reaction with 82a gave a mixture of acetoxylated and benzoyloxylated products (see Chapter 4.2.1). Therefore, the choice of nucleophile is not restricted to groups already bound to the iodine center. Moreover, our previ-ous studies on the palladium pincer complex-catalyzed borylation of allylic alcohols indicated that diboron reagents such as bis(pinacolato)diboron (26) readily undergo transmetallation with palladium pincer complexes (cf. Chap-ter 2). Therefore, we decided to investigate the possibility of developing a C-H borylation method based on an oxidation-transmetallation concept. Catalytic C-H borylation is a highly valuable route to organoboronates from simple starting materials.117,195,196 A majority of the known C-H boryla-tion reactions use iridium,197-199,268-272 rhodium273-278 or ruthenium279,280 cata-lysts. Palladium catalysis has rarely281-284 been employed in these processes. Only a limited number of studies have been performed on palladium-catalyzed borylation of alkenes via C-H functionalization.281,282 One possible reason for this is that palladium is not efficient in cleaving vinylic/allylic C-H bonds under the typical reducing conditions of borylation processes, using diboronates or borohydrides as boronate sources. Gratifyingly, we have found that palladium-catalyzed C-H borylation of alkenes can be achieved under oxidative conditions. Simple alkenes 77l-p were borylated using bis(pinacolato)diboron (26) and palladium pincer com-plex 1d under mild reaction conditions. An essential component of the bory-lation reaction was hypervalent iodine reagent 82c. The reactions were per-

49

formed at ambient temperature in neat or diluted alkene to obtain the corre-sponding borylated products 88 in high yields (Scheme 39).

Scheme 39. Palladium-catalyzed C-H borylation of alkenes under oxidative condi-tions

In this process, one of the Bpin groups in 26 is transferred to the substrate, whilst the other is oxidized to TFA-Bpin. Thereby, borohydrides are not formed under the employed oxidative conditions. Formation of borohydrides usually leads to hydroboration of the alkene, resulting in an inseparable mix-ture of alkyl and alkenylboronates.197-199 Therefore, a clear synthetic advan-tage of the applied oxidative conditions is that the alkenyl (or allyl) boro-nates 88 can be isolated in pure form. We found that simple alkenes 77l-n, allylsilane 77o and vinylboronate 77p were readily borylated under the oxi-dative conditions (Table 10). At present though, the reaction has a rather limited substrate scope. The reactions were performed either in neat alkene (method A) or using excess of alkene in dichloromethane (method B). Decreasing the alkene con-centration usually led to a drop in yield. Addition of base, water, and excess phenyl iodide to the crude reaction mixture (method C) led to a subsequent Suzuki-Miyaura285,286 coupling of the in situ generated vinylboronates (en-tries 8 and 10, Table 10). Although Pd(OAc)2 (79) catalyzed the reaction, significantly higher yields were obtained with pincer complex 1d (cf. entries 1 and 3, 4 and 5, Table 10). The organoboronate products 88 were in most cases fairly stable and could therefore be purified by silica gel chromatography. The exception is 88f, which completely decomposed under purification by chromatography on silica gel. Therefore, the yield given for 88f in Table 10 was determined by 1H NMR spectroscopy of the crude mixture. Although 88f was unstable on silica gel, it reacted in the above described Suzuki–Miyaura coupling (entry 10, Table 10).

50

Table 10. C-H borylation of alkenes using hypervalent iodine reagentsa

aAlkene 77 (1.875 mmol), oxidant 82c (0.15 mmol), diboronate 26 (0.30 mmol) and catalyst

1d or 79 (5 mol%), were stirred at 20 °C for 16 h. bMethod A: reaction was performed in neat

alkene. Method B: CH2Cl2 (0.1 mL) was added. Method C: the reaction was terminated by a

Suzuki–Miyaura coupling. cIsolated yields (%), apart for entry 9 (NMR yield). dRatio of

vinylic/allylic products: 4:1 (entry 4), 1:1 (entry 5), and 1:6 (entry 6).

The borylation reaction usually proceeds with a high selectivity for the vi-nylic products but cycloalkenes 77l-n show an interesting trend. Borylation of cyclopentene (77m) provided vinylboronate 88a as single product in high yield. However, the reaction of cyclohexene (77l) with 1d as the catalyst resulted in the vinylic (88b) and allylic forms in a 4:1 ratio (entries 1-2 and 4, Table 10). In the reaction catalyzed by Pd(OAc)2 the selectivity (and yield) dropped, and the vinyl/allyl ratio became 1:1 (entry 5, Table 10). The selectivity was reversed for cycloheptene (77n), as the vinylic and allylic products (88c) were formed in a 1:6 ratio (entry 6, Table 10). A similar switch of selectivity was observed by Sabo-Etienne and Caballero in the

51

ruthenium-catalyzed C-H borylation of cycloalkenes.280 According to these authors, the allyl/vinyl selectivity is controlled by conformational factors, and the ring flexibility of cycloheptene favours the formation of the allylic isomer 88c.

4.3.1 Proposed Mechanism Although the reaction mechanism of the presented C-H borylation is not fully understood, we propose a plausible catalytic cycle, based on the earlier findings described in this chapter. As with the oxidation of pincer complex 1d with 82a (Scheme 37), we also found that 82c is a good oxidant for pal-ladium by monitoring the reaction between 1d and 82c by 1H NMR spec-troscopy. Thus, we propose that the catalytic cycle of the C-H borylation reaction is initiated by an oxidative addition to the hypervalent iodine re-agent 82c to obtain Pd(IV) intermediate 89a. Thereafter, this electron defi-cient Pd(IV) complex undergoes a transmetallation with diboronic reagent 26 affording 89b.

BpinR

H

PdMe2N NMe2

Br

PdMe2N NMe2

TFATFA

Br

PdMe2N NMe2

TFA

Br

PdMe2N NMe2

Br

TFA-

PdMe2N NMe2

Br

82c

PhI

26

TFA-Bpin

+ TFA-H

RBpin

+

TFA-

+

1d

89a

89b89c

89d

IV

II

Oxidativeaddition

Transmetallation

Insertion

pinB pinBR

R Scheme 40. Palladium-catalyzed C-H borylation of alkenes under oxidative condi-tions

The transmetallation probably proceeds via a four-center transition state, in which fission of the B-B bond occurs simultaneously with the formation of a Pd-Bpin bond and a TFA-Bpin bond.214 This process probably involves a temporary dissociation of the other TFA ligand to generate a free coordina-tion site for the transmetallation process. An initial formation of the active borylation reagent from 26 and 82c cannot be ruled out; however, we were not able to verify such a process by NMR spectroscopy. After the transmet-

52

allation, an alkene is coordinated (89c) and the Bpin ligand undergoes inser-tion into the double bond to give 89d. An elimination–decomplexation se-quence provides the corresponding organoboronate product and regenerates catalyst 1d. Without the transmetallation step (89a to 89b), a nucleophilic attack or insertion of the trifluoroacetate ligand would have been expected, in analogy with the reaction discussed in Chapter 4.2. The use of 82c has some impor-tant benefits, such as its high oxidation potential and the relatively poor nu-cleophilicity of the released trifluoroacetate. Probably the most important conceptually new feature of this C-H borylation reaction is the possible for-mation of Pd(IV) intermediates, such as 89a, which presumably transmetal-late with B2pin2 more readily than the Pd(II) species, the most oxidized spe-cies in typical palladium-catalyzed borylation reactions. To the best of our knowledge, there have been only two papers, published by Sneddon and co-workers,281,282 on the palladium-catalyzed C-H borylation of alkenes. How-ever, in these studies, borane clusters were used as the boronate source and the catalytic reaction afforded an isomeric mixture of alkyl and vinyl penta-borane derivatives. In summary, a novel palladium-catalyzed C-H borylation reaction based on an oxidative functionalization-transmetallation concept was presented. The key steps involve oxidation of the catalyst to a Pd(IV) species, which then undergoes a transmetallation reaction with a diboronic reagent providing easy access to pinacolboronates.

53

5. General Conclusions and Outlook

In this thesis it has been demonstrated that palladium pincer complexes are versatile catalysts for a range of synthetic transformations. A novel method for preparing allylic boronates starting from allylic alcohols was developed using palladium pincer complexes or other palladacycles. The mild condi-tions applied in the borylation reaction allowed further transformations of the in situ generated allylic boronates. A range of highly selective one-pot allylation reactions were developed, giving access to a variety of stereode-fined products. The one-pot approach is not only convenient from a practical point of view, but is also crucial for exploiting reactive synthons as allylbo-ronates without their isolation. This concept could be extended to other types of one-pot reactions for the synthesis of small organic building blocks. Furthermore, we demonstrated that hypervalent iodine reagents are excel-lent oxidants for selective C-H functionalization of alkenes using palladium catalysis. A novel palladium-catalyzed method for C-H borylation of olefins based on an oxidation-transmetallation sequence was developed. Mechanis-tic studies indicated that Pd(IV) species are probable intermediates in these reactions. The oxidative functionalization method has a potential for further developments such as broadening of the substrate scope and enantioselective catalysis.

54

Acknowledgements

I would like to thank: Professor Kálmán J. Szabó, my research advisor for his excellent guidance, support and inspiration. Professor Jan-Erling Bäckvall, for showing interest in my research. My co-authors: Professor Gerard van Koten, Professor Robertus J. M. Klein Geb-bink, Professor Varinder K. Aggarwal, Dr. Vilhelm J. Olsson, Dr. Sara Sebelius, Dr. Juhanes Aydin, Dr. Guillaume Dutheuil, Dr. Marcella Gagliardo, Dr. Nilesh C. Me-hendale, Dr. Lukasz T. Pilarski, Dr. Benjamin Willy, Johanna M. Larsson, Cesar Estay, Dietrich Böse and Andreas Kipke for fruitful collaborations.

Dr. Lukasz T. Pilarski, Dr. Benjamin Willy, Dr. Eszter Borbas and Johanna M. Lars-son for proofreading and valuable suggestions.

All nice co-workers at the department and all past and present members of the Szabó group: Dr. Olov A. Wallner, Dr. Niclas Solin, Dr. Sara Sebelius, Dr. Juhanes Aydin, Dr. Vilhelm J. Olsson, Dr. K. Senthil Kumar, Dr. Muthu Seenivasaperumal, Dr. Lukasz T. Pilarski, Dr. Benjamin Willy, Johanna M. Larsson, Pär Janson, Petter Östberg, Andreas Kipke, Dietrich Böse, Cesar Estay, Verónica López-Carillo, He-lena Larsson, Andreas Rydén, Cathrin S. Conrad, Mahmoud J. Sayah, Jola Pospech, Elias Pershagen and Tony Zhao. The TA-staff: Olle Bristrand, Kristina Romare, Pia Seffers, Agneta Rörs, Britt Eriksson, Ola Andersson, Martin Roxengren and Joakim Staffas. Dr. Juhanes Aydin, Dr. Vilhelm J. Olsson and all others for nice company on con-ference trips! Friends and family for support. IDECAT, Vetenskapsrådet, K&A Wallenbergs Stiftelse, John Söderbergs Stiftelse, Astra Zeneca Sweden, Svenska Kemistsamfundet, Ångpanneföreningens Forskningsstiftelse, Hilda Rietz Stiftelse and Sture Erikssons Fond för Cancer- och Hjärtforskning for their generous financial support.

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