Heck Reactions with Aryl Chlorides: Studies of Regio- and Stereoselectivity

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(1)Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 76. Heck Reactions with Aryl Chlorides Studies of Regio- and Stereoselectivity GOPAL K. DATTA. ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2008. ISSN 1651-6192 ISBN 978-91-554-7256-6 urn:nbn:se:uu:diva-9202.

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(214) “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.

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(216) 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 Chlorides 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 Asymmetric Chelation-Controlled Heck Reaction Using Aryl Bromides: Increased Preparative Scope and Effect of Ring Size on Reactivity and Selectivity. Tetrahedron: Asymmetry, 2008, 19, 11201126. Reprints were made with permission from the publishers..

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(218) 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 E-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.

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(220) Abbreviations. Ac 3-AP Ar BINAP bmim Bu Cy dba de DDQ DFT dippb dippp DMA DME DMF dppb dppe dppf dppm dppp EDG ee equiv Et EWG GC HOMO HPLC i-Pr L LC LUMO M Me MS. acetyl 3-aminopyridine-2-carboxaldehyde thiosemicarbazone aryl 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 1-n-butyl-3-methylimidazolium butyl cyclohexyl dibenzylideneacetone diastereomeric excess 2,3-dichloro-5,6-dicyanobenzoquinone density functional theory 1,4-bis(diisopropylphosphino)butane 1,4-bis(diisopropylphosphino)propane N,N-dimethylacetamide dimethoxyethane dimethylformamide 1,4-bis(diphenylphosphino)butane 1,2-bis(diphenylphosphino)ethane 1,1'-bis(diphenylphosphino)ferrocene 1,1-bis(diphenylphosphino)methane 1,3-bis(diphenylphosphino)propane electron donating group enantiomeric excess equivalent ethyl electron withdrawing group gas chromatography highest occupied molecular orbital high pressure liquid chromatography isopropyl ligand liquid chromatography lowest unoccupied molecular orbital metal methyl mass spectrometry.

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

(222) 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 formation 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 attention 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 palladium-catalyzed cross coupling and vinylic substitution reactions were discovered, 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 diverse 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.. 13.

(223) 1.1.2 Palladium-Catalyzed Coupling Reactions Palladium can catalyze numerous organic transformations, including C-C, CO, C-P, C-S, and C-N bond-forming reactions. Among these, C-C bond formation 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). [Pd], Base. R X + R'. Ar-Ar'. [Pd], Ar'-M Cross coupling. R +. Heck. Ar-X. R' [Pd], CuI, Base R Sonogashira. Ar. R. R'. R. Scheme 1. Illustrative examples of palladium(0)-catalyzed C-C bond-forming reactions. 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 transformations to take place. Palladium possesses certain characteristic properties that make it unique.13,18 x Low susceptibility to undergo one-electron transfer processes (radical reactions) x High functional group tolerance x Preference for the 0 and +2 oxidation states, facilitating the regeneration of catalytic palladium species x High electronegativity (2.2 on the Pauling scale), facilitating easy transmetallation from other metal-carbon bonds x User-friendly due to its relative insensitiveness to moisture, acid and air x Accessible HOMO and LUMO energies, facilitating concerted reactions due to low activation barriers x 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 crosscoupling reactions occurs through ligand exchange and transmetallation followed by reductive elimination to release the product and regenerate active 14.

(224) 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. E-Hydride elimination furnishes the desired product together with a palladium hydride, which then undergoes base-mediated reductive 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 transformations, 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 formation,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 organopalladium 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). Ar ArHgX +. PdX2. + HgX2 + HX + Pd(0) R. + R Ar. ArH. +. PdX2. +. + R. 2 HX +. Pd(0). R. Scheme 2. 43,44. Both the reactions depicted above require stoichiometric amounts of palladium (in the absence of a Pd(0) reoxidant) for the vinylic substitution processes to occur.43 A few years later, the catalytic version of this vinylic substitution 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 became 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).. 15.

(225) R X. Pd(0)-Catalyst. + R'. Base. R = Aryl, Vinyl, Benzyl. R R'. X = I, Br, Cl, OTf etc.. 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 understood.57 A postulate describing Pd(IV) complexes as key intermediates has attracted some attention ten years ago.58 Base. HBaseX. R Pd(0)L2 R' Internal rotation (4) and E-elimination L X R Pd L H H R' (3). L L Pd(0)L3 L L Pd(0)L4 L = PAr'3. L R Pd X(L). Syn-insertion R'. R X (1). Oxidative addition. L R Pd X L X = I, Br, Cl, OTf etc. (2) S-Complex formation. R'. Scheme 4.43. The original Heck cycle (Scheme 4) can be divided into four steps: (1) oxidative addition in which the electrophilic substrate RX reacts with Pd(0)L2 to produce RPd(II)XL2; (2) S-complex formation where either the ligand L or X is displaced and Pd coordinates with the olefinic double bond; (3) syninsertion in which R and Pd(II)XL2 are inserted over the double bond, generating a V-organo-palladium complex; and finally (4) E-elimination: after internal rotation, ligated Pd and a E-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 cycle. 16.

(226) 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 reaction 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 commercially 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 catalytic 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 S-Complex Formation and Insertion S-Complex formation and insertion80,81 are the key steps that govern the regiochemical82 and stereochemical83,84 (in the case of prochiral olefins) outcome of the Heck reaction. The reaction conditions (neutral or cationic) and the electronic and steric effects of the substituents on the olefin moiety influence the insertion [D (internal) or E (terminal)] and as a consequence, the regio- or stereoselectivity. Following S-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 TSD or TSE. TSD leads to the D-product whereas TSE produces a E-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-E-substituted product. On the other hand, electron-rich olefins generally produce a mixture of D-product and E-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-. 17.

(227) tional conditions in case of non-electron-poor alkenes (electronically neutral and electron-rich alkenes) (Scheme 5). ArX. Ar. Pd(0). + EWG. EWG. EWG = COOR, COR, CN, Ph etc. Ar. Ar ArX. + EDG. Pd(0). + EDG. + Ar. Ar +. EDG = Heteroatom, alkyl etc.. Ar. Ar. EDG. EDG. Several double-bond + isomers when EDG = alkyl. Scheme 5. Heck reactions with electron-poor and electron-rich alkenes.43,56 Y = O, N, (CH2) Y. + P Ar Pd P. X-. Y P Ar Pd P. X = OTf, OAc, Halide. X P. P. = dppp, dppf. P Ar. ArX. P Pd. X. Y P. P Pd (0). Reduction P. Pd(OAc)2. P P H Pd P D-Arylation. X Ar HBaseX. Base Y. Scheme 6. Heck reaction with electron-rich olefins via cationic intermediates.43. 18.

(228) The regioselectivity in the Heck reaction with electron-rich olefins depends on the nature of the S-complex. Typically, a positively charged S-complex will mainly furnish the D-substituted product (Scheme 6), while a neutral Scomplex will predominantly lead to the E-substituted product (Scheme 7). The metal center of a positively charged S-complex is stabilized by two neutral ligands or one neutral bidentate ligand (Scheme 6). On the other hand, the metal center of a neutral S-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 Y = O, N, (CH2) Y P Ar Pd X Y. +. P X Pd Ar Y. P X = I, Br, Cl, OTf P = PAr'3. Ar Pd X P. P ArX. P2Pd(0). Reduction P. X P Pd. Ar. Ar. X Pd. + Y. P. Y. Pd(OAc)2. P2Pd(II)HX. HBaseX. P. D- & E-Arylation Ar. Ar. Base. + Y. Y. Scheme 7. Heck reaction with electron-rich olefins via neutral intermediates.43. The terminal E-carbon is more electron-rich in enol ethers and enamides, due to the mesomeric effect, and is therefore more susceptible to bind to electron-poor Pd(II), compared to the sp2-carbon of the formally negatively charged aryl group attached to the metal centre. However, achieving the Dproduct is believed to be sterically more demanding. These conflicting fac19.

(229) 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 triflates and bidentate ligands. This methodology is completely D-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 conditions96,97 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 D-selectivity.102,103 At the end of the 1980s, Andersson and Hallberg developed an indirect way of achieving selective terminal Earylation 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 Olefin. Cationic Pathway Neutral Pathway E:D E:D. O. E. D O O. R. NH2 CN Ph OH. 100:0. 100:0. 100:0. 100:0. 100:0 60:40. 100:0 90:10 R = H, 100:0 R = Alkyl, 90:10. R. R = H, 0:100 R = Alkyl, 5:95. R. 20:80. 80:20. 10:90. 80:20. 5:95. mixture of products. OH O O. O. 0:100. 60:40. R. 5:95. not reported. R. 0:100. 30:70. NR2 0:100. 100:0. N H N O O O. 20.

(230) Modest yields and reasonable E-selectivity (up to E:D = 9:1) were obtained with electron-deficient aryl groups. It was found that the highest Eselectivity was obtained when chloride coordinated with the metal center in the oxidative addition intermediate.44,106 The terminal selectivity was substantially 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 D/E ratios were observed. On the other hand, when using a specific 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 combinations of ionic liquids and organic solvents114,115 have been well-exploited in regioselective50 Heck arylation of electron-rich olefins. The regioselectivity obtained in neutral and cationic Heck reactions using a selection of diverse olefins is presented in Table 1. 1.1.3.3 E-Elimination and Palladium(0) Regeneration The final step in the catalytic cycle is E-elimination providing the final product. Following internal rotation in the V-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 transisomer.12,48 Recently published results of a mechanistic study indicate that, under certain conditions and using allyl ethers as substrate, single bond rotation has a higher barrier than E-hydride elimination, and is thus selectivity determining.116 To some extent, the dissociation of olefin from the palladium(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 Eelimination/reduction steps wherein the elimination is base-promoted have been published.119. 21.

(231) 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 reaction 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 presents 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 reactions 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 chelationcontrolled 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 between palladium and the heteroatom is necessary to present the Pd to the olefin during insertion, and to allow subsequent removal of Pd through Eelimination.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 22.

(232) 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 2pyridyl as the donor group, was proven to be ideal for obtaining exclusive Eselectivity (Scheme 8). O. O Pd(0) / PAr'3. Ar. ArX D E. Arylpalladium(II) complex. NR2. O. NR2 Pd PAr'3 PAr'3. Chelation and reorganization. Pd NR 2 PAr'3 S-Complex. Ar. Ar Ar. O. NR2. O. E-Elimination. Ar'3P Pd NR2 PAr'3 V-Complex. Scheme 8. Amino-directed chelation-controlled E-arylation of a linear vinyl ether.. Increasing the tether length led to poor E-selectivity.121 Analogs of chelating vinyl ethers, where either the donor dimethylamino was replaced by isopropyl, 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 S-complex controls migratory insertion through a favored, 6-membered ring intermediate. Insertion may also be electronically influenced, facilitating the reduction of the electron 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 (E:D = 1:1) when the chelating vinyl ether A (Scheme 9) was replaced by butyl vinyl ether in a + control experiment.120,121 O. Pd(OAc)2 PPh3. N. PPh3. O. Pd N. Ar E-Product Ar D/E = 1/99. ArOTf +. + N. N O A. Pd(OAc)2 dppp. O Ph P Ph. N. Ar. O. Pd P. Ar. Ph Ph. D-Product D/E = 99/1. Scheme 9. Switch of regioselectivity. Chelation control vs. ligand control in a Heck reaction.43,121. 23.

(233) The observation that the bidentate ligand favored the exclusive formation of the D-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 phosphane ligand, has been found to play a crucial role in the regioselective outcome 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 q or close, favors D-selectivity (Scheme 10).. O N D:E = 1:99. Ph2P PPh2 dppm, T = 73°. N. PhOTf, Pd(OAc)2 Ph Et3N. O D A. PPh2 PPh2 dppp, T | 90°. O N. E PhOTf, Pd(OAc)2 Et3N. Ph D:E = 99:1. Scheme 10.. Deviating angles in the case of dppe (< 90 q) and dppb (> 90 q) led to less Dselectivity 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 q) 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 D-arylation and dimethylamino-accelerated di- and tri-arylation was achieved using the chelating vinyl ether A as presented in Scheme 11.107 Ar2Br, Pd(OAc)2 Ph3P O NaOAc, K2CO3. Ar1Br, Pd(OAc)2 O dppp, TlOAc N D N 80 °C E Ar1 A O Ar1. 100 °C. Ar2 Ar2. Ar2 Ar2. Scheme 11. Triarylation of a chelating vinyl ether.107. 24. O N 1 Ar. HCl (aq) TBME 14-66% (overall).

(234) Later, 2-pyridyl-directed exclusive E,E-diarylation of vinylsilane,124,125 2pyrimidyl-directed E,E-diarylation and D,E,E-triarylation of vinyl thioether,127 (by Itami and Yoshida et al.) (Scheme 12) and dimethylaminodirected E-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.. N. Si. Ar1I; Ar2I (one pot) Pd2(dba)3.CHCl3 Et3N, (2-furyl)3P THF, 60 oC 65-74%. N. Si Ar1 2. Ar E:Z > 99:1 1. t-BuLi, THF -78 oC 3 2. Ar I, Pd(PPh3)4 N CuI, 50 oC. Ar1I; Ar2I (one pot) Pd(Pt-Bu3)2 N Et3N N. S. Toluene, 60 oC 81-95%. N. S 3. DDQ, rt t-Bu 55-82% Ar1 2. Ar E:Z > 99:1. N N. S 3. Ar. Ar1 Ar. 2. 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 developed 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 E-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, phosphineoxazoline often furnished high enantioselectivity. Despite the benefit of using catalytic amounts of chiral catalyst, the major limitation of this methodology 25.

(235) was the requirement of electron-rich olefins (poor S-acceptors, good Vdonors) under cationic conditions. At end of the 1990s, Carretero et al. demonstrated an outstanding application of dimethylamino-directed auxiliary, or chelation-controlled stereoselective synthesis of 2-aryl-3-sulfinyl-2,5-dihydrofurans in high ee's (Scheme 13).139 O O. S. +. ArI, Pd(OAc)2 Ag2CO3, dppp. O. O O. Ar Pd L S N. N. S. Ar. O. N. de = 70-88% 139. Scheme 13.. The high enantiomeric excess was achieved by the coordination of the dimethylamino group to Pd(II), and thus selective presentation of V-adduct during the asymmetric insertion. To understand the insertion mode, nonamino-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 chelation-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 chelation-controlled Heck reactions, it was established that chelating vinyl ether A O. O N. N. O. N. A. B. C. Figure 1.. (Fig. 1) was well designed to providing E-selective Heck arylation. For further development of this concept from the domain of regioselectivity to the. N. O Ar-X X = I, Br. Scheme 14.. 26. 163. Pd(OAc)2. H. N. O. X. O. N. O Pd Ar. Ar. HCl (aq). Ar (90-98% ee).

(236) domain of stereoselectivity, the terminal vinylic group was substituted by a prochiral 2-methyl cyclopentenyl moiety maintaining the optimal twocarbon spacing between the vinylic oxygen and the donor nitrogen. Chelating 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 diastereoselective 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 purities (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.. H. N. X. O Pd. Ar. Figure 2. Si-face addition furnishing the (R)-2-aryl-2-methyl cyclopentanone after hydrolysis (in the presented model Ar = Ph).163. 27.

(237) 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 chlorides are attractive arylpalladium precursors because they are readily available 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 combination 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 protocol 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.) Cl (a). R1. +. Base, Solvent Temperature. R. (b) N. NH2 + Cl. Pd(OAc)2 PPh3, NaHCO3 Ph. R1. Catalyst R. NH2. NH2. o. DMF, 135 C. N. Ph. S. N. N NH2 H Antitumor agent, 3-AP N. 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 1,2bis(diphenylphosphino)ethane (dppe).187 In the early 1990s, Milstein et al. discovered the bulky, electron-rich, chelating phosphane ligand (1,428.

(238) bis(diisopropylphosphino)butane (dippb) (Structure D, Fig. 3) which provides a palladium catalyst that can effectively couple electron-poor and borderline aryl chlorides.169. P Pd P. n(H2C). (CH2)n. P D. P. P Pd. n = 3, dippp Milstein et al. n = 4, dippb P(t-Bu)3 G [(t-Bu)3PH]BF4 Air stable Fu et al.. P(t-Bu)2 Fe Hartwig et al.. O. E. O 2. N. H N. PdL2 2. F. Herrmann et al.. 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 styrene 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 hexafluorophosphates or tetrafluoroborate (room temperature ionic liquids) as Nheterocyclic carbene precursors188,189 and palladium complexes of Nheterocyclic carbene ligands with bulky substituents190 have been wellexploited in Heck reactions with aryl chlorides.191 At the end of the 1990s, Fu et al. reported the general Pd/P(t-Bu)3catalyzed Heck coupling of diverse aryl chlorides with a series of electronrich, electron-poor and electron-neutral olefins.175,176 Among other electronrich 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 fluorescence-based assay, where they screened more than 40 phosphane ligands.192 Beller et al. also reported successful Heck coupling of unactivated and hindered aryl chlorides using the bulky electron-rich catalyst di(1-adamantyl)-nbutylphosphane (Table 2, entry 8).193 Among a set of bulky, electron-rich dialkylaryl- and trialkylphosphanes, P(t-Bu)3 and di(1-adamantyl)-n29.

(239) 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 Entry. R. 1169 4-NO2, CHO H, CH3. R1. Catalyst. Ph. Pd(OAc)2 iPr2P. 2175 4-COMe, H Ph 4-OMe, 2-OMe COOMe 3185. 174. 4. 4-CHO COMe H, OMe 2-CH3. Conditions. Ph. 4-NO2, CHO COOBu. 5195. 4-OMe. Ph COOBu. 6196. 4-NO2 CHO, H. Ph COOBu. O. NaOAc DMF 150 oC. 55-95. Cs2CO3 dioxane 100-120 oC. 70-84. PiPr2. Pd2(dba)3/P(tBu)3. PiPr2 Pd Cl PiPr2. Yield (%). CsOAc, 81-99 dioxane 120 oC, 180 oC. O Catalyst F (Fig. 3) n-Bu4NBr co-cat.. NaOAc DMA 130 oC. 99. Pd(OAc)2 NMP N,N-dimethyl-E-alanine 130 oC. 30-96. 140 oC. 10-97. DMF. 82-96. Bu + _ NH OAc N. N. PdCl2 7197. 4-COMe NO2. Ph COOt-Bu. Cl N. Pd. Cl N OH. S 8172. 4-CHO COMe, CN. Ph COOBu. Catalyst E (Fig. 3) n-Bu4NBr co-cat.. TBAB NaOH 130 oC NaOAc DMA 130 oC. The positions of R and R1 are given in Scheme 15 [Equation (a)].. 30. 32-81.

(240) 2. Aims of the Present Study. The main aim of the present study was to investigate the use of aryl chlorides as substrates in regio- and stereoselective intermolecular Heck reactions. 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 E-blocker.. -. To design novel reaction conditions for aryl and vinyl chlorides as substrates in chelation-controlled stereoselective Heck transformations.. -. To synthesize C-2-substituted and C-2-non-substituted cyclic proline vinyl ethers of different sizes and to examine their scope and limitations in intermolecular diastereoselective Heck reactions.. 31.

(241) 3. Results and Discussion. 3.1 Regioselective E-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 arylation/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 involving 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 employing in situ microwave heating in combination with the [(t-Bu)3PH]BF4 preligand was investigated. Initially, 4-chloroanisole, an electron-rich, deactivated arylpalladium precursor, was chosen as the model substrate for cou32.

(242) 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 microwave heating in a sealed vessel, using 2.0 equiv of butyl acrylate (1) and 1.0 equiv of 4-chloroanisole (2a) (Scheme 17). COOBu COOBu. Cl + R. 2. 1. [Pd] Ligand, Base Solvent Air atmosphere. R. 3. Scheme 16. Heck vinylation of aryl chlorides under air.. Under the subjected conditions (180 qC, 60 min), the reaction did not proceed to completion. Applying a higher temperature (190 qC) and longer irradiation time (90 min) resulted in a maximum of 27% conversion of the starting 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 microwaveactive “molecular irradiators” heating the reaction system quickly.210,211 Three different kinds of ionic liquids188 were tested: 1-butyl-3methylimidazolium hexafluorophosphate (bmimPF6),212 1-butyl-3methylimidazolium tetrafluoroborate (bmimBF4), and tetrabutyl ammonium bromide (TBAB).213 Screening of these ionic additives in association with different palladium precatalysts (Herrmann’s palladacycle [trans-di(P-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%). COOBu Palladacycle COOBu [(t-Bu)3PH]BF4, Cy2NMe. Cl + MeO 2a. 1. bmimPF6-dioxane Mw, 60 min, 180 oC Air atmosphere. MeO 3a. Scheme 17. Model Heck reaction between 1 and 2a under microwave conditions.. 33.

(243) 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 qC in order to avoid catalyst decomposition and subsequent incomplete conversion of the starting material. After selective screening, the best combination of reaction time, catalyst loading, and solvent system was identified to be 60 min of heating 1 and 2a with 10.0 mol% Herrmann’s palladacycle, 20.0 mol% [(t-Bu)3PH]BF4 and 1.0 equiv (with respect to 2a) of bmimPF6 (208 PL) with 400 PL 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 Entry. Time (min). Aryl chloride. Isolated. Product. yieldb (%) COOBu. Cl 1. 2a MeO. 60. 3a. MeO. 60. COOBu. Cl 2. 2b. 60. 3b. 85. Me. Me. COOBu Cl 2c. 3. 3c. 60. Me. Me Me. 86. COOBu. Me Cl 2d. 4 Me. 3d. 60. 80, 47c. Me. Reaction conditions: bmimPF6 (208 PL), 1,4-dioxane (400 PL), Herrmann’s palladacycle (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 qC. b > 95% pure according to GC/MS. c Conventional oil-bath heating at 180 qC for 90 min. Shorter heating times afforded lower yields of 3d. a. 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. 34.

(244) 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 heteroaryl chloridesa Time (min). Aryl chloride. Entry. Isolated. Product. yieldb (%) COOBu. Cl 1. 2e. 40. 3e. CF3 COOBu. CF3 Cl. 2. 90. 2f 40. 3f. N. N. 91. COOBu. Cl 3. 2g 40 N. N. 3g COOBu. 88. 3h COOBu. 65. Cl 2h 60. 4. Cl 5. 2i. 60. 3i. 81. Reaction conditions: bmimPF6 (208 PL), 1,4-dioxane (400 PL), Herrmann’s palladacycle (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 qC. b > 95% pure according to GC/MS. a. Encouraged by the results presented in Table 3, I decided to proceed to develop a milder reaction protocol employing electron-deficient, electronneutral 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).. 35.

(245) Table 5: Heck vinylation of electron-poor aryl chloridesa Time (min). Aryl chloride. Entry. Isolated. Product. yieldb (%) COOBu. Cl 1 MeOOC. 2j 30 MeOOC. 3j. 93. COOBu Cl 2 OHC. 2k 30. OHC. 3k. 94. COOBu Cl 3. 30 NC. 2l. 95 NC. 3l COOBu. Cl. 4 Ac. 2m. Cl. 5 F3C. 2n. 90, 53c. 30 Ac. 3m COOBu. 30. 80 F3C. 3n. Reaction conditions: bmimPF6 (208 PL), 1,4-dioxane (400 PL), Herrmann’s palladacycle (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 qC. b > 95% pure according to GC/MS. c Conventional oil-bath heating at 180 qC for 60 min. Shorter heating times afforded lower yields of 3m.. a. 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 qC 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 palladacy36.

(246) cle and 30 min of microwave heating. A modest 69% isolated yield of (E)-4acetyl stilbene (5) was obtained as a result (Scheme 18). Ph Ph. Cl + Ac 2m. 4. Palladacycle [(t-Bu)3PH]BF4, Cy2NMe bmimPF6-dioxane Mw, 30min, 180 oC Air atmosphere. Ac 5, 69%. Scheme 18.. To understand the effect of bmimPF6 quantitatively, microwave model reactions were performed between 2m and 1 using pure 1,4-dioxane and compared 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 irradiation period of 60 min), the temperature with and without bmimPF6 was 180 qC. 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 deprotonated imidazolylidine may act as a carbene ligand to palladium.190,216 Thus, the reaction may possibly be catalyzed by imidazolylidine-palladium carbenoid species together with the expected Pd-[P(t-Bu)3] complex.217 Alternatively, the differing results observed with traditional heating and microwave heating might be explained by the problems of measuring the correct tem37.

(247) 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 methodology 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 vinylating agents since regioselective Heck arylation of enol ethers66 has tremendous synthetic potential. Arylation of enol ethers followed by hydrolysis opens up the route for the preparation of different carbonyl compounds. Furthermore, successful selective internal (D-) arylation of vinyl ethers, enamides, allylic compounds,43,50,56,114 and silyl enol ethers219-222 has been reported. It has been established in Heck methodology that the cationic route using bidentate ligands favors D-arylation of electron-rich acyclicmonosubstituted olefin, whereas neutral conditions facilitate predominantly E-arylation.50 This has also been supported by DFT calculations.223,224 Earlier efforts to achieve terminal E-selectivity of electron-rich olefins were summarized in Section 1.1.3.2.1. However, no direct and general protocol employing 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. 38.

(248) and better E-selectivity with sluggish p-anisyl chloride than the tested alternatives [Pd(OAc)2, Pd(PCy3)2, and Pd2(dba)3]. OBu 4 4-NMe2-Ph : + 4-NMe2-Ph OBu 1. OBu. 4-NMe2-Ph-Br +. Pd2(dba)3 P(t-Bu)3 Cy2NMe Dioxane, rt. 4-Ac-Ph-Cl. OBu 4-Ac-Ph 1 : + 4-Ac-Ph OBu 10. OBu. +. E:Z = 3:1 Yield = 97% (as mixture of regioisomers). E:Z = 5:1 Yield = 87% (as mixture of regioisomers along with 5% unreacted 4-Ac-Ph-Cl). 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, demonstrating 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 preligand [(t-Bu)3PH]BF4 (Method A). This protocol was investigated with 9 different aryl chlorides (Scheme 20, Table 6). E. O D. Cl. R1 O. Palladacycle, [(t-Bu3)PH]BF4 R. 2. Microwaves, 60 min 160 oC, Method A or B. R. 9 (E-product). R1 +. O R. R. D-product. 1. 6: R = -n-Bu 7: R1 = -CH2CH2NMe2 8: R1 = -CH2C3H5. Scheme 20.. 39.

(249) Following microwave irradiation at 160 qC for 60 min, all the aryl chlorides furnished more than 98% conversion based on GC-MS analysis. High values for regioselectivity (E/D = 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 E-selectivity was reduced to (E/D

(250) 65:35. To improve the E-selectivity with 2a, Pd(II)-presenting chelating vinyl ether 7 (A, Fig. 1) was used instead of 6, which resulted in an improvement of E/D-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 E/D ratios and conversions were carefully determined from crude reaction mixtures using 1H-NMR and by GC-MS using adamantane or 2,3-dimethylnaphthalene as internal standard. Regioisomers were assumed to have the same GC-MS response factors. To obtain correct E/D ratios, GC-MS response factors were also calculated for the corresponding acetophenones (produced by hydrolysis of easy-to-cleave D-arylated vinyl ethers in the reaction mixture).. 40.

(251) Table 6: Terminal E-arylation of alkyl vinyl ethers with aryl chlorides in aqueous DMF Entry 1. Ar-Cl. 4-NO2-Ph-Cl. Olefin Method 6. A. 4-CF3-Ph-Cl. Yielda (%). 97:3. 61. 97:3. 64. OBu. 97:3. 65. OBu. 97:3. 75. OBu. 89:11. 62. OBu. 90:10. 60. OBu. 80:20. 52. OBu. 80:20. 53. OBu. 65:35. 40. O(CH2)2NMe2 85:15. 63. 4-NO2-Ph. OBu 9a. 2o 2. E/D. Product. 6. A. 4-CF3-Ph. OBu 9b. 2n 3. 4-CHO-Ph-Cl. 6. A. 6. A. 4-CHO-Ph 9c. 2k 4. 4-Ac-Ph-Cl. 4-Ac-Ph 9d. 2m 5. 2-Cl-Naphthalene 6. A. 2-Naphthyl 9e. 2p 6. Ph-Cl. 6. Ph. A. 9f. 2h 7. 4-Me-Ph-Cl. 6. A. 4-Me-Ph 9g. 2c 8. 2-Me-Ph-Cl. 6. A. 2-Me-Ph 9h. 2b 9. 10. 4-MeO-Ph-Cl 2a. 6. 2a. 7. A. 4-MeO-Ph 9i. A. 4-MeO-Ph. 9j 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 PL H2O and 2 mL DMF in sealed vessels. Microwave heating, 160 oC for 60 min. a Isolated yield ofE-arylated E- and Z-products, >95% purity of 9 by GC-MS and 1H-NMR, average of five runs7he E/D ratio was determined by GC-MS and calculated as E-E + E-Z)/(D+ aryl methyl ketone).. 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 (E/D = 97:3 vs. 91/9) with improved yield (75%, Table 6, 41.

(252) entry 4) of terminally arylated regioisomer (E-E + E-Z) compared to the mixture of regioisomers reported in Scheme 19. Traditional oil-bath heating at 160 qC 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 employing in situ microwave irradiation.202,227 To investigate the effect of P(t-Bu)3 in the regioselective terminal arylation of butyl vinyl ether, a series of comparative experiments were performed 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). ED. 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 PL H2O, and 2 mL DMF in sealed vessels. Microwave heating, 160 qC for 60 min gave >95% conversion. Isolated yields >95% purity of linear E-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 [(tBu)3PH]BF4 delivered better isolated yields and E-selectivity of 9 compared to PPh3-catalyzed reactions, proving the regio-determining power of alkyl phosphine ligands.. 42.

(253) Table 8: Terminal E-arylation of alkyl vinyl ethers with aryl chlorides in PEG 200 Entry 1. Ar-Cl. 4-NO2-Ph-Cl. Olefin Method 6. B. 4-CF3-Ph-Cl. Yielda (%). 98:2. 60. 98:2. 65. OBu. 98:2. 62. OBu. 98:2. 70. OBu. 92:8. 60. OBu. 93:7. 59. OBu. 83:17. 52. OBu. 82:18. 54. OBu. 78:22. 46. O(CH2)2NMe2 90:10. 70. 4-NO2-Ph. OBu 9a. 2o 2. E/D. Product. 6. B. 4-CF3-Ph. OBu 9b. 2n 3. 4-CHO-Ph-Cl. 6. B. 6. B. 4-CHO-Ph 9c. 2k 4. 4-Ac-Ph-Cl. 4-Ac-Ph 9d. 2m 5. 2-Cl-Naphthalene 6. B. 2-Naphthyl 9e. 2p 6. Ph-Cl. 6. Ph. B. 9f. 2h 7. 4-Me-Ph-Cl. 6. B. 4-Me-Ph 9g. 2c 8. 2-Me-Ph-Cl. 6. B. 2-Me-Ph 9h. 2b 9. 10. 4-MeO-Ph-Cl 2a. 6. 2a. 7. B. 4-MeO-Ph 9i. B. 4-MeO-Ph. 9j 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 ofE-arylated E- and Z-products, >95% purity of 9 by GC-MS and 1H-NMR, average of five runs. The E/D ratio was determined by GC-MS and calculated as E-E + E-Z)/(D+ aryl methyl ketone).. In 2002, Chandrasekhar et al. reported high E-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 43.

(254) 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-pentamethylpiperidine) 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 incomplete transformations with ED-ratios of up to 85/15 were achieved. Neither 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, improved E-selectivity was achieved in cases of aryl moieties with EDGs (Table 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 temperatures (160 qC) and also delivered high terminal selectivity for chelationcontrolled 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 ED = 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 arylation of an enamide using an aryl chloride as a coupling partner. Ar-Cl. Olefin. Method. Product. Yield (%). 75:25. 45. O. O 2h. E:D. N 10. B Ph. N E-11. 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 reaction outcome. 4-Bromotoluene was selected for arylation instead of the corresponding 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 [(tBu)3PH]BF4 yielded better E-selectivity than traditional PPh3.. 44.

No results found