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ACTA

UNIVERSITATIS

UPSALIENSIS

UPPSALA

2008

Digital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Pharmacy 76

Heck Reactions with ArylChlorides

Studies of Regio- and Stereoselectivity

GOPAL K. DATTA

ISSN 1651-6192ISBN 978-91-554-7256-6urn:nbn:se:uu:diva-9202

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To my parents

“Life is not what one lived, but what one remembers and how one remembers it in order to recount it.”

- Gabriel García Márquez Nobel Laureate in Literature, 1982

In the preface of Living to Tell the Tale

List of Papers

This thesis is based on the following papers, which will be referred to in the text by their Roman numerals.

I Gopal K. Datta, Karl S. A. Vallin and Mats Larhed A Rapid Microwave Protocol for Heck Vinylation of Aryl Chlo-rides under Air. Molecular Diversity, 2003, 7, 107-114

II Gopal K. Datta, Henrik von Schenck, Anders Hallberg, and Mats Larhed Selective Terminal Heck Arylation of Vinyl Ethers with Aryl Chlorides: A Combined Experimental-Computational Approach Including Synthesis of Betaxolol. Journal of Organic Chemistry, 2006, 71, 3896- 3903

III Gopal K. Datta and Mats Larhed

High Stereoselectivity in Chelation-Controlled Intermolecular Heck Reactions with Aryl Chlorides, Vinyl Chlorides and Vinyl Triflates. Organic & Biomolecular Chemistry, 2008, 6, 674-676 (Featured article in the category of Metal-Catalyzed Asymmetric Synthesis and Stereoselective Reactions, Synfacts, 2008, 5, 497)

IV Gopal K. Datta, Patrik Nordeman, Jakob Dackenberg, Peter Nilsson, Anders Hallberg and Mats Larhed Enantiopure 2-Aryl-2-Methyl Cyclopentanones by an Asymmet-ric Chelation-Controlled Heck Reaction Using Aryl Bromides: Increased Preparative Scope and Effect of Ring Size on Reactiv-ity and Selectivity. Tetrahedron: Asymmetry, 2008, 19, 1120-1126

Reprints were made with permission from the publishers.

Contents

1. Introduction...............................................................................................13 1.1 An Overview of Palladium Catalysis and the Heck Reaction ............13

1.1.1 General........................................................................................13 1.1.2 Palladium-Catalyzed Coupling Reactions ..................................14 1.1.3 The Heck Reaction .....................................................................15

1.2 Chelation-Controlled Regio- and Stereoselective Intermolecular Heck Reactions ..................................................................................................22

1.2.1 Chelation Control in the Heck Reaction .....................................22 1.2.2 Chelation-Controlled Regioselectivity and Reactivity Enhancement in Heck Reactions .........................................................22 1.2.3 Chelation-Controlled Stereoselectivity in Heck Reactions.........25

1.3 Aryl Chlorides in Heck Reactions......................................................28 1.3.1 General........................................................................................28 1.3.2 Palladium Ligands/Catalysts for Aryl Chloride Activation........28

2. Aims of the Present Study.........................................................................31

3. Results and Discussion .............................................................................32 3.1 Regioselective �-Arylation of Electron-Poor and Electron-Rich Olefins with Aryl Chlorides (Papers I and II) ..........................................32

3.1.1 Aryl Chlorides as Coupling Partners for Electron-Poor Olefin ..32 3.1.2 Aryl Chlorides as Coupling Partners for Electron-Rich Olefins 38

3.2 Stereoselective Intermolecular Heck Arylation of Electron-Rich Cyclic Vinyl Ethers (Papers III and IV)...................................................50

3.2.1 Overview ....................................................................................50 3.2.2 Synthesis of Chelating Cyclic Vinyl Ethers ...............................51 3.2.3 Stereoselective Heck Reactions with Cyclic Five-Membered C-2 Methyl Vinyl Ether ..............................................................................52 3.2.4 Stereoselective Heck Reactions with a Cyclic Six-Membered Vinyl Ether ..........................................................................................58 3.2.5 Specific Achievements ...............................................................61

4. Concluding Remarks.................................................................................62

Acknowledgements.......................................................................................63

References.....................................................................................................68

Abbreviations

Ac acetyl 3-AP 3-aminopyridine-2-carboxaldehyde thiosemicarbazone Ar aryl BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl bmim 1-n-butyl-3-methylimidazolium Bu butyl Cy cyclohexyl dba dibenzylideneacetone de diastereomeric excess DDQ 2,3-dichloro-5,6-dicyanobenzoquinone DFT density functional theory dippb dippp DMA

1,4-bis(diisopropylphosphino)butane 1,4-bis(diisopropylphosphino)propane N,N-dimethylacetamide

DME dimethoxyethane DMF dimethylformamide dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1'-bis(diphenylphosphino)ferrocene dppm 1,1-bis(diphenylphosphino)methane dppp 1,3-bis(diphenylphosphino)propane EDG electron donating group ee enantiomeric excess equiv equivalent Et ethyl EWG electron withdrawing group GC gas chromatography HOMO highest occupied molecular orbital HPLC high pressure liquid chromatography i-Pr isopropyl L ligand LC liquid chromatography LUMO lowest unoccupied molecular orbital M metal Me methyl MS mass spectrometry

Mw microwaves n-Bu normal butyl NMP N-methylpyrrolidone NMR nuclear magnetic resonance PEG Poly(ethylene glycol) Ph phenyl PMP 1,2,2,6,6-pentamethyl-piperidine rt room temperature TBAB tetrabutyl ammonium bromide TBME tert-butyl methyl ether t-Bu tertiary butyl THF tetrahydrofuran TLC thin layer chromatography Tol tolyl Triflate trifluoromethanesulfonyl X halide or pseudohalide

13

1. Introduction

1.1 An Overview of Palladium Catalysis and the Heck Reaction

1.1.1 General Whether it be the selective preparation of fine chemicals, or the synthesis of life-saving medicinally active drug molecules, the key steps involve the for-mation of new carbon-carbon bonds.1-8 This has inspired organic chemists to develop a plethora of reactions over the past century,9 however, most atten-tion has been devoted to the formation of saturated C-C bonds. Throughout most of the 20th century, copper was almost the only well-known transition metal able to create carbon-carbon bonds between unsaturated moieties. The copper-mediated reaction known as the Ullmann reaction, first reported in 1901,10 was used to synthesize biaryl (aryl-aryl) compounds. This reaction required high temperatures (around 200 °C) together with stoichiometric amounts of copper metal, and its scope was limited to the formation of symmetrical biaryls.11 In the late 1960s and early 1970s, a variety of palla-dium-catalyzed cross coupling and vinylic substitution reactions were dis-covered, which enabled the creation of new bonds between different sp2 carbon centers.12,13 Since the discovery of these reactions, the scope of metal-catalyzed reactions has increased tremendously, and as a consequence, palladium catalysis has become an essential and versatile tool for organic synthesis.14

Palladium and palladium-based complexes15 are unique catalysts among the other transition metals because of their inherent ability to catalyze di-verse organic transformations,13 while being atom economical and providing milder reaction conditions, as well as higher functional-group tolerance.16,17 The discussion in the following section encompasses palladium-catalyzed reactions, in particular regio- and stereoselective16-18 Heck reactions. A brief overview of palladium-catalyzed organic transformations is presented first.

14

1.1.2 Palladium-Catalyzed Coupling Reactions Palladium can catalyze numerous organic transformations, including C-C, C-O, C-P, C-S, and C-N bond-forming reactions. Among these, C-C bond for-mation is the reaction of largest interest for organic chemists. Consequently, a series of transition-metal-catalyzed coupling reactions that include the Heck reaction, Suzuki reaction, Sonogashira reaction, Stille reaction and others, has arisen (Scheme 1).

Scheme 1. Illustrative examples of palladium(0)-catalyzed C-C bond-forming reac-tions. M = BR2 (Suzuki-Miyaura), SnR3 (Stille), MgX (Kumada), SiR3 (Hiyama), ZnX (Negishi) etc.; X = halide, triflate, nonaflate, sulfonate etc.; R/R' = diverse.

Palladium is the most widely used metal in the coupling reactions depicted above. It is a late transition metal located in group 8 of the periodic table. Thus, palladium has partially filled d orbitals that are essential to both its electron-donating and electron-accepting properties. Adding suitable donor or acceptor ligands can fine-tune this property allowing appropriate trans-formations to take place. Palladium possesses certain characteristic proper-ties that make it unique.13,18

� Low susceptibility to undergo one-electron transfer processes (radical reactions)

� High functional group tolerance � Preference for the 0 and +2 oxidation states, facilitating the re-

generation of catalytic palladium species � High electronegativity (2.2 on the Pauling scale), facilitating

easy transmetallation from other metal-carbon bonds � User-friendly due to its relative insensitiveness to moisture, acid

and air � Accessible HOMO and LUMO energies, facilitating concerted

reactions due to low activation barriers � Suitable van der Waals radius, accommodating both tetrahedral

and square-planar geometry during interconversion of Pd(0) to Pd(II) when four ligands are present

All the coupling and cross-coupling reactions proceed through oxidative addition to a Pd(0) center. The next step of the Sonogashira and other cross-coupling reactions occurs through ligand exchange and transmetallation fol-lowed by reductive elimination to release the product and regenerate active

R XR'

Ar-XAr-Ar'[Pd], Ar'-M R

R'

R

Ar R

R R'+

[Pd], Base+

Heck

Cross coupling

[Pd], CuI, Base

Sonogashira

15

Pd(0) species. In the Heck reaction, on the other hand, oxidative addition is followed by olefin insertion instead of transmetallation. This insertion forms a new C-C bond. �-Hydride elimination furnishes the desired product to-gether with a palladium hydride, which then undergoes base-mediated reduc-tive elimination to regenerate Pd(0) and complete the catalytic cycle.

Palladium catalysis is not limited to the above-mentioned coupling and cross-coupling reactions, but also includes numerous organic transforma-tions, such as carbonylation,19 amidation20,21 and amination,20 cyanation,22 hydrogenation,23 annulation,24 dehalogenation,25 borylation,26 fluorination,27 allylic alkylation,28 enolate coupling,29 debenzylation,30,31 and ether forma-tion,32 etc.

1.1.3 The Heck Reaction In the late 1960s, R. F. Heck discovered that arylpalladium salts, obtained from transmetallation with organomercury compounds, could participate in various vinylic substitution reactions.33-39 Almost simultaneously, Moritani, Fujiwara, and coworkers performed vinylic substitutions using organopalla-dium precursors via the direct electrophilic palladation of arenes.40-42 These processes involved the reduction of a palladium(II) salt to palladium(0) (Scheme 2).

Scheme 2. 43,44

Both the reactions depicted above require stoichiometric amounts of palla-dium (in the absence of a Pd(0) reoxidant) for the vinylic substitution proc-esses to occur.43 A few years later, the catalytic version of this vinylic substi-tution process was independently discovered by Mizoroki and Heck using organic halides, catalytic amounts of palladium and a base, but without using any reoxidant.45-47 This reaction revolutionized the contemporary concept of palladium catalysis and, after significant development by Heck et al., it be-came a textbook reaction called the Heck reaction or Heck olefination.48-56 The Heck reaction is defined as a vinylic substitution reaction in which a vinylic hydrogen is replaced by an aryl, vinyl, or benzyl group (Scheme 3).

ArHgX + PdX2 +R R

Ar+HgX2 HX + Pd(0)+

ArH + PdX2 +R R

Ar2 HX + Pd(0)+

16

Scheme 3.43

The catalytic cycle of the Heck reaction has been studied extensively and is based on a Pd(0)/Pd(II) redox system48 (Scheme 4). This has been generally accepted since 1970, although some parts of the catalytic cycle that occur upon the addition of different additives or ligands are still not fully under-stood.57 A postulate describing Pd(IV) complexes as key intermediates has attracted some attention ten years ago.58

Scheme 4.43

The original Heck cycle (Scheme 4) can be divided into four steps: (1) oxi-dative addition in which the electrophilic substrate RX reacts with Pd(0)L2 to produce RPd(II)XL2; (2) �-complex formation where either the ligand L or X is displaced and Pd coordinates with the olefinic double bond; (3) syn-insertion in which R and Pd(II)XL2 are inserted over the double bond, gener-ating a �-organo-palladium complex; and finally (4) �-elimination: after internal rotation, ligated Pd and a �-hydrogen is syn-eliminated as HPd(II)XL2 and the desired Heck product is produced. The base-mediated regeneration of the active Pd(0)L2 allows it to re-enter the new catalytic cy-cle.

R X +R' R'

RPd(0)-CatalystBase

R = Aryl, Vinyl, Benzyl X = I, Br, Cl, OTf etc.

R Pd XL

L

R X

(4) Oxidativeaddition

(2)

�L

Pd(0)L2

�L LPd(0)L3

X = I, Br, Cl, OTf etc.

(3)R Pd X(L)

L

(1)

R'R'

Pd

R'

RX

L

L

R'

�-Complexformation

R

Internal rotationand �-elimination

Pd(0)L4

L

Syn-insertion

L = PAr'3HH

Base HBaseX

17

1.1.3.1 Oxidative Addition During oxidative addition, Pd(0) is oxidized to Pd(II) and bound to an aryl or vinyl group and a leaving group, commonly a halide or a pseudohalide. The order of reactivity for leaving groups is as follows:59-62 diazonium salt63 > iodide64 > triflate65 > bromide66 > tosylate67,68 = mesylate67 = chloride69,70 > phosphate.68,71 Organic fluorides are inert as leaving groups under Heck re-action conditions. The active 14-electron complex Pd(0)L2 is often generated from an appropriate Pd(II) precursor and utilized ligands. The Pd(0)L2 is in equilibrium with more highly saturated inactive complexes. However, if the sterically demanding phosphine ligand P(t-Bu)3 is used, the active Pd(0) species may be a 12-electron complex.70 Many Pd(II) precatalysts are com-mercially available. Commonly used Pd(II) sources are Pd(OAc)2, PdCl2, PdCl2(PPh3)2, etc. and all are reduced in situ prior to entering the Heck cata-lytic cycle. Examples of commercially available Pd(0) sources are Pd(PPh3)4, Pd(Pt-Bu3)2, Pd(dba)2 or Pd2dba3. In general, the reduction of Pd(II) to Pd(0) is believed to be promoted by the phosphine ligand,72,73 the base,74 the olefin46,75 or the solvent.76

Amatore et al. demonstrated that excess PPh3 facilitates the reduction of Pd(OAc)2 to Pd(0), forming [Pd(0)(PPh3)2OAc]- and triphenylphosphine oxide.72,77 They also indentified and characterized Pd(0) species participating in oxidative addition produced in solution utilizing Pd(dba)2 in association with mono- and bidentate ligands.78,79

1.1.3.2 �-Complex Formation and Insertion �-Complex formation and insertion80,81 are the key steps that govern the regiochemical82 and stereochemical83,84 (in the case of prochiral olefins) out-come of the Heck reaction. The reaction conditions (neutral or cationic) and the electronic and steric effects of the substituents on the olefin moiety influ-ence the insertion [� (internal) or � (terminal)] and as a consequence, the regio- or stereoselectivity. Following �-coordination, the palladium complex rotates clockwise or counter-clockwise so that the aryl and Pd are in the same olefinic plane, forming the square-shaped transition state TS� or TS�. TS� leads to the �-product whereas TS� produces a �-product.

1.1.3.2.1 Regioselectivity: Emphasis on Electron-Rich Olefins The regioselectivity of the Heck reaction is governed by both electronic and steric effects. Under classical Heck conditions, electron-poor olefins react smoothly to furnish the trans-�-substituted product. On the other hand, elec-tron-rich olefins generally produce a mixture of �-product and �-product (cis- and trans-isomers). Additionally, double bond migration,85,86 diarylated products (products in which a heteroatom substituent bound to the alkene has been eliminated), or sometimes even tar, were generated under the tradi-

18

tional conditions in case of non-electron-poor alkenes (electronically neutral and electron-rich alkenes) (Scheme 5).

Scheme 5. Heck reactions with electron-poor and electron-rich alkenes.43,56

Scheme 6. Heck reaction with electron-rich olefins via cationic intermediates.43

ArXEDG

EDG EDG EDG

Ar

Ar

Ar

Ar

Ar

Ar

+ +

+ +

Pd(0)+

Several double-bond isomers when EDG = alkylEDG = Heteroatom, alkyl etc.

ArXEWG EWG

ArPd(0)+

EWG = COOR, COR, CN, Ph etc.

Ar Pd PP

Y

+

X = OTf, OAc, HalideAr Pd PP

X

Y

Y

Ar PdPP

X

Pd(0)

Y

Ar

H Pd PP

X �-Arylation

Reduction

BaseHBaseX

Pd(OAc)2

ArX

P P

Y = O, N, (CH2)

P P

X -

= dppp, dppfP P

19

The regioselectivity in the Heck reaction with electron-rich olefins depends on the nature of the �-complex. Typically, a positively charged �-complex will mainly furnish the �-substituted product (Scheme 6), while a neutral �-complex will predominantly lead to the �-substituted product (Scheme 7). The metal center of a positively charged �-complex is stabilized by two neu-tral ligands or one neutral bidentate ligand (Scheme 6). On the other hand, the metal center of a neutral �-complex is coordinated with a ligand and a counterion (halide) (Scheme 7). Reversibility in “cationic” and “neutral” Heck reactions has recently been proposed by Jutand et al.87

Scheme 7. Heck reaction with electron-rich olefins via neutral intermediates.43

The terminal �-carbon is more electron-rich in enol ethers and enamides, due to the mesomeric effect, and is therefore more susceptible to bind to elec-tron-poor Pd(II), compared to the sp2-carbon of the formally negatively charged aryl group attached to the metal centre. However, achieving the �-product is believed to be sterically more demanding. These conflicting fac-

Ar Pd XP

P

Y

Ar PdP

Y

X Pd ArP

Y

Y

Ar PdXP

P

Y

Pd ArX P

P

P2Pd(0)

Y

Ar

Y

Ar+

�- & �-Arylation

+

Reduction

BaseHBaseX

X = I, Br, Cl, OTf

+

Pd(OAc)2

ArX

X

Y = O, N, (CH2)

P

P2Pd(II)HX

P = PAr'3

20

tors reduce the selectivity. The problem of obtaining internal selectivity with terminal electron-rich olefins was solved by the pioneering work of Cabri et al., who discovered the cationic version of the Heck reaction using aryl tri-flates and bidentate ligands. This methodology is completely �-selective for electron-rich olefins.50,88-90 Strongly coordinating bidentate ligands such as dppp, and weak counter-anions such as triflates (Scheme 6) are usually needed,50,55 but aryl halides can be used with the appropriate additives, like silver(I)91-93 and thallium(I)94,95 salts, to scavenge the halide. The selectivity pattern in certain Heck reactions can be controlled under Jeffery condi-tions96,97 by using a suitable tetraalkylammonium salt instead of silver or thallium additives.98-101 Strong polar solvents, such as water or ionic liquids, are also used to promote the ionization of the arylpalladium halide complex and to provide high �-selectivity.102,103 At the end of the 1980s, Andersson and Hallberg developed an indirect way of achieving selective terminal �-arylation of n-butyl vinyl ether using aroyl chlorides as the Ar-Pd precursor under decarbonylative reflux conditions.44,104

Table 1: Regioselectivity in Heck reactions. R = alkyl, H.43,50,90,105

O

O

R

NH2

O

CN

Ph

R

OH

ROH

O

O

N

O

HN R

O RO

Olefin Cationic Pathway Neutral Pathway ��:�� :�

100:0 100:0

100:0 100:0

100:0 100:060:40

R = H, 100:0R = Alkyl, 90:10

R = H, 0:100R = Alkyl, 5:95

80:2020:80

80:2010:90

mixture of products5:95

60:400:100

5:95 not reported

0:100 30:70

ONR2

0:100 100:0

90:10

��

21

Modest yields and reasonable �-selectivity (up to �:� = 9:1) were obtained with electron-deficient aryl groups. It was found that the highest �-selectivity was obtained when chloride coordinated with the metal center in the oxidative addition intermediate.44,106 The terminal selectivity was sub-stantially increased by the use of chelating alkyl vinyl ether and aryl halides (e.g. Structure A, Fig. 1).107,108 Utilizing a novel tetraphosphine-palladium catalyst, Doucet and Santelli obtained high regioselectivities in favor of the linear isomer when using sterically demanding cyclohexyl- or t-butyl vinyl ether and electron-deficient aryl bromides.109 With unhindered n-butyl vinyl ether poor �/� ratios were observed. On the other hand, when using a spe-cific poly(ethylene glycol) polymer (PEG-2000) as solvent, high terminal selectivity was found with a series of aryl bromides (irrespective of their chemical nature), together with classic palladium acetate.110

During the past few years, PEG,110 water,111,112 ionic liquids,113 and com-binations of ionic liquids and organic solvents114,115 have been well-exploited in regioselective50 Heck arylation of electron-rich olefins. The regioselectiv-ity obtained in neutral and cationic Heck reactions using a selection of di-verse olefins is presented in Table 1.

1.1.3.3 �-Elimination and Palladium(0) Regeneration The final step in the catalytic cycle is �-elimination providing the final prod-uct. Following internal rotation in the �-complex, the hydrogen departing is positioned syn to the palladium metal. Elimination of the palladium hydride complex furnishes the desired arylated or vinylated olefin. The elimination step is reversible and favors the thermodynamically more stable trans-isomer.12,48 Recently published results of a mechanistic study indicate that, under certain conditions and using allyl ethers as substrate, single bond rota-tion has a higher barrier than �-hydride elimination, and is thus selectivity determining.116 To some extent, the dissociation of olefin from the palla-dium(II) hydride complex is slow, and this may facilitate the re-addition to the double bond, producing a double-bond isomer.117,118 The base-induced scavenging of HX from the Pd(II) complex produces the reduced, active Pd(0)L2 species (Scheme 4), which thereafter re-enters the catalytic cycle. Results that suggest an alternative mechanism for the �-elimination/reduction steps wherein the elimination is base-promoted have been published.119

22

1.2 Chelation-Controlled Regio- and Stereoselective Intermolecular Heck Reactions

1.2.1 Chelation Control in the Heck Reaction The phenomenon of controlling regio- and stereoselectivity in the Heck reac-tion by employing a substrate-bound, removable, catalyst-directing group is generally known as “chelation control”. In this type of reaction, the substrate alkene is attached to a donor group, which essentially coordinates and pre-sents the aryl/vinylpalladium intermediate to generate the alkene-palladium complex. Thus, the introduction of an aryl/vinyl group onto the olefin moiety will pass through in an intramolecular fashion and change the process from being a bimolecular to a pseudo-unimolecular one. Coordinating groups such as tertiary amines/pyridines,107,120-127 diarylphosphines,128 carbamates,129-131 hydroxyl,132-137 and sulfinyl138-140 are effective for coordination to Pd(II), and are described as reagent- or catalyst-directing groups.141 Chelation control can be utilized either in inter- or intramolecular Heck reactions.

Pioneering research in the field of intramolecular asymmetric Heck reac-tions has been carried out by the Overman,142 Shibasaki,143 and Feringa.144,145 A substantial number of donor-group-directed intramolecular regio- and stereoselective Heck reactions have been performed by Grigg,146 Overman,147-149 Carretero,150 and Oestreich137,151-153 et al. However, as this field is beyond the scope of this thesis, only the amino-directed chelation-controlled intermolecular version will be discussed.

1.2.2 Chelation-Controlled Regioselectivity and Reactivity Enhancement in Heck Reactions Reports of X-ray structures of olefin/heteroatom-comprising compounds, which concurrently coordinate to a Pd(II) center in a bidentate manner are quite common in the literature.125,154,155 The stability and size of the chelate ring are the key factors for controlling the insertion. Optimal bonding be-tween palladium and the heteroatom is necessary to present the Pd to the olefin during insertion, and to allow subsequent removal of Pd through �-elimination.123 The latter step is essential for successful catalysis. Among other donor atoms, nitrogen is excellent, because amines are not prone to oxidation under Heck reaction conditions, as are phosphines. Oxygen, on the other hand, is a less powerful atom in chelation-controlled protocols due to the weak coordination between “hard” oxygen and “soft” Pd.

In chelation-controlled intermolecular Heck reactions, vinyl ethers equipped with a dimethylamino group were proven to be beneficial. The length of tether between oxygen and the donor nitrogen has been found to be

23

a crucial factor for a regioselective outcome.121 Two-carbon spacing between O and N in the chelating vinyl ethers, having either dimethyl-amino or 2-pyridyl as the donor group, was proven to be ideal for obtaining exclusive �-selectivity (Scheme 8).

Scheme 8. Amino-directed chelation-controlled �-arylation of a linear vinyl ether.

Increasing the tether length led to poor �-selectivity.121 Analogs of chelating vinyl ethers, where either the donor dimethylamino was replaced by iso-propyl, or 2-pyridyl was replaced by a phenyl group, have been synthesized and careful study revealed the importance of chelating N in order to ensure the desired regioselectivity.121 The chelated N-Pd �-complex controls migra-tory insertion through a favored, 6-membered ring intermediate. Insertion may also be electronically influenced, facilitating the reduction of the elec-tron density at the terminal carbon of the chelating vinyl ether by moving the free oxygen electron-pairs out of plane.

The regioselectivity was seen to change dramatically (�:� = 1:1) when the chelating vinyl ether A (Scheme 9) was replaced by butyl vinyl ether in a control experiment.120,121

Scheme 9. Switch of regioselectivity. Chelation control vs. ligand control in a Heck reaction.43,121

ArPd

P

O

PPh3Pd

ArN

O

ArOTf

P PhPh

PhPh

+

Pd(OAc)2 PPh3

Pd(OAc)2dppp

N

ON

ON

ON

Ar

Ar

�-Product�/� = 1/99

�-Product�/� = 99/1

+

+

A

PdPAr'3

Ar'3P

Ar

NR2

O

PdPAr'3

NR2Ar

OONR2PdPAr'3

PAr'3Ar

ONR2Ar

Pd(0) / PAr'3

ONR2

�-Complex

�-Complex

�-Elimination

Chelation andreorganization

Arylpalladium(II) complex

ArX

�

�

24

The observation that the bidentate ligand favored the exclusive formation of the �-product confirmed the strong influence of the ligand-driven reaction in which the dimethylamino group was not allowed to coordinate to the metal center (Scheme 9).122

Also the bite angle (P-Pd-P), produced by employing a bidentate phos-phane ligand, has been found to play a crucial role in the regioselective out-come in Heck reactions using chelating vinyl ether A (Scheme 10). Thus, by screening alternative bidentate ligands such as dppm, dppe, dppp, dppb, and dppf, it was concluded that a bite angle of 90 or close, favors �-selectivity (Scheme 10).

Scheme 10.

Deviating angles in the case of dppe (< 90 ) and dppb (> 90 ) led to less �-selectivity due to somewhat lower diphosphane-palladium chelate stability and potential Pd chelation by A.121 Replacement of monodentate Ph3P by a bidentate phosphane dppp (P-Pd-P = 90 ) resulted in a regiochemical switch (Scheme 9).

The effect of chelation control and reactivity enhancement was further developed by Nilsson, Larhed, and Hallberg. By choosing the appropriate reaction conditions, impressive sequential ligand-controlled �-arylation and dimethylamino-accelerated di- and tri-arylation was achieved using the che-lating vinyl ether A as presented in Scheme 11.107

Scheme 11. Triarylation of a chelating vinyl ether.107

ON �

�80 °C

ON

Ar1

ON

Ar1Br, Pd(OAc)2dppp, TlOAc

HCl (aq)TBME

Ar2

Ar2

Ar1

Ar2Br, Pd(OAc)2Ph3P

NaOAc, K2CO3

O

Ar1

Ar2

Ar2

100 °C

14-66%(overall)

A

ON �

�

Ph2P PPh2 PPh2 PPh2dppm, = 73° dppp, � 90°

�:� = 1:99 �:� = 99:1

ON

Ph

ON

PhPhOTf, Pd(OAc)2Et3N

PhOTf, Pd(OAc)2Et3NA

25

Later, 2-pyridyl-directed exclusive �,�-diarylation of vinylsilane,124,125 2-pyrimidyl-directed �,�-diarylation and �,�,�-triarylation of vinyl thio-ether,127 (by Itami and Yoshida et al.) (Scheme 12) and dimethylamino-directed �-arylation of 2-anilido-substituted sulfinyl olefin (by Carretero et al.)138 substantially strengthened the concept of using nitrogen auxiliary in chelation-controlled regioselective intermolecular Heck reactions.

Scheme 12. Chelation-controlled multiarylations.124-127,152

1.2.3 Chelation-Controlled Stereoselectivity in Heck Reactions The first intermolecular version of the asymmetric Heck reaction was devel-oped by Hayashi et al. using 2,3-dihydrofurans and aryl triflates.156 In asymmetric Heck reactions, a preferential asymmetric insertion on either the Re- or Si-face of the prochiral olefin employed, followed by �-elimination, generates a new chiral center (tertiary or quaternary) displacing the double bond from its original position.95,157,158 The stereochemistry can be controlled with cyclic olefins either by employing a homogeneous catalytic system with chiral bidentate ligands143 or, alternatively by relying on substrate-bound, removable, catalyst-directing groups.108 Among many ligands used in asymmetric Heck reactions, the two most successful ones are the axially chiral P,P-bidentate (R-BINAP) ligand introduced by Noyori et al.159 and the chiral N,P-bidentate phosphineoxazoline ligand developed by Pfaltz et al.160,161 In the ligand-modulated asymmetric Heck reaction, phosphineoxa-zoline often furnished high enantioselectivity. Despite the benefit of using catalytic amounts of chiral catalyst, the major limitation of this methodology

N Si N Si

Ar2Ar1

Ar1I; Ar2I (one pot)Pd2(dba)3.CHCl3Et3N, (2-furyl)3P

THF, 60 oC65-74%

E:Z > 99:1

N

N

S N

N

S

Ar2Ar1

Ar1I; Ar2I (one pot)Pd(Pt-Bu3)2

Et3N

Toluene, 60 oC

81-95%

E:Z > 99:1

N

N

S

Ar2Ar1Ar3

1. t-BuLi, THF -78 oC

2. Ar3I, Pd(PPh3)4 CuI, 50 oC3. DDQ, rt 55-82%

t-Bu

26

was the requirement of electron-rich olefins (poor �-acceptors, good �-donors) under cationic conditions.

At end of the 1990s, Carretero et al. demonstrated an outstanding applica-tion of dimethylamino-directed auxiliary, or chelation-controlled stereoselec-tive synthesis of 2-aryl-3-sulfinyl-2,5-dihydrofurans in high ee's (Scheme 13).139 Scheme 13.139 The high enantiomeric excess was achieved by the coordination of the di-methylamino group to Pd(II), and thus selective presentation of �-adduct during the asymmetric insertion. To understand the insertion mode, non-amino-containing 4-arylsulfinyl-2,3-dihydrofurans were synthesized and subjected to Heck arylation under the same conditions. Interestingly, the opposite diastereomers (de = 34-56%) dominated, proving the route of chela-tion-controlled diastereo-facial insertion.139,140

Among the nitrogen-based chiral auxiliaries, the proline-based pyrrolidine ring has been extensively exploited in asymmetric synthesis.157,162 During the systematic work by Andersson, Larhed, and Hallberg in the field of chela-tion-controlled Heck reactions, it was established that chelating vinyl ether A

Figure 1.

(Fig. 1) was well designed to providing �-selective Heck arylation. For fur-ther development of this concept from the domain of regioselectivity to the Scheme 14.163

OS

NPd LAr O

OS O

ArI, Pd(OAc)2Ag2CO3, dppp

+O

S OArN N

de = 70-88%

ON

O ON N

A B C

ON

Ar-X O PdN

H

Ar

X ON

ArHCl (aq)

Pd(OAc)2

O

Ar

(90-98% ee)X = I, Br

27

domain of stereoselectivity, the terminal vinylic group was substituted by a prochiral 2-methyl cyclopentenyl moiety maintaining the optimal two-carbon spacing between the vinylic oxygen and the donor nitrogen. Chelat-ing vinyl ethers B and C (Fig. 1) were thus synthesized for evaluation as Heck substrates. This conceptual development of Pd(II)-presenting linker from linear N,N-dimethylamino ethyl (B, Fig. 1) to the rigidified (S)-prolinol moiety (C, Fig. 1) led to great success in the field of amino-directed di-astereoselective intermolecular Heck reactions.163 The chiral prolinol moiety allowed selective Si-facial insertion of tetra-substituted olefin C (Fig. 2) to produce exclusively the mono-arylated product which was hydrolyzed in situ to furnish (R)-2-aryl-2-methyl cyclopentanones with high enantiomeric puri-ties (Scheme 14).163 On the other hand, non-chiral chelating vinyl ether B (Fig. 1) gave racemic cyclopentenones at good yields after Heck arylation and subsequent hydrolysis, despite the difference in N-Pd(II) coordination strength between the two olefins.123 Recently published density functional theory (DFT) calculations164 also support the chelation-controlled Si-facial insertion of the ArPdX complex into the vinyl ether double bond of C.

Figure 2. Si-face addition furnishing the (R)-2-aryl-2-methyl cyclopentanone after hydrolysis (in the presented model Ar = Ph).163

O PdN

H

Ar

X

O PdN

H

Ar

X

28

1.3 Aryl Chlorides in Heck Reactions

1.3.1 General Among the available aryl halides, aryl chlorides are sluggish in the Heck reaction due to the relatively high C-Cl bond energy. However, aryl chlo-rides are attractive arylpalladium precursors because they are readily avail-able and inexpensive compared to aryl iodides and bromides.165,166 Heck coupling of styrene with chlorobenzene catalyzed by Pd/C was reported by Julia et al. at the beginning of the 1970s.167 Later, a series of Heck reactions with chlorobenzene and electron-poor aryl chlorides were conducted with the newer ligands, and the outcomes were acceptable.165 The use of basic phosphine ligands to promote smooth oxidative addition and the combina-tion of NaI and NiBr to increase the reaction rates has been shown to be successful.168-170 However, slow oxidative addition and the requirement of expensive, air-sensitive catalysts prevent the development of a general pro-tocol for aryl chlorides and the scope was limited to the electron-poor aryl chlorides. In the case of achiral Heck reactions, noteworthy research with aryl chlorides has been presented by several groups, including those of Spencer,171 Milstein,169 Herrmann,172-174 Fu,175-177 Beller,178,179 Zapf,180 Li,181 DuPont,182 Djakovitch,183 Reetz,184 and Jensen.185 (See Table 2 for a selection of examples.)

Scheme 15. (a) The Heck reaction with aryl chlorides. Descriptions of R, R1 and examples of Heck reaction are given in Table 2. (b) An illustrative example of a Heck reaction with an activated heteroaryl chloride was developed by Niu et al. for the synthesis of the antitumor agent 3-AP.186

1.3.2 Palladium Ligands/Catalysts for Aryl Chloride Activation In the mid 1980s, Davison et al. successfully demonstrated a Heck reaction with chlorobenzene and styrene using the bidentate 1,2-bis(diphenylphosphino)ethane (dppe).187 In the early 1990s, Milstein et al. discovered the bulky, electron-rich, chelating phosphane ligand (1,4-

Cl

R R+

Catalyst

Base, SolventTemperature

R1(a)

R1

N Cl

NH2

N

NH2

PhPh

N

NH2Pd(OAc)2

PPh3, NaHCO3

DMF, 135 oC+

Antitumor agent, 3-AP

NNH

NH2

S(b)

29

bis(diisopropylphosphino)butane (dippb) (Structure D, Fig. 3) which pro-vides a palladium catalyst that can effectively couple electron-poor and bor-derline aryl chlorides.169

Figure 3. Some important ligands/catalysts for Heck aryl chloride activation.

Reactions with electron-rich aryl chlorides were low yielding. However, the similar bulky, chelating phosphine ligand dippp (Structure D, Fig. 3), and monodentate P(i-Pr)3 remained inactive in this reaction. In the mean time, Heck coupling with activated aryl chlorides (attached with EWGs) and sty-rene or acrylates has been reported using Herrmann’s palladacycle (Structure E, Fig. 3), carbene ligands (Structure F, Fig. 3), phosphorus ligands using nBu4NBr as co-catalyst, phosphane- or phosphate-based palladacycles and PCP-pincer complexes70 (Table 2). 1,3-Dialkylimidazolidinium hexafluoro-phosphates or tetrafluoroborate (room temperature ionic liquids) as N-heterocyclic carbene precursors188,189 and palladium complexes of N-heterocyclic carbene ligands with bulky substituents190 have been well-exploited in Heck reactions with aryl chlorides.191

At the end of the 1990s, Fu et al. reported the general Pd/P(t-Bu)3-catalyzed Heck coupling of diverse aryl chlorides with a series of electron-rich, electron-poor and electron-neutral olefins.175,176 Among other electron-rich bulky alkyl phosphines, P(t-Bu)3 and di(t-butyl)phosphanylferrocene (Structures G and H, Fig. 3), were proven by Hartwig et al. to be the most effective for Heck coupling of unactivated aryl chlorides through a fluores-cence-based assay, where they screened more than 40 phosphane ligands.192 Beller et al. also reported successful Heck coupling of unactivated and hin-dered aryl chlorides using the bulky electron-rich catalyst di(1-adamantyl)-n-butylphosphane (Table 2, entry 8).193 Among a set of bulky, electron-rich dialkylaryl- and trialkylphosphanes, P(t-Bu)3 and di(1-adamantyl)-n-

Pd P (CH2)nPP

Pn(H2C)

n = 3, dipppn = 4, dippbMilstein et al.

Fe

P(t-Bu)2P(t-Bu)3

[(t-Bu)3PH]BF4 N

NPdL2

2Air stableFu et al. Hartwig et al.

PPd

O

O

Herrmann et al.

2

D

G H

E

F

30

butylphosphane resulted in the highest yields and turnover numbers for the reaction between 4-chlorotoluene and styrene. Hartwig et al. demonstrated the presence of a weak agostic interaction between the metal and a ligand hydrogen (from one of the butyl groups of alkyl phosphines) by X-ray and spectroscopic studies of the structure of a T-shaped arylpalladium(II) halide oxidative addition complex.194 The extra stability of this oxidative addition intermediate revealed the usefulness of bulky, electron-rich alkyl phosphanes in Heck reactions employing unactivated aryl chlorides.

Table 2: Examples of Heck reactions with aryl chlorides The positions of R and R1 are given in Scheme 15 [Equation (a)].

Entry R R1 Catalyst Conditions Yield (%)

iPr2PPiPr2

Pd(OAc)2

Pd

O

O

PiPr2

PiPr2

Cl

1169 4-NO2, CHOH, CH3

Ph NaOAcDMF

150 oC

55-95

2175

3185

Pd2(dba)3/P(tBu)3

4174

4-COMe, H4-OMe, 2-OMe

Cs2CO3dioxane

100-120 oC

70-84

5195

6196

4-CHOCOMe H, OMe2-CH3

CsOAc,dioxane

120 oC, 180 oC

81-99Ph

7197

8172

COOBu4-NO2, CHO NaOAcDMA130 oC

99n-Bu4NBr co-cat.

PhCOOMe

Catalyst F (Fig. 3)

4-OMe PhCOOBu

Pd(OAc)2N,N-dimethyl-�-alanine

NMP130 oC

30-96

4-COMeNO2

PhCOOt-Bu

S

N N OH

PdCl Cl DMF

TBABNaOH130 oC

82-96

PhCOOBu n-Bu4NBr co-cat.

NaOAcDMA130 oC

32-81

PhCOOBu

N N

NHBu +

OAc_

PdCl2

140 oC 10-97

4-CHOCOMe, CN

Catalyst E (Fig. 3)

4-NO2 CHO, H

31

2. Aims of the Present Study

The main aim of the present study was to investigate the use of aryl chlo-rides as substrates in regio- and stereoselective intermolecular Heck reac-tions. The specific aims were as follows:

- To investigate aryl chlorides as substrates in microwave-accelerated

Heck coupling reactions with butyl acrylate under air, and to study their order of reactivity.

- To perform regioselective terminal Heck arylation of alkyl vinyl

ethers (both chelating and non-chelating) with aryl chlorides, and to use the methodology developed to synthesize a �-blocker.

- To design novel reaction conditions for aryl and vinyl chlorides as

substrates in chelation-controlled stereoselective Heck transforma-tions.

- To synthesize C-2-substituted and C-2-non-substituted cyclic proline

vinyl ethers of different sizes and to examine their scope and limita-tions in intermolecular diastereoselective Heck reactions.

32

3. Results and Discussion

3.1 Regioselective �-Arylation of Electron-Poor and Electron-Rich Olefins with Aryl Chlorides (Papers I and II)

3.1.1 Aryl Chlorides as Coupling Partners for Electron-Poor Olefin

3.1.1.1 General Until 1998, there were no truly general methods for Heck aryla-tion/vinylation with aryl chlorides.70 The discovery of bulky, electron-rich alkyl phosphines rapidly changed the situation, although long reaction times and extremely inert conditions were required to perform Heck reactions due to the rapid oxidation of alkyl phosphines to the corresponding phosphine oxides. Importantly, Fu et al. discovered an air-stable version of P(t-Bu)3 by converting it to the corresponding phosphonium salt, [(t-Bu)3PH]BF4, and demonstrated its applicability in metal-catalyzed coupling reactions.177

At the beginning of the new millenium, microwave technology started to have a substantial effect on drug discovery and preparative organic synthesis by reducing reaction times from days to hours, minutes or seconds.198-201 In the time period of 1996-2002, palladium-catalyzed coupling reactions in-volving organic iodides, bromides and triflates using microwave irradiation were reported,113,202,203 but no protocols for organic chlorides were known.204,205

3.1.1.2 Developing the Protocol and Exploring Scope and Limitation Bearing in mind the above facts, and inspired by the work of Fu et al., the possibility of accelerating Heck vinylation of aryl chlorides under air em-ploying in situ microwave heating in combination with the [(t-Bu)3PH]BF4 preligand was investigated. Initially, 4-chloroanisole, an electron-rich, deac-tivated arylpalladium precursor, was chosen as the model substrate for cou-

33

pling with electron-poor butyl acrylate (1). Fu’s published reaction system was investigated (with [(t-Bu)3PH]BF4, Pd2dba3 as the palladium source, Cy2NMe as the base and 1,4-dioxane as the solvent) under controlled mi-crowave heating in a sealed vessel, using 2.0 equiv of butyl acrylate (1) and 1.0 equiv of 4-chloroanisole (2a) (Scheme 17).

Scheme 16. Heck vinylation of aryl chlorides under air.

Under the subjected conditions (180 C, 60 min), the reaction did not pro-ceed to completion. Applying a higher temperature (190 C) and longer irra-diation time (90 min) resulted in a maximum of 27% conversion of the start-ing material 4-chloroanisole using microwave-transparent 1,4-dioxane as solvent. To increase the energy absorption efficiency of the solvent system, ionic liquids206-209 were added to the mixture, as they act as microwave-active “molecular irradiators” heating the reaction system quickly.210,211 Three different kinds of ionic liquids188 were tested: 1-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6),212 1-butyl-3-methylimidazolium tetrafluoroborate (bmimBF4), and tetrabutyl ammonium bromide (TBAB).213 Screening of these ionic additives in association with different palladium precatalysts (Herrmann’s palladacycle [trans-di(�-acetato) bis o-(di-o-tolyl-phosphino)benzyl�dipalladium(II)],214 Pd(OAc)2, PdCl2, or Pd2(dba3)) in the microwave-acclerated model reaction showed that the most thermostable ionic additive, bmimPF6,215 in combination with Herrmann’s palladacycle, furnished the highest conversion of 2a (65%). Scheme 17. Model Heck reaction between 1 and 2a under microwave conditions.

Cl

R R

Ligand, Base

Solvent

COOBuCOOBu

Air atmosphere1 32

+

[Pd]

Palladacycle

bmimPF6-dioxaneMw, 60 min, 180 oC

[(t-Bu)3PH]BF4, Cy2NMe

Air atmosphere

COOBu

1

COOBu

MeO3a

Cl

MeO2a

+

34

Based on this positive outcome using bmimPF6, the scope of this ionic liquid was further explored with different amounts of 1,4-dioxane using 1 and the sluggish aryl chloride 2a. The reaction temperature was carefully chosen to be 180 C in order to avoid catalyst decomposition and subsequent incom-plete conversion of the starting material. After selective screening, the best combination of reaction time, catalyst loading, and solvent system was iden-tified to be 60 min of heating 1 and 2a with 10.0 mol% Herrmann’s pallada-cycle, 20.0 mol% [(t-Bu)3PH]BF4 and 1.0 equiv (with respect to 2a) of bmimPF6 (208 �L) with 400 �L of 1,4-dioxane. Shorter reaction times or lower catalyst loading resulted in incomplete conversion of 2a. Attempts to conduct the reaction without bmimPF6 resulted in incomplete conversion of 2a (up to 90%), neither did the use of inert conditions improve the reaction outcome.

Table 3: Heck vinylation of electron-rich aryl chloridesa

a Reaction conditions: bmimPF6 (208 �L), 1,4-dioxane (400 �L), Herrmann’s pal-ladacycle (10.0 mol%), [(t-Bu)3PH]BF4 (20.0 mol%), 2a-d (1.0 mmol), 1 (2.0 mmol), and Cy2NMe (1.5 mmol), 180 C. b > 95% pure according to GC/MS. c Con-ventional oil-bath heating at 180 C for 90 min. Shorter heating times afforded lower yields of 3d.

This method afforded 60% isolated yield of butyl 4-methoxycinnamate (3a) (Scheme 17 and Table 3, entry 1), and was selected as the standard reaction

MeO COOBu

COOBuMe

MeMe

Me

Entry Aryl chloride

Time(min) Product

Isolatedyieldb (%)

MeO

Cl

Cl

C l

Cl

Me

MeMe

Me

1 60 60

2 60 85

3 60 86

4 60 80, 47c

COOBu

COOBu

2a

2b

2c

2d

3a

3b

3c

3d

35

condition to perform vinylation of electron-rich and sterically hindered aryl chlorides. This condition resulted in rewarding outcomes (Table 3).

Table 4: Heck vinylation of electron-neutral and electron-poor aryl and het-eroaryl chloridesa

a Reaction conditions: bmimPF6 (208 �L), 1,4-dioxane (400 �L), Herrmann’s pal-ladacycle (5.0 mol%), [(t-Bu)3PH]BF4 (10.0 mol%), 2e-i (1.0 mmol), 1 (2.0 mol), and Cy2NMe (1.5 mmol), 180 C. b > 95% pure according to GC/MS.

Encouraged by the results presented in Table 3, I decided to proceed to de-velop a milder reaction protocol employing electron-deficient, electron-neutral aryl and heteroaryl chlorides together with microwave and traditional oil-bath heating. Effort to lower the catalyst concentration was successful and arylation could be performed employing only 1.5-5.0 mol% Herrmann’s palladacycle. Ten different cinnamic acid esters (3e-n) were synthesized using otherwise identical conditions (Tables 4 and 5).

Cl

1 40 90

2 40 91

3 40 88

4 60 65

5 60 81

COOBu

2e

2f

2g

2h

3e

3f

3g

3h

CF3CF3

Cl

N N

COOBu

Cl

Cl

N

COOBu

COOBu

N

Cl

COOBu

2i 3i

Entry Aryl chloride

Time(min) Product

Isolatedyieldb (%)

36

Table 5: Heck vinylation of electron-poor aryl chloridesa

a Reaction conditions: bmimPF6 (208 �L), 1,4-dioxane (400 �L), Herrmann’s pal-ladacycle (1.5 mol%), [(t-Bu)3PH]BF4 (3.0 mol%), 2j-n (1.0 mmol), 1 (2.0 mmol), and Cy2NMe (1.5 mmol), 180 C. b > 95% pure according to GC/MS. c Conven-tional oil-bath heating at 180 C for 60 min. Shorter heating times afforded lower yields of 3m.

Excellent yields were obtained, as can be seen in Tables 4 and 5. However, a somewhat lower yield was observed in the case of chlorobenzene (Table 4, entry 4) due to dehalogenation of the starting halide at elevated temperature. Classic oil-bath heating at 180 C for vinylation of 2d and 2m were not as successful (Table 3, entry 4 and Table 5, entry 4). Incomplete conversion of the starting aryl chlorides resulted in lower yields than in the microwave experiments.

To extend the scope of the protocol, I decided to investigate the arylation of styrene (4) under similar conditions. A model reaction of 4 with 2m was performed under similar conditions using 1.5 mol% Herrmann’s palladacy-

1 30 93

2 30 94

3 30 95

4 30 90, 53c

5 30 80

COOBu

AcCOOBu

F3C

COOBu

MeOOCCOOBu

OHCCOOBu

NC

Cl

Ac

Cl

F3C

Cl

MeOOC

Cl

OHC

Cl

NC

2j 3j

2k 3k

2l 3l

2m 3m

2n 3n

Entry Aryl chloride

Time(min) Product

Isolatedyieldb (%)

37

cle and 30 min of microwave heating. A modest 69% isolated yield of (E)-4-acetyl stilbene (5) was obtained as a result (Scheme 18).

Scheme 18. To understand the effect of bmimPF6 quantitatively, microwave model reac-tions were performed between 2m and 1 using pure 1,4-dioxane and com-pared with the same reaction with bmimPF6 and 1,4-dioxane (Table 5, entry 4).

Figure 4. Initial temperature profiles for the reaction of 4-chloroacetophenone (2m) and butyl acrylate (1) in (i) pure 1,4-dioxane and (ii) a 1,4-dioxane-ionic liquid (bmimPF6) solvent system (Table 5, entry 4).

The effect of efficient heating in the presence of bmimPF6 was clearly visible from the temperature profile (Fig. 4). However, after 8-9 min (of a total irra-diation period of 60 min), the temperature with and without bmimPF6 was 180 C. Running the reaction without bmimPF6 for 70 min did not improve the yield of 3m. The increased yield and rapid heating of the reaction in the presence of bmimPF6 indicates that this ionic liquid not only increases the heating efficiency by acting as a “molecular-irradiator” but may also help the catalytic system to perform better. At elevated temperatures, the deproto-nated imidazolylidine may act as a carbene ligand to palladium.190,216 Thus, the reaction may possibly be catalyzed by imidazolylidine-palladium carbe-noid species together with the expected Pd-[P(t-Bu)3] complex.217 Alterna-tively, the differing results observed with traditional heating and microwave heating might be explained by the problems of measuring the correct tem-

PalladacyclePh

bmimPF6-dioxane Mw, 30min, 180 oC

[(t-Bu)3PH]BF4, Cy2NMeCl

Ac

Ph

Air atmosphere2m 5, 69%4

+Ac

38

perature during microwave irradiation.202 The good results obtained when using non-inert conditions may be a consequence of the reduced solubility of oxygen in organic solvents at high temperatures.

3.1.1.3 Outcome The outcome of the developed protocol was satisfactory. A general protocol for Pd-catalyzed vinylation was achieved irrespective of the chemical nature of the aryl chlorides. Small-scale coupling reactions were fast and high yielding. To the best of my knowledge, this is the first general Heck meth-odology using deactivated aryl chlorides under non-inert condition.218

3.1.2 Aryl Chlorides as Coupling Partners for Electron-Rich Olefins

3.1.2.1 General Among the available electron-rich olefins, enol ethers are often used as vi-nylating agents since regioselective Heck arylation of enol ethers66 has tre-mendous synthetic potential. Arylation of enol ethers followed by hydrolysis opens up the route for the preparation of different carbonyl compounds. Fur-thermore, successful selective internal (�-) arylation of vinyl ethers, ena-mides, allylic compounds,43,50,56,114 and silyl enol ethers219-222 has been re-ported. It has been established in Heck methodology that the cationic route using bidentate ligands favors �-arylation of electron-rich acyclic-monosubstituted olefin, whereas neutral conditions facilitate predominantly �-arylation.50 This has also been supported by DFT calculations.223,224 Earlier efforts to achieve terminal �-selectivity of electron-rich olefins were summa-rized in Section 1.1.3.2.1. However, no direct and general protocol employ-ing aryl chlorides for terminal-selective Heck reactions with n-butyl vinyl ether was available until 2005.

3.1.2.2 Determination of the Reaction Conditions Inspired by the preparative results reported by Fu et al. using P(t-Bu)3 in Heck arylation of n-butyl vinyl ether using 4-dimethylaminobromobenzene and 4-chloroacetophenone as substrates and Pd2(dba)3 as palladium source176 (Scheme 19), and based on my previous results (discussed in Section 3.1.1),218 I decided to investigate and develop a protocol for terminal Heck arylation of n-butyl vinyl ether with sluggish p-anisyl chloride.

The initial series of experiments showed that Cy2NMe was a productive base and that [(t-Bu)3PH]BF4 acted as an air-stable source of P(t-Bu)3 under non-inert microwave conditions. Among various kinds of Pd(0)225 sources employed, Herrman’s palladacycle214,226 continuously provided higher yields

39

and better �-selectivity with sluggish p-anisyl chloride than the tested alter-natives [Pd(OAc)2, Pd(PCy3)2, and Pd2(dba)3].

Scheme 19. Heck arylation of n-butyl vinyl ether reported by Fu et al.176 The reaction was unsuccessful in the absence of [(t-Bu)3PH]BF4, demon-strating that the active catalyst is Pd(0)-P(t-Bu)3, and not a Pd(0)-P(o-tol)3 derived species. Appropriate reaction conditions were thus carefully chosen in aqueous DMF using 1.0 mmol of 2, 3.0 mmol of 6 or 7, 3.0 mmol of Cy2NMe, 5.0 mol% of Herrmann’s palladacycle, and 10.0 mol% of preli-gand [(t-Bu)3PH]BF4 (Method A). This protocol was investigated with 9 different aryl chlorides (Scheme 20, Table 6). Scheme 20.

4-NMe2-Ph-Br OBu+OBu4-NMe2-Ph

OBu

4-NMe2-Ph+

4:1

E:Z = 3:1

OBu+OBu

OBu

+1:10

E:Z = 5:1

Pd2(dba)3P(t-Bu)3Cy2NMe

Dioxane, rt

Yield = 87%(as mixture of regioisomersalong with 5% unreacted4-Ac-Ph-Cl)

Yield = 97%(as mixture of regioisomers)

4-Ac-Ph-Cl4-Ac-Ph

4-Ac-Ph

ClPalladacycle, [(t-Bu3)PH]BF4

��

OR1

OR1

Microwaves, 60 min160 oC, Method A or B2 9 (�-product)

6: R1 = -n-Bu

7: R1 = -CH2CH2NMe2

8: R1 = -CH2C3H5

O

�-product

R

+R R R

40

Following microwave irradiation at 160 C for 60 min, all the aryl chlorides furnished more than 98% conversion based on GC-MS analysis. High values for regioselectivity (�/� = 97:3) were obtained when using aryl chlorides with EWGs giving acceptable yields (61-75%) of terminal arylated products (Table 6, entries 1-4). However, the terminal selectivity was reduced in the case of borderline aryl chlorides and aryl chlorides with EDGs (Table 6, entries 5-9). With p-anisyl chloride (2a), the �-selectivity was reduced to (�/�� 65:35. To improve the �-selectivity with 2a, Pd(II)-presenting chelat-ing vinyl ether 7 (A, Fig. 1) was used instead of 6, which resulted in an im-provement of �/�-selectivity to 85/15, with a better isolated yield of 63% 9j (Table 6, entry 10).

All terminal Heck vinyl ether products (9a-j, Table 6) were obtained as E/Z mixtures. The �/� ratios and conversions were carefully determined from crude reaction mixtures using 1H-NMR and by GC-MS using adaman-tane or 2,3-dimethylnaphthalene as internal standard. Regioisomers were assumed to have the same GC-MS response factors. To obtain correct �/� ratios, GC-MS response factors were also calculated for the corresponding acetophenones (produced by hydrolysis of easy-to-cleave �-arylated vinyl ethers in the reaction mixture).

41

Table 6: Terminal �-arylation of alkyl vinyl ethers with aryl chlorides in aqueous DMF

Compared to the reaction with n-butyl vinyl ether and 2m reported by Fu et al. (Scheme 19), the microwave methodology described above furnished better regiocontrol (�/� = 97:3 vs. 91/9) with improved yield (75%, Table 6,

OBu

Ar-Cl

4-NO2-Ph-Cl 4-NO2-Ph

4-CF3-Ph-Cl

4-CHO-Ph-Cl

4-Ac-Ph-Cl

2-Cl-Naphthalene

Ph-Cl

4-Me-Ph-Cl

2-Me-Ph-Cl

4-MeO-Ph-Cl

A

A

A

A

A

A

A

A

A

4-CF3-Ph

4-CHO-Ph

4-Ac-Ph

2-Naphthyl

Ph

4-Me-Ph

2-Me-Ph

4-MeO-Ph

Product

2o

7

8

9

2c

2b

2a

6

6

6

6

6

6

6

6

6

�/�

97:3

97:3

97:3

89:11

90:10

80:20

80:20

65:35

61

64

65

75

62

60

52

53

40

9a

9b

9c

9d

9e

9f

9g

9h

9i

Entry MethodYielda

(%)

1

2

3

4

5

6

Olefin

97:3

2n

2k

2m

2p

2h

OBu

OBu

OBu

OBu

OBu

OBu

OBu

OBu

A 4-MeO-Ph O(CH2)2NMe27 63

9j

85:152a10

Reaction conditions (Method A): 1.0 mmol 2, 3.0 mmol 6 or 7, 0.05 mmol Herrmann,s

palladacycle, 0.10 mmol [(t-Bu)3PH]BF4, 3.0 mmol Cy2NMe, 200 �L H2O and 2 mL

DMF in sealed vessels. Microwave heating, 160 oC for 60 min. a Isolated yield of��-arylated

E- and Z-products, >95% purity of 9 by GC-MS and 1H-NMR, average of five runs��he�

�/� ratio was determined by GC-MS and calculated as��-E + �-Z)/(��+ aryl methyl ketone).

42

entry 4) of terminally arylated regioisomer (�-E + �-Z) compared to the mix-ture of regioisomers reported in Scheme 19. Traditional oil-bath heating at 160 C for 1 or 2 h of the Heck transformation presented in entry 9 (Table 6) did not consume the yield-limiting aryl chloride. This may be a result of the lack of wall effects (and subsequent catalyst decomposition) when employ-ing in situ microwave irradiation.202,227

To investigate the effect of P(t-Bu)3 in the regioselective terminal aryla-tion of butyl vinyl ether, a series of comparative experiments were per-formed using conventional PPh3 or P(t-Bu)3 liberating [(t-Bu)3PH]BF4 (Table 7).

Table 7. Comparative experiments for regioselective terminal arylation of 6 in aqueous DMF using different phosphine ligandsa

Entry Ar-X Phosphine ligand (L)

�� Isolated yield of 9

1 4-NO2-Ph-Cl (2o) PPh3 84:16 26

2 4-NO2-Ph-Cl (2o) [(t-Bu3)PH]BF4 96:4 61

3 4-CHO-Ph-Cl (2k) PPh3 82:18 25

4 4-CHO-Ph-Cl (2k) [(t-Bu3)PH]BF4 96:4 65

5 4-CHO-Ph-Br (2q) PPh3 80:20 21

6 4-CHO-Ph-Br (2q) [(t-Bu3)PH]BF4 98:2 66 a Reaction conditions: 1.0 mmol aryl halide, 3.0 mmol 6, 0.05 mmol Herrmann’s palladacycle, 0.10 mmol ligand or preligand, 3.0 mmol Cy2NMe, 200 �L H2O, and 2 mL DMF in sealed vessels. Microwave heating, 160 C for 60 min gave >95% con-version. Isolated yields >95% purity of linear �-product 9, as determined by GC-MS and 1H-NMR.

Interestingly, P(t-Bu)3-catalyzed entries resulted in higher selectivity towards the linear product than PPh3-promoted reactions (Table 7). Even the use of corresponding aryl bromide 2q instead of 2k did not alter the selectivity pattern. In all the reactions investigated (Table 7), P(t-Bu)3-liberating [(t-Bu)3PH]BF4 delivered better isolated yields and �-selectivity of 9 compared to PPh3-catalyzed reactions, proving the regio-determining power of alkyl phosphine ligands.

43

Table 8: Terminal �-arylation of alkyl vinyl ethers with aryl chlorides in PEG 200

In 2002, Chandrasekhar et al. reported high �-selectivity in Heck arylation of n-butyl vinyl ether with aryl bromides in PEG-2000.110 The usefulness of PEG as an environmentally benign solvent in palladium-catalyzed reactions has also been reported in a number of publications.228-240 I, thus decided to

OBu

Ar-Cl

4-NO2-Ph-Cl 4-NO2-Ph

4-CF3-Ph-Cl

4-CHO-Ph-Cl

4-Ac-Ph-Cl

2-Cl-Naphthalene

Ph-Cl

4-Me-Ph-Cl

2-Me-Ph-Cl

4-MeO-Ph-Cl

B

B

B

B

B

B

B

B

B

4-CF3-Ph

4-CHO-Ph

4-Ac-Ph

2-Naphthyl

Ph

4-Me-Ph

2-Me-Ph

4-MeO-Ph

Product

2o

7

8

9

2c

2b

2a

6

6

6

6

6

6

6

6

6

�/�

98:2

98:2

98:2

92:8

93:7

83:17

82:18

78:22

60

65

62

70

60

59

52

54

46

9a

9b

9c

9d

9e

9f

9g

9h

9i

Entry MethodYielda

(%)

1

2

3

4

5

6

Olefin

98:2

2n

2k

2m

2p

2h

OBu

OBu

OBu

OBu

OBu

OBu

OBu

OBu

B 4-MeO-Ph O(CH2)2NMe27 70

9j

90:102a10

Reaction conditions (Method B): 1.0 mmol 2, 3.0 mmol 6 or 7, 0.05 mmol Herrmann,s

palladacycle, 0.10 mmol [(t-Bu)3PH]BF4, 5.0 mmol PMP, and 2 mL of PEG-200 in sealed

vessels. Microwave heating, 160 oC for 60 min. a Isolated yields of��-arylated E- and

Z-products, >95% purity of 9 by GC-MS and 1H-NMR, average of five runs. The �/� ratio

was determined by GC-MS and calculated as��-E + �-Z)/(��+ aryl methyl ketone).

44

investigate available PEG varieties241 as solvents together with the Herrmann’s palladacycle/[(t-Bu)3PH]BF4 catalytic system in an attempt to obtain better terminal selectivity in the arylation of vinyl ethers. I chose chlorobenzene (2h), a borderline aryl chloride, to screen four different kinds of commercially available PEG-varieties using similar conditions as in Method A. The use of a more bulky base PMP (1,2,2,6,6-pentamethyl-piperidine) instead of Cy2NMe was the only change. Exploiting PEG-200 and PEG-2000 varieties with methylated chain-end hydroxyl groups (masked) or PEG 2000 with free hydroxyl functions (unmasked), only in-complete transformations with ��-ratios of up to 85/15 were achieved. Nei-ther the PEG-related ether DME nor ethylene glycol resulted in more than 50% conversion of limiting 2h. In contrast, unmasked PEG-200 produced the desired phenylation (Method B, Table 8, entry 6). When using unmasked PEG-200, all available chlorides were arylated (Table 8), and notably, im-proved �-selectivity was achieved in cases of aryl moieties with EDGs (Ta-ble 8, entries 7-9). Aryl moieties with EWGs and borderline aryl chlorides produced similar outcomes to those using the aqueous DMF protocol (Method A, Table 7). Unmasked PEG-200 was found to withstand high tem-peratures (160 C) and also delivered high terminal selectivity for chelation-controlled arylation (entry 10 in Table 8). Besides the chelating vinyl ether, this PEG methodology was exploited for terminal arylation of an enamide, vinyl pyrrolidone (10). Selectivity in favor of the linear product of �� = 75/25 with a modest yield of 45% (E)-11 (Scheme 21) was accomplished. To the best of the author’s knowledge, this is the first reported terminal aryla-tion of an enamide using an aryl chloride as a coupling partner. Scheme 21. Phenylation of enamide 10 using Method B.

At this point, after developing two productive methods, I performed further control experiments to demonstrate the effect of solvent and ligand on reac-tion outcome. 4-Bromotoluene was selected for arylation instead of the cor-responding chloro counterpart in order to ensure that the reaction went to completion in the absence of an alkyl phosphine ligand (Table 9). Model reactions were performed and it was evident from reactions based on both aqueous DMF and unmasked PEG-200 medium that P(t-Bu)3-liberating [(t-Bu)3PH]BF4 yielded better �-selectivity than traditional PPh3.

Ar-Cl

BN

O

Ph

Product

10

�:�

75:25 45

Method Yield (%)Olefin

2hN

O

E-11

45

Table 9. Effect of solvents and ligands in regioselective Heck arylation of alkyl vinyl ether 6 and 4-bromotoluenea a Reaction conditions: 1.0 mmol 4-bromotoluene, 3.0 mmol 6, 0.05 mmol Herrmann’s palladacycle, 0.10 mmol ligand or no ligand, 3.0 mmol PMP, 200 �L H2O, and 2 mL DMF or 2 mL unmasked PEG-200 in sealed vessels. Microwave heating, 160 C for 60 min gave >95% conversion.

Interestingly, when the reaction was carried out in unmasked PEG-200, without the aid of extra ligand, a higher �-selectivity was observed than with reactions in the presence of P(t-Bu)3 (84:16 vs. 74:26, entries 5 and 6, Table 9), indicating a direct participation of the polymer in the insertion process. This hypothesis was supported by a computational study in which a hydro-gen-bond-stabilized transition state geometry was indentified for the �-arylation process using methyl vinyl ether as the alkene (Fig. 5).

Entry Solvent Phosphine ligand (L) ��

1 DMF/water PPh3 62:38

2 DMF/water [(t-Bu3)PH]BF4 67:33

3 DMF/water None 67:33

4 PEG-200 PPh3 60:40

5 PEG-200 [(t-Bu3)PH]BF4 74:26

6 PEG-200 None 84:16

Figure 5. Optimized structure of TS� stabilized by palladium chelation and a hydrogen bond interaction between the methyl vinyl ether oxygen and PEG chain-end hydroxyl. Only the polar hydrogen is displayed, for clarity (model and calcula-tion by Dr. H. v. Schenck).

46

3.1.2.3 Computational Insight into the Terminal Selectivity In brief, DFT calculations were conducted at B3LYP level of theory by Dr. H. v. Schenck in order to better understand the regioselectivity governing the insertion step in the Heck reaction with aryl chlorides242 through a neutral pathway. A set of para-substituted [phenylpalladium(II) chloride complexes was studied (Scheme 22).

Scheme 22. Regio-determining insertion of methyl vinyl ether.

Figure 6. Transition state structures identified by DFT calculations for the reaction pathways, providing the �- or the �-phenylated methyl vinyl ether.69

RPd

L

ClO

I J

RPd

O

LCl

RPd

LCl

O

R

R

O

OR

Pd

Cl

L

TS�

�-Arylated product 9

�-Arylated product

TS�

L = Ligand : PH3; PPh3; P(t-Bu)3Olefin = Methyl vinyl ether for simplification (instead of n-butyl vinyl ether)

Following the �-coordination, the palladium-complex rotates clockwise or counter-clockwise into the olefinic plane, forming the transition state geometries TS� or TS�

Insertion

47

The electronic effect of the phenyl para-substituent on the regiochemical outcome was determined by varying the substituent R (R= -OCH3, -C10H7, -H, -CHO, -NO2), including both EDGs and EWGs. Steric effects of palla-dium-coordinating phosphines were investigated by using ligands, L, of in-creasing size (L= PH3, PPh3, P(t-Bu)3). The experimentally used butyl vinyl ether was mimicked by methyl vinyl ether in the calculations to reduce the number of rotatable bonds. Thus the following conclusions were made:

- EDGs produce the weakest �-interaction while EWGs give stronger �-interactions for all ligands investigated i.e. PH3, PPh3, and P(t-Bu)3.

- The electronic influence decreases as the size of the coordinating phosphines increases during �-complexation.

- TS� is less stable than TS� due to steric interaction between the olefin methoxy group and the phenyl ring (Fig. 6), anticipating an increase in �-selectivity as L increases in size. This can be directly observed from the values of ��E* (Table 10). The more bulky ligand P(t-Bu)3 gives better �-selectivity than PH3. This computational finding is in good agreement with my experimental results using butyl vinyl ether (see Tables 7 and 9).

Table 10. Computational results for the insertion of methyl vinyl ether with selected p-substituted neutral phenylpalladium(II) complexes

Entry R Ligand (L) �E*�a �E*�b ��E*c

1 -OMe PH3 17.5 17.8 -0.3

2 -H PH3 19.4 18.3 1.1

3 -CHO PH3 22.0 19.4 2.6

4 -OMe PPh3 19.8 20.3 -0.5

5 -H PPh3 23.5 21.2 2.3

6 -CHO PPh3 24.4 21.2 3.2

7 -OMe P(t-Bu)3 20.9 20.2 0.7

8 -H P(t-Bu)3 22.8 21.1 1.7

9 -CHO P(t-Bu)3 25.1 21.3 3.8 a Reaction barrier of insertion forming the �-product [kcal/mol]. b Reaction barrier of insertion forming the �-product [kcal/mol]. c ��E*=�E�*-�E�* [kcal/mol].

48

3.1.2.4 Synthesis of the Target Molecule using the Methodology Developed Selective terminal Heck arylation of alkyl vinyl ether has tremendous poten-tial in pharmaceutical chemistry. Inspired by the synthesis of Metoprolol (active substance in Seloken ZOC®, AstraZeneca) by Hallberg et al., where the key step involved terminal Heck arylation of methyl vinyl ether by 4-bromonitrobenzene,243 I decided to investigate if the �-selective methodol-ogy could be used to synthesize the well-known �-blocker Betaxolol.

Scheme 23. Synthesis of Metoprolol by Hallberg et al.243

The racemic form of Betaxolol (trade name Betoptic S®) is used for the treatment of hypertension, glaucoma, and angina pectoris. Among several published methods, there were no examples of synthesizing this molecule from easily available and inexpensive 4-chloronitrobenzene (2o).244,245 Cyclopropylmethyl vinyl ether 8 was synthesized by palladium-catalyzed transvinylation of cyclopropylmethanol and ethyl vinyl ether using bidentate 2,2'-bipyridyl ligand. The crucial Heck arylation was found to perform best in aqueous DMF (Method A instead of B), furnishing a 60% isolated yield of the key intermediate 12 in a highly regioselective Heck transformation (�/� = 97:3, Scheme 24). Thereafter, Pd/C-catalyzed microwave-accelerated transfer hydrogenation, exploiting ammonium formiate as the hydride source, was carried out to reduce both the double bond and the nitro group simultaneously, producing 13 at a yield of 79%. Alternatively, direct conver-sion of aryl chloride 2o to 4-substituted aniline 13, without purifying 12, resulted in a slightly improved two-step yield (55%). Diazotation in the presence of sodium nitrite, H2SO4 below 0 C and a fruitful reaction with water was then performed to generate phenol 14 at a 50% yield. This slightly disappointing yield was partly due to the small reaction scale. The addition of (S)-3-isopropylamino-1,2-epoxypropane,246 followed by reflux in ethanol for 8 h, produced the active (S)-enantiomer of Betaxolol as the free base. The corresponding hydrochloride salt (15) was obtained at high purity after react-ing with dry HCl in diethyl ether and succeeding crystallization. Overall, (S)-

Br

NO2 NH2

O+ Pd/C + Et3N

1. O

2. H2

O

O

OH HN

Metoprolol

49

Betaxolol.HCl (15) was prepared at a total yield of 16.5% based on the start-ing material 2o (Scheme 24).

Scheme 24. Synthesis of Betaxolol. (i) Method A, (ii) Pd/C, HCOONH4, EtOH, 80 C, 40 min, Microwaves, (iii) NaNO2/H2SO4, 0-5 C, H2O, (iv) a) (S)- 3-isopropylamino-1,2-epoxypropane, NaOH, reflux, 8 h, b) Dry HCl in Et2O.

3.1.2.5 Specific Outcomes Two different sets of reaction conditions were developed employing a Pd(0)/P(t-Bu)3 catalysis for selective terminal Heck arylation of alkyl vinyl ethers with 9 different aryl chlorides. The importance of using P(t-Bu)3 to obtain �-selectivity was shown both experimentally and computationally. Unmasked PEG-200 not only acted as a solvent but also influenced terminal selectivity by H-bonding in the key transition state. The regioselective meth-odology was utilized to synthesize the �1-selective beta-blocker Betaxolol.

NO2

Cl

OH

O

NO2

O

O

O

OH HN

NH2

O

HCl

2o 12 13

14 15, (S)-Betaxolol.HCl

8i (60%) ii (79%)

iii (50%) iv (60%)

Direct protocol (55%)

O

50

3.2 Stereoselective Intermolecular Heck Arylation of Electron-Rich Cyclic Vinyl Ethers (Papers III and IV)

3.2.1 Overview The palladium-catalyzed Heck reaction33,48,51-53,56 has become an essential tool for C-C bond formation,14 and has been used for diverse applications in organic synthesis.43,55,77 This unique process could be even more useful if the stereochemical outcome could be controlled. The stereochemistry can be controlled with cyclic olefins by exploiting either a chiral bidentate ligand143,247,248 or a substrate-bound catalyst-directing group.152,108 It is a well-known fact that a higher degree of substitution makes the olefin less reactive towards both addition and substitution reactions. Thus Heck aryla-tion of a tri- or tetra-substituted olefin is difficult but can be achieved via an intramolecular pathway.142,249,250 Asymmetric synthesis251 of quaternary car-bon252-257 centers with high stereopurity via intermolecular Heck reaction is therefore difficult.258

A substantial amount of research in the field of Pd(0)-catalyzed �-arylation of carbonyl compounds has been conducted by Hartwig et al. and Buchwald et al.259,260 In a seminal investigation, Buchwald et al. nicely de-lineated an enantioselective and direct �-arylation procedure of cyclic ke-tones furnishing a chiral quaternary �-carbon center with 88-94% ee em-ploying palladium(0) catalysis, an axially chiral ligand, and NaOt-Bu as the base.260-263 Nonetheless, the scope of this method was limited due to the re-quirement for blocking of the non-alkylated �-carbon of the ketone to avoid arylation at this position.

Scheme 25. Pd(0)-catalyzed asymmetric �-arylation of a cyclic ketone by Buchwald et al.260

O

NPh

Ph-Br

O

NPh

Ph

O

Ph

Pd2(dba)3, NaOt-BuToluene, rt

1. HCl, THF2. NaOH

Yield = 91%ee = 93%

Yield = 80%, ee = 93%

P(i-Pr)2

O

+

51

I thus decided to investigate the scope and limitations of chelating cyclic enol ethers/vinyl ethers with aryl, and vinyl halides in stereoselective Heck reactions. Previous results by Nilsson et al. were depicted in Scheme 14.163

3.2.2 Synthesis of Chelating Cyclic Vinyl Ethers The concept of alkenes containing a metal-directing amino group has been demonstrated by several groups as a valuable chemical strategy to improve the propensity of substituted alkenes to take part in intermolecular Heck reactions, and thus control the stereochemical outcome of the proc-ess.107,140,108 Vinyl ethers 16 and 17 were synthesized according to an earlier reported method.163 Vinyl ethers 18, 19 were synthesized via a similar acid-catalyzed transacetalization-elimination process. The reactions with the cyclohexanone derivatives were somewhat slow compared to the five-membered analogs (Scheme 26).

Scheme 26. Synthesis of chelating vinyl ethers 16-20.

Purification of vinyl ethers 18 and 19 was tedious. Even after considerable effort and repeated chromatographic purification, vinyl ether 18 was ob-tained at only 90% purity (18:19 = 90:10). Six-membered non-C-2 methyl vinyl ether 20 was also produced in a similar process and after careful flash silica chromatography in the presence of Et3N, the resulting yield of 20 was 68%. After purification, 16, 18, and 20 were subjected to Heck aryla-tion/vinylation with aryl/vinyl chlorides, vinyl triflates, and aryl bromides. Olefins 17 and 19 were only briefly investigated and will not be further dis-cussed.

R

ON

R

ON+

OHNR

O 1) PTSA, HC(OMe)3

2), HCl (g)

3) Distillation( )n ( )n ( )n

n = 1, 2R = Me, n = 1 16 (38%) 17 (36%)

R = Me, n = 2 18 (32%) 19 (34%)

R = H, n = 2 20 (68%)

R = H, Me

(S)

52

3.2.3 Stereoselective Heck Reactions with Cyclic Five-Membered C-2 Methyl Vinyl Ether

3.2.3.1 Organic Chlorides as Coupling Partners It was proven by my previously obtained results that the electron-rich alkyl phosphine P(t-Bu)3 was important for aryl chloride activation and subse-quent arylation of the chelating vinyl ether 7. Keeping this in mind, an initial coupling of 16 (1.0 equiv) with electron-rich aryl chloride 2c (1.3 equiv) was performed under neutral reaction conditions. In the presence of LiCl (2.0 equiv), NaOAc (1.2 equiv), K2CO3 (1.2 equiv) and 5.0 mol% of highly ac-tive Pd(t-Bu3P)2 in 2.2 mL of aqueous DMF (10% water), 16 furnished com-plete conversion after 18 h of oil-bath heating at 100 C. The formed �-arylated Heck product 21a was isolated at 51% yield after careful silica chromatography in the presence of Et3N, showing an excellent di-astereomeric purity according to 1H-NMR (Scheme 28).

Scheme 27. General representation of investigated chelation-controlled stereoselec-tive intermolecular Heck reaction.

Scheme 28.

ON

ON

+

16 21a 2c

(>91% de by 1H-NMR)

Classic heating, 100 oCYield = 51%

Pd(t-Bu3P)2LiCl, NaOAc, K2CO3

Standard neutralconditions

DMF-H2O (20:1)ClMe

Me

ON

R-XPd(t-Bu3P)2

OPd

N

R

XH

ON

RHCl (aq)

O

R+

16 21 (R)-22

R = aryl or vinylX = Cl, Br or OTf

2

via neutral chelated�-complex

Standard neutral conditions�

�

53

In order to assure reproducibility, the synthesis of 21a was repeated, and after complete consumption of limiting vinyl ether 16, as confirmed by GC-MS, productive acidic hydrolysis yielded 2-methyl-2-tolyl cyclopentanone 22b at a yield of 57% and 91% ee as detected by chiral HPLC. Motivated by this outcome, a series of aryl chlorides were investigated employing the same neutral chloride-containing reaction protocol.

Table 11. Stereoselective Heck arylation of 16 with aryl chlorides and sub-sequent hydrolysis

a The reactions were performed at 100 °C under air with 16 (0.15 mmol) as the yield-determining substrate using standard neutral conditions. Ketones 22 were obtained after hydrolysis with conc. HCl (aq). Isolated yields are averages of three runs. Purity >95 % by GC/MS. b Ee of (+) isomer of 22 by chiral HPLC (average of three runs).

Cl

Me2N

ClMe

Me

Cl

Cl

NC Cl

91 (%)

94 (%)

D

Cl

Ac Cl

PhOC Cl

OHC Cl

Aryl chloride eebEntry

4 11 h 94 (%)

5 12 h

2 18 h

1

3

59 (%) 22e

60 (%) 22d

91 (%)57 (%) 22b

9 h 68 (%) 22a

6

7

[�]23

20 h 90 (%)55 (%) 22c

8 h 93 (%)69 (%) 22f

8 h 92 (%)67 (%) 22g

8 h 96 (%)60 (%) 22h

8 h 92 (%)65 (%) 22i

+46°

+79°

+21°

+39°

+12°

+44°

+52°

+58°

8

9

+86°

Isolated yieldaTime

2r

2c

2b

2h

2i

2m

2k

2s

2l

54

Under the subjected chelation-controlled and Pd(0)/P(t-Bu)3-catalyzed con-ditions, all investigated aryl chlorides resulted in acceptable yields and ex-cellent enantiomeric purities of the cyclopentanones 22 (90-96% ee) (Table 11, Fig. 7). Competing hydrolysis of 16 prevented the reaction from being higher yielding. Reaction times for all the highly stereoselective transforma-tions performed with 16 were long (8-20 h).

Table 12. Stereoselective Heck arylation of 16 with aryl chlorides under microwave irradiation and subsequent hydrolysis

Table 13. Stereoselective vinylation of 16 using vinyl chlorides/triflates and subsequent hydrolysis a The reactions were performed at 140 °C (Table 12) and 100 °C (Table 13) under air with 16 (0.15 mmol) as the yield-determining substrate, using standard neutral conditions. Ketones were obtained after hydrolysis with conc. HCl (aq). Isolated yields are averages of three runs. Purity >95 % by GC/MS. b Ee of (+) isomer of 22 by chiral HPLC (average of three runs).

ClMe

Cl

Ac Cl

OHC Cl

Aryl chloride eebEntry

1

1 h

2

85 (%)62 (%) 22f3

1 h 89 (%)63 (%) 22g

1 h 88 (%)54 (%) 22d

1.5 h 84 (%)50 (%) 22b

4

Isolated yieldaTime

2m

2k

2h

2c

OTf

Et

Et

OTf

Et

Et

Cl

DVinyl-Cl/OTf eebEntry

1

2

3

[�]23

15 h 90 (%)60 (%) 22j

4

Isolated yieldaTime

2t

2v

2w

+11°

+10°

+15°

22 h

24 h

58 (%) 22j

59 (%) 22k

89 (%)

90 (%)

Cl 2u +15°18 h 61 (%) 22k 90 (%)

55

In order to accelerate the reactions, selected experiments were carried out under high-density microwave heating at 140 °C, while maintaining the other reaction conditions.202 In spite of 1-1.5 h of microwave irradiation at 140 °C, the yields were not improved. Enantioselectivities for isolated 2-aryl-2-methyl cyclopentanones were reduced to 84-89% (Table 12).

It was illustrated by Overman142 and Shibasaki143 that vinyl triflates can be exploited in asymmetric intramolecular Heck reactions for the construc-tion of tetra-substituted carbon centers. Hence in order to increase the prepa-rative usefulness, I decided to investigate vinyl chlorides 2t,u and vinyl tri-flates 2v,w as vinylating agents (Table 13). The results of these vinylation reactions were interesting. Vinyl triflates were unexpectedly found to react more sluggishly than the corresponding chlorides under the same neutral reaction conditions. However, high enantioselectivities were achieved (Table 13, entries 1-4) for all 2-methyl-2-vinyl cyclopentanones together with mod-est yields. Figure 7. An example of chiral separation of compound 22g (Table 11, entry 7 and Table 12, entry 4) demonstrating switching of retention of (+), (R) and (-), (S) iso-mers when changing the column from Reprosil NR to NR-R during chiral HPLC.

56

Receiving the positive results using vinyl triflates under neutral reaction conditions, I decided to investigate the scope of aryl triflates under such reaction conditions. Unfortunately, aryl triflates (4-CN-phenyl (2x), phenyl, 1-naphthyl and 4-tolyl triflates) did not participate in useful arylation reac-tions under the neutral reaction conditions employed. I therefore decided to switch the protocol from neutral to cationic94,122 conditions, and to investi-gate 2x (2.0 equiv) as the arylating agent in the absence of a halide additive (Scheme 29).

Scheme 29. Stereoselective Heck arylation under cationic reaction conditions.

The arylation of 16 was monitored by GC-MS analysis, and after complete conversion of 16 the Heck product 21b was hydrolyzed to 22i at 63% yield and 88% ee. The reaction time with 16 and 2x under cationic conditions (Scheme 29) was longer than that using 4-CN-phenyl chloride (2l) under standard neutral conditions (Table 11, entry 9). Phenyl, 1-naphthyl and 4-tolyl triflates did not furnish the desired arylation under the same cationic conditions. The reason for this is unknown.

3.2.3.2 Aryl Bromides as Coupling Partner In our earlier report, tetra-substitued chelating vinyl ether 16 was arylated with seven different aryl iodides and two reactive aryl bromides using Pd(OAc)2 to produce 2-aryl-2-methyl cyclopentanones 22 with excellent ee's.163 Unfortunately, the phosphine-free protocol was not generally appli-cable to all available aryl bromides. Thus, I decided to examine the model reaction between 16 and 4-bromo benzaldehyde (2q) using the bulky 14-electron catalyst Pd(t-Bu3P)2.70 The Heck coupling of olefin 16 (1.0 equiv, 0.15 mmol) with aryl bromide 2q (1.3 equiv) in the presence of LiCl (2.0 equiv), NaOAc (1.2 equiv), K2CO3 (1.2 equiv), and 5.0 mol% of Pd(t-Bu3P)2 in 2.2 mL of aqueous DMF (10% water), resulted in complete consumption of 16 after 9 h of oil-bath heating at 100 °C (Scheme 30). The combination of LiCl, NaOAc, and K2CO3 was necessary to facilitate full conversion, and the removal of any one of these additives led to a reduced yield.107

ON 1. Pd(OAc)2

O

+

16 22i ee = 88%Yield = 63%

2xEt3N, PPh3, DMF 100 oC, 20 h

�

�

2. HCl (aq), 30 min

Cationic reaction conditions

NC OTf

CN

57

Scheme 30.

Compound 21c was obtained at excellent diastereomeric purity based on 1H-NMR and was isolated at an acceptable yield of 69%. As vinyl ethers are easily hydrolyzed and the aromatic aldehydic group is reactive towards addi-tion reactions, careful silica chromatography in the presence of 2% Et3N resulted in pure 21c. This is an interesting class of compound containing a free aldehydic functionality together with a masked keto group. Thus, 21c provides an opportunity to exploit the reactive aldehyde group for further transformations without affecting the protected ketone (Scheme 30). The reaction was repeated, and product 21c was thereafter hydrolyzed by addi-tion of 0.5 mL conc. HCl to produce 22g at a yield of 68% and 94% ee (Ta-ble 14, entry 3). This fruitful method was utilized with nine different aryl bromides containing both EDGs, EWGs, and potentially palladium(II)-coordinating substituents in para-, meta-, and ortho positions. In all cases, arylated products were hydrolyzed in situ, generating 2-aryl-2-methyl-cyclopentanones 22 at adequate two-step, one-pot yields with high enanti-omeric purities (85-94% ee) (see Table 14). The electronic properties of the aryl moities did not affect the enantiopurity very much. However, the steric influence of the ortho-substituted aryl bromide 2d' produced the lowest ee and additional catalyst loading was required for this slow reaction after 20 h to achieve complete conversion of 16. Furthermore, competing hydrolysis of 16 and dehalogenation of 2d' resulted a low yield (45%) of 22c.122

While Pd(OAc)2 could only catalyze the participation of reactive aryl bromides in the arylation of the sluggish tetra-substituted olefin 16, the elec-tron-rich Pd(t-Bu3P)2 complex smoothly promoted oxidative addition, inser-tion, and �-hydride elimination of all the investigated aryl bromides. Hence, a natural extension of this work was to expand the investigation of aryl bro-mides to include the six-membered cyclic olefins (18, 20).

ON

ON

+

16 21c 2q

(>91% de by 1H-NMR)

Classical heating9 h, 100 oC Yield = 69%

Pd(t-Bu3P)2LiCl, NaOAc, K2CO3

DMF-H2O (10:1)BrOHC

CHO

�

�

58

Table 14. Aryl bromides in asymmetric arylation with 16 and subsequent hydrolysis

a The reactions were performed at 100 °C under air with 16 (0.15 mmol, 1.0 equiv) using 5.0 mol% of Pd(t-Bu3P)2. Ketones (R)-22 were obtained after hydrolysis with conc. HCl (aq). Isolated yields are averages of three runs. Purity >95 % by GC/MS. b Ee of (R)-22 by chiral HPLC (average of three runs). c Additional 5.0 mol% Pd(t-Bu3P)2 was added after 20 h. Recorded optical rotation values; 22a: +39°, 22b: +86°, 22f: +12°, 22g: +21°, 22i: +44°.

3.2.4 Stereoselective Heck Reactions with a Cyclic Six-Membered Vinyl Ether Based on my previously obtained results, the tetra-substituted six-membered vinyl ether 18 (18:19 = 90:10) was treated with aryl chlorides under the same standard neutral conditions as described in Section 3.2.3.1. Surprisingly, no productive arylation reactions were observed. Similarly, tetra-substituted

Br

Me2N

BrMe

Me

Br

Br

NC Br

90

92

Br

Ac Br

PhOC Br

OHC Br

Aryl bromide eeb (%)Entry

6 10 h 89

5 14 h

8 14 h

9

7

58 (%) 22e

54 (%) 22d

9160 (%) 22b

10 h 62 (%) 22a

4

3

36 h 85c45 (%) 22c

10 h 9364 (%) 22f

10 h 9468 (%) 22g

10 h 9160 (%) 22h

10 h 9262 (%) 22i

2

1

Isolated yieldaTime

2f '

2e'

2d'

2c'

2b'

2a'

2q

2z

2y

59

olefin 18 failed to participate in the desired arylation reactions despite many attempts using different reaction conditions and both aryl bromides and io-dides as arylpalladium sources. The predominant features were hydrolysis of 18, release of palladium-catalyst-poisoning (S)-1-methyl-2-pyrrolidine-methanol,107,122,123 and extensive formation of the homocoupled biaryl side-product. The catalysts were thus rapidly degraded and the starting materials quickly consumed resulting in successive failure. In order to investigate the effect of a six-membered ring in chelation-controlled arylation, I moved on to tri-substituted vinyl ether 20 (Scheme 31). Scheme 31.

Vinyl ether 20 was studied using aryl iodides as arylating agents and Pd(OAc)2 as precatalyst. Unfortunately, reactions were too slow, provided inadequate/no yields or the formation of predominantly biaryls. I therefore decided to try aryl bromides as arylpalladium precursors. High-density in situ microwave heating198,264-267 of sealed reaction mixtures has been benefi-cial in accelerating chemistry development by increasing reaction rates and by providing high reaction control. I used this technology under inert condi-tions for the rapid development of useful reaction conditions exploiting aryl bromides.

In my attempt to modify the thermostability of the catalytic system, mi-crowave-stable Herrmann’s palladacycle was again exploited in combination with the (t-Bu)3P-liberating salt [(t-Bu)3PH]BF4. Heck arylation using 20 (1.0 equiv, 0.075 mmol), and aryl bromide 2g' (2.0 equiv) in the presence of LiCl (2.0 equiv), NaOAc (1.2 equiv), K2CO3 (1.2 equiv), 5.0 mol% air-stable Herrmann’s palladacycle, and 10.0 mol% [(t-Bu)3PH]BF4 in 2.2 mL of aqueous DMF (10% water) under high-density microwave heating at 150 °C for 90 min (Condition C) furnished full conversion of 20. The mono arylated vinyl ether 23e showed excellent diastereoselectivity based on GC-MS (de = 97%) and 1H-NMR analysis, and was isolated at a 42% yield after chroma-tographic purification. In order to increase the preparative utility of this mi-crowave methodology, Condition C was tested with four additional aryl bromides producing Heck products 23a-d at modest yields (34-38%) but with excellent diastereopurities (94-98% de, Table 15). Nevertheless, under the same conditions, three other aryl bromides carrying EWGs were exam-ined but results were not satisfying (4-Ac-Ph-Br (2a'), 25%; 4-CN-Ph-Br (2y), 20%; 4-CHO-Ph-Br (2q), 30%). With the intention of amending the

20 23a-e

Condition C or D

ON

ON

2

+ BrR

R [Pd]

60

yield of the arylated product 23, I decided to perform similar coupling trans-formations with classic oil-bath heating and the more active, but less ther-mostable 14-electron catalyst Pd(t-Bu3P)2. Test coupling using 20 (1.0 equiv, 0.15 mmol) and 2g' (1.3 equiv) in the presence of LiCl (2.0 equiv), NaOAc (1.2 equiv), K2CO3 (1.2 equiv), and 5.0 mol% Pd(t-Bu3P)2 in 2.2 mL of aqueous DMF (10% water) at 100 °C for 40 h (Condition D) produced a better yield of 23e (55%), while maintaining the same high diastereoselectiv-ity (Table 15). Based on this result, all asymmetric arylation reactions were also conducted under Condition D, resulting in improved yields in two addi-tional cases (Table 15, entries 3 and 4), although aryl bromides with EWGs remained unreactive.

Table 15. Diastereoselective Heck arylation of 20 with aryl bromides

a Condition C: The reactions were performed at 150 °C under microwave heating with 20 (0.075 mmol, 1.0 equiv) using 5.0 mol% Herrmann’s palladacycle and 10.0 mol% [(t-Bu)3PH]BF4. Condition D: The reactions were performed at 100 °C using classical heating with 20 (0.15 mmol, 1.0 equiv) using 5.0 mol% Pd(t-Bu3P)2. Iso-lated yields are averages of three runs. Purity >95 % by GC/MS. b De of (-) isomer of 23 by GC-MS (average of three runs) and 1H-NMR.

In spite of using an extra amounts of 2 in both Conditions C and D, only small amounts of biarylated product were observed.107 To some extent, the lower yields in the arylation reactions of the tri-substituted cyclohexene vi-nyl ether 20, compared to the cyclopentenyl analog 16, can be illustrated by the sluggish rate of reaction, allowing concomitant hydrolysis of 20 to rival.

Br

Me

BrMe

Me

Br

Br

Br

CD

CD

CD

CD

CD

DAryl bromide

deb

(%)Entry

2

1

4

5

3

[�]23Isolated yieldaTime

2g'

2e'

2d'

2c'

2b'

Condition

90 min40 h

90 min40 h

90 min52 h

90 min40 h

90 min40 h

38% 35%

38% 36%

34% 46%

37% 40%

42% 55% 23e

23a

23b

23c

23d

-50°

-40°

-54°

-52°

-31°9598

9898

9498

9694

9798

61

The slow reaction kinetics may be the consequence of conformational mobil-ity of the six-membered ring and the lack of ring strain release upon inser-tion. These results support a previous report of sluggish arylation of 3,4-dihydro-2H-pyran using chiral P,N-ligands.248

3.2.5 Specific Achievements

3.2.5.1 The Use of Organic Chlorides and 16 Highly stereoselective Pd(0)-catalyzed �-arylation and �-vinylation of a tetra-substituted cyclopentenyl vinyl ether has been accomplished using che-lation control under standard neutral conditions. This Pd(0)/P(t-Bu)3-catalyzed process comprises a T-shaped oxidative addition intermediate, instead of tetra-coordinated 16-electron square planar Pd-complex, with less bulky aryl phosphine ligands.

DFT268 calculations by Huang predicted chelation-controlled Si-face in-sertion of the neutral intermediate PhPdCl complex into the 16 vinyl ether double bond, generating an R-configuration of the evolved quaternary center. This theoretical result was in agreement with optical rotation measurements of my isolated carbonyl compounds 22 produced with Pd(0)/P(t-Bu)3 system (Table 11).163 The 2-aryl-2-methyl cyclopentanones formed (22) were ob-tained with excellent enantioselectivities (90-96%). This is the first reported use of organic chlorides as substrates in stereoselective Heck reactions.269,270 I believe that this protocol constitutes a preparatively useful supplement to direct Pd(0)-catalyzed �-arylation methods,259,260,271 especially when the use of inexpensive starting materials and mild reaction conditions are of utmost importance.

3.2.5.3 The Use of Aryl Bromides with 16 and 20 Highly diastereoselective139,140,163 Heck arylation reactions were performed using aryl bromides and tetra-substituted vinyl ether 16, or tri-substituted vinyl ether 20, with the aid of a chiral Pd(II)-coordinating pyrrolidine auxil-iary.107,152,163 Good to high enantiomeric purities of 22 (85-94%) were ob-tained after acidic hydrolysis of the monoarylated Heck product obtained via the reaction of 16 and a set of aryl bromides. The absolute configuration of the C-2 arylated carbon in six-membered vinyl ethers 23 was assigned as (R) based on X-ray crystallographic results for the methyl ammonium salt of the five-membered analog.272 Although the reactions were sluggish and pro-duced relatively low yields of 23, all asymmetric arylation reactions with the tri-substituted cyclohexene vinyl ether 20 were highly diastereoselective (94-98% de). Temperature-controlled microwave irradiation speeded up the di-astereoselective arylation of the sluggish six-membered vinyl ether 20.273-275 This K2CO3-mediated, highly stereoselective protocol may be preferable to the strong-base-promoted direct �-arylation methodologies.259,260,271

62

4. Concluding Remarks

The specific conclusions arising from this work are briefly summarized be-low:

- A general procedure for the Heck coupling of aryl chlorides with

butyl acrylate under air was developed using microwave irradiation and a readily available commercial palladium catalyst.

- A highly regioselective terminal Heck arylation methodology for

alkyl vinyl ethers (both non-chelating and chelating) was devel-oped using aryl chlorides. Computational results were in agreement with the experimentally obtained selectivity. The protocol was util-ized to demonstrate the novel synthesis of the �1-selective beta-blocker Betaxolol.

- The first ever stereoselective Heck arylation/vinylation protocol us-

ing aryl/vinyl chlorides was developed. - C-2 substituted and non-C-2-substituted five- and six-membered

cyclic proline vinyl ethers of different sizes were synthesized and their scope and limitations were studied in intermolecular di-astereoselective Heck reactions using both aryl chlorides and bro-mides.

Electron-rich alkyl phosphine P(t-Bu)3 was found to be important for the activation of organic chlorides in both re-gio- and stereoselective Heck coupling reactions.

Chelation was the key to achieving high stereoselectivity using either five- or six-membered cyclic vinyl ether. Ad-ditionally, it was evident from the experiments that six-membered cyclic vinyl ethers were much more sluggish than the five-membered analog in diastereoselective Heck arylation reactions.

63

Acknowledgements

This work was carried out at the Department of Medicinal Chemistry, Divi-sion of Organic Pharmaceutical Chemistry, Uppsala University (2003-2008). I am truly indebted to many people, without whom this thesis would not have been completed.

To begin with, I would like to express my sincere gratitude to:

Professor Mats Larhed, my supervisor, (Head of the Division of Organic Pharmaceutical Chemistry) for accepting me as a Ph.D. student and for being an excellent advisor throughout my graduate studies. Your introduction to state-of-the-art metal-organic chemistry and constant enthusiasm for new ideas inspired me to see my career pathway clearly. Your creativity, perfec-tionism, effectiveness, and broad knowledge in chemistry, together with humbleness were truly encouraging and amazingly contagious. Your leader-ship, transparency in decision-making, warmth and philosophy of helping others when needed made me see that it is possible to pursue cutting-edge research and be a considerate, friendly person at the same time. I greatly enjoyed working with you, and I thank you very much for your guidance, advice, and comment about me during “Developmental Talk”. I find it diffi-cult to express my appreciation to you in words. Professor Anders Hallberg, my assistant supervisor, (Vice Chancellor, Upp-sala University, 2006-) for providing me with the excellent opportunity to carry out my graduate studies at this department. It was fascinating to par-ticipate in the scientific group meetings in your presence. Your vast knowl-edge in chemistry and medicinal chemistry, your leadership skills, and never-ending support and encouragement have ensured an enjoyable and stimulating working atmosphere at the department. It was also an honor to learn from you how to make important and effective academic-administrative decisions, how to succeed, and how to think ten steps ahead. I am very grateful for everything you have done for me. I would like to thank both Professor Mats Larhed and Professor Anders Hallberg for providing freedom and specially equal opportunities at work.

64

My co-authors; I thank you all for your skillful work and timely, efficient scientific collaboration. I certainly enjoyed working with you. Gunilla Eriksson (Chief administrator), for everything you have done for me. Your devotion to your work has been a constant inspiration to me. I will remember all the late-night coffees and conversation with you. You, unlike most other people, do not measure your work in hours and minutes. I admire you and can not imagine the department without you. To me, you are a true role model for this society. I appreciate your concern and text messages dur-ing my difficult times. Kristofer Olofsson, it was simply great to know you. You became one of my closest and must trusted friends. Our personal discussions, eating meals at your house, and discussing music, movies, books, and life in general over the years made our friendship stronger. I am thankful to both you and Ha for being close to me all the time. You, Ha and Josefin gave me lot of homely warmth. Skål for a life-long friendship! My master’s students Patrik Nordeman and Jakob Dackenberg; for doing excellent work and my SOFOSKO students, Sandra Funning and Ashkan Fardost, for good collaboration. You have all contributed tremendously to my “prolinol research”. I wish you all good luck in your future careers. I thank The Swedish Research Council and the Knut and Alice Wallenberg Foundation for financially supporting my research, Biotage AB, Parallellda-torcentrum (PDC) at the Swedish Royal Institute of Technology for instru-mental support, and finally The Swedish Academy of Pharmaceutical Sci-ences, the AML Foundation of Småland’s Nation, and Uppsala University’s Vice-Chancellor’s Grant from Wallenberg’s fund for academic funding. Sorin Srbu (system administrator), for all computer related help. Tack! Professor Anders Karlen and Assoc.Professor Uno Svensson for pleasant teaching collaboration. Andreas, Karl Vallin, Per-Anders, Robert, Hanna, Alejandro, Stefanie Schlummer, Mahalingam, Wu, Per, Niklas, Pradeepkumar P.I., Lauri; for all the nice times we had and for your friendships. Kristofer, Tamara, Karl V., Johan W., Per-Anders, Andreas, Alejandro; for constructive criticism & Helen Sheppard for linguistic revision of this thesis. All past and present members of the palladium group, for valuable scientific discussions.

65

OFK (Organisk Farmaceutisk Kemi), where do I begin…I have had such a wonderful time here. Everyone at the department contributed a great deal during my stay. To name a few would be too little! A heart-full thanks to; the teaching teams, specially A5, GC-MS & LC-MS team, NMR-team, or-dering team, OFK-IT, lab-safety & inventory team, Biolipox and Actar team, fest-team, and all small teams to keep OFK in such a good shape and an enjoyable working place. The wonderful memories of all academic seminars, group studies, champagne for first publications, spikningstårta, mutual col-laborations, sport activities (football, cricket, table tennis, brännboll, floor-ball, swimming and skiing), EM/VM tips, scheduling unpacking weeks and coffee weeks, cut & paste parties, disputationsfest, ski-trips, Christmas-lunch, organikerdagarna, Läkemedelskongressen, nation-ventures, inven-tory-day picnic, movie-nights, moving-in parties, Uppsala short film festi-vals, and innumerable dinner outings and get-together parties, made my Uppsala-days truly eventful! Listening colleagues in fun coffee-room stories and debates about “OFK golf”, “chemists vs. TV chemists”, “so called glori-fication of med. chem. projects vs. simplification of method developments”, “achieving vs. receiving”, “individual vs. team”, “grading vs. non-grading”, “quality vs. quantity”, “feminism vs. chauvinism”, “rights vs. obligations”, “talker vs. doer”, “giver vs. taker”, “democracy vs. hypocracy”, “bandy vs. innebandy”, “veg. vs. non-veg.”, “cats vs. dogs as better pets”, “state welfare socialism vs. capitalism”, “lagom vs. extrem”, “Sweden vs. rest of Scandina-via”, “social democrats vs. moderates”, even “Lars Lagerbäck vs. Sven-Goran Eriksson”, and many more, were hilarious and full of perspectives! Uppsala with its drifting student community with bubbly youngsters who always make you feel young unless someone says “hey, you are old!” or you find out “the elegant presence so many newly born babies with their cute vital statistics” in coffee-room’s black board and feel….humm!...we are getting matured! Despite language barriers, many differences in opinions, disappointments, agreeing to disagree with each other, and difficult & unfor-tunate personal times in life, the memory of OFK will be ever lasting. I re-spect your professionalism. OFK truly became an inseparable part of my life with collage of memories. I wish all of you a good luck to your ensuing pro-fessional and personal life. This work would not be such an enjoyable and colorful one without all of you. Ett stort TACK till allihopa! Skål! Professor Lars-Olof Sundelöf, for his invaluable advice regarding academi-cally related issues. I sincerely appreciated your help. Dr. Peter Reinholdsson, for being an outstanding teaching mentor and for giving me important advice regarding teaching-related matters. I am thankful to you for providing me with the opportunity to be an invited speaker during the PU’s International Teacher Training Course.

66

Professor Kristina Luthman, for her inspiring talk at a time in my life when I truly needed it. Marie Sundqvist; for her effort and encouragement during my initial difficult days in Uppsala, and Professor Bo Sundqvist (Vice Chancellor, Uppsala University, 1997-2006) for taking the time to look at my papers, and for valuable comments. I thank you both very much. Dr. Mark Divers, (AstraZeneca, Södertälje) for his valuable advice, and dis-cussions on the phone during his busy days. Dr. Swaraj Paul and Dr. Santanu Dasgupta, for always being nice and help-ful. Thank you very much. I would like to thank all my friends and colleagues in Uppsala Studentkår for the project we carried out to fight discrimination and exploitation, and our work to bring about true equality. Thank you also to everyone who helped me to obtain valuable information from various authorities on issues such as salary, tax and immigration. I truly appreciate your help.

� � � � � � � � � � � � � � � Apart from all the people who have helped me in Sweden, many have been very important in my earlier studies in India. I would like to thank them here. The Late Professor Parimal K. Sen (Former Head of the Department of Chemistry, Presidency College, Calcutta), for his constant inspiration during the days I was considering the change from chemistry to administrative jobs. This work would not have been possible without your help early on and your constant encouragement to pursue me to do a Ph.D. I wish you could be here today to see my thesis. I am greatly indebted to you. Professor Asish De, for providing me with a project student position at the laboratory in I.A.C.S., Calcutta, and for introducing me to thiophene chemis-try. Thank you very much for all your help during my initial “chemistry bench-working” days. My special thanks also go to; Professor Achintya Kr. Sarkar (Presidency College), Professor N. G. Kundu (I.A.C.S., Calcutta), Dr. Prabal Sengupta (Presidency College), Dr. Chandan Saha (School of Tropical Medicine, Calcutta), Professor Dipak Kr. Mandal (Presidency College), Dr. Gautam Chatterjee (Presidency College), Dr. Chandra Kanta Banerjee (V.C Col-lege, the University of Calcutta), Dr. Bibhuti Maji and Professor Swapan

67

Sengupta, for being excellent teachers and sources of never-ending inspira-tion during my university days, and Professor Amal Kr. Mukhopadhyay (former Principal, Presidency College, Calcutta) for your personal help. I will remember you my whole life. Thank you. My previous academic institutions; I.A.C.S., Presidency College, Rahara R. K. Mission, Barasat M. G. M. High School. It was memorable! Mr. Swapan Manna, my mentor and friend-philosopher-guide – it has been a long walk and without your support, advice and understanding I would not be who I am today. When I look back on the hardest times of my life, you inspired me although you were on the other side of the globe. I am most grateful to you. Thank you so very much. All my friends at home, I have had such nice times with you all. My grandparents, uncles, aunts, cousins & all family members and relatives; for their care and concern about me. To mention a few would be unfair, and to name everyone is impossible. I am deeply thankful to all of you for your contributions. In my long absence from home, I have at least known that there is always someone close to my parents. It is a wonderful feeling to have you all as a family. Dora, many thanks for all the beautiful moments. Skål! My only sister Ratna, my niece Riley, and my brother-in-law Tapas; you brought so much joy into my life that I can not express it in words. Your love and support have been a constant source of energy over the years. I could not have done it without you. My Parents, I simply do not have the words to express my feelings and grati-tude. Your effort, patience, and enormous sacrifice for others have estab-lished the foundation on which our whole family rests. We would not have come this far without your boundless dedication. Your strength, courage, and dedication to helping others, even during long painful days of illness and suffering, were admirable. In this materialistic and me-only world, you truly devoted your lives to others and helped so many people to succeed, and this has influenced me immensely over the years. Without the unconditional love, belief, endless support and inspiration of my mother and father I wouldn’t be able to write this, the very last page of my thesis. Gopal K. Datta Uppsala, August 11, 2008.

68

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Acta Universitatis UpsaliensisDigital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Pharmacy 76

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A doctoral dissertation from the Faculty of Pharmacy, UppsalaUniversity, is usually a summary of a number of papers. A fewcopies of the complete dissertation are kept at major Swedishresearch libraries, while the summary alone is distributedinternationally through the series Digital ComprehensiveSummaries of Uppsala Dissertations from the Faculty ofPharmacy. (Prior to January, 2005, the series was publishedunder the title “Comprehensive Summaries of UppsalaDissertations from the Faculty of Pharmacy”.)

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