CATALYTIC CNITROGEN COMPOUNDS 2-

CATALYTIC C

NITROGEN COMPOUNDS 2-

Directores: Dr. Juan Carlos Carretero Gonzálvez

Facultad de Ciencias

Departamento de Química Orgánica

CATALYTIC C −−−− H FUNCTIONALIZATION OF AROMAT NITROGEN COMPOUNDS DIRECTED BY THE

-PYRIDYLSULFONYL GROUP

BEATRIZ URONES RUANO

Directores: Dr. Juan Carlos Carretero Gonzálvez Catedrático (UAM)

Dr. Ramón Gómez Arrayás Profesor Titular (UAM)

Madrid, Mayo de 2013

OF AROMATIC

DIRECTED BY THE

This PhD Thesis has been done at the Department of Organic Chemistry at the Universidad Autónoma de Madrid under the supervison of Prof. Dr. Juan Carlos Carretero and Prof. Dr. Ramón Gómez Arrayás.

This work was supported by the Ministerio de Ciencia e Innovación (MICINN, CTQ2009- 07791/BQU), the Ministerio de Economía y Competitividad (MINECO, CTQ 2012-35790) and the Consejería de Educación de la Comunidad de Madrid (programme AVANCAT, S2009/PPQ- 1634). B.U. thanks the MICINN for a FPU predoctoral fellowship and N.R. for a contract through her Marie Curie Career Integration Grant - CIG (CHAAS-304085).

To Ramón. whose expertise, understanding, and patience, added considerably to my graduate experience. I appreciate his vast knowledge and skill in many areas and his guidence in writing reports. Thanks for making things easier until the last minute.

A very special thanks goes out to Dr. Jorge Fernández Molina, without whose motivation and encouragement I would not have considered to do a PhD. Also thank you very much for being “tol rato tol tiempo en descontacto total” and never let me down.

When I started this adventure, my mum gave me a great advice: It’s going to be a hard trip, so stick to people that loves you and support you! Maria, you are one of a kind! Thanks for being my family in Madrid, support me, encourage me and also celebrate the good moments.

You have been a true friend all this time (esto es para siempre!).

Nuria, there isn’t enough words to thank you and to express all my gratitutde for everything you have done for me. You were the last one arriving but you have became such a great friend.

THANK YOU for being just the way you are. You are the only few people that can me make me laugh when I’m stressed…. Thanks for all your help and support and never let me down! I couldn’t have done it without you, that’s for sure… I love you!!!

I must also acknowledge my colleagues in the Organic Chemistry Department for their support and good moments, in special to the members of my research group for the exchanges of knowledge, skills, and venting of frustration during my graduate program, which helped enrich the experience.

Appreciation also goes out to those who provided me with helpful advice at times of critical need; Nana, Ester, Mariona, Isa ….. Primi! Thanks for your permanent smile.

I would also like to thank my family for the support they provided me through my entire life and in particular, I must acknowledge my grands without whose love, encouragement and faith, I would not have embarked on this adventure.

“On ne voit bien qu'avec le coeur; l'essentiel est invisible pour les yeux”

Antoine de Saint-Exupéry, Le Petit Prince

“The whole problem with the world is that fools and fanatics are alsways so certain of themselves and wisers full of doubts”

Bertrand Russell

To my family, in special to my grandparents

INDEX

1. Introduction ... 25

1.1. Importance and challenges of C−H functionalization ... 25

1.2. General approaches for catalytic C−H Functionalization ... 27

1.3. C−H functionalization via aryl-metal intermediates: use of directing groups... 28

1.3.1. Non-removable directing groups ... 33

1.3.2. Removable, auxiliary directing groups ... 35

1.4. Precedents of our research group ... 45

1.5. Research objectives and Thesis organization ... 57

2. Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles ... 63

2.1. Importance of the 2,2’-biindole as structural motif ... 63

2.2. Synthesis of 2,2’-biindoles ... 65

2.2.1. Initial approaches to the 2,2’-biindole skeleton ... 65

2.2.2. Transition metal-catalyzed cross-coupling approach to 2,2’-biindoles... 69

2.2.3. Oxidative homocoupling reaction ... 71

2.3. Aim of the project... 77

2.4. Catalytic dehydrogenative homocoupling of indoles: synthesis of 2,2’-biindoles ... 79

2.4.1. Screening of the catalytic system and the reaction conditions ... 79

2.4.2. Evaluation of the directing role N-(2-pyridyl)sulfonyl protecting group... 86

2.4.3. Reaction scope ... 88

2.4.4. N-Deprotection via reductive desulfonylation reaction ... 92

2.4.5. Mechanistic proposal ... 92

2.4.6. Intramolecular version: oxidative coupling of bis(1H-indol-3-yl)methanes ... 93

2.5. Conclusions ... 97

3. C−H olefination of anilines and arylalkylamines ... 101

3.1. Importance of anilines and arylalkylamines ... 101

3.2.3. Rh-catalyzed C−H olefination of aromatic amines ... 119

3.3. C−H olefination of aryl alkylamines ... 125

3.4. Aim of the project ... 129

3.5. C−H ortho-olefination reaction of N-sulfonyl aniline derivatives ... 132

3.5.1. C−H olefination of N-methyl anilines: optimization studies ... 132

3.5.2. Structural versatility of the N-alkyl group ... 136

3.5.3. Structural versatility of the alkene coupling parter ... 143

3.5.4. Structural variations at the aniline counterpart ... 145

3.5.5. Application to indole synthesis ... 147

3.6. Tether elongation: C−H olefination of arylalkylamines ... 149

3.6.1. C−H olefination of benzylamines ... 151

3.6.2. C−H olefination of phenethylamines and γ-arylpropylamines ... 157

3.7. Deprotection ... 163

3.7.1. Attempts to isolate the palladacycle ... 164

3.8. Conclusions ... 167

4. C−H di-ortho-olefination of carbazoles ...173

4.1. Importance of carbazoles ... 173

4.2. Synthesis of carbazoles ... 175

4.2.1. C−C bond formation: metal-catalyzed cyclization of diarylamine derivatives (route a) ... 176

4.2.2. C−N bond formation: cyclization of 2-aminobiphenyl derivatives (route b) ... 184

4.2.3. Direct functionalization of the carbazole skeleton: functionalization at C1/C8 positions ... 191

4.3. Aim of the project ... 196

4.4. Results and discussion ... 198

4.4.1. N-sulfonanylation of the NH-carbazole ... 198

4.4.2. Screening of the reaction conditions ... 198

4.4.3. Evaluation of the role of the N-(2-pyridyl)sulfonyl directing/protecting group ... 202

4.4.4. Di-ortho olefination ... 204

4.4.6. Substrate scope ... 207

4.4.7. C−H olefination of other nitrogen-containing compounds... 214

4.4.8. Deprotection of olefinated N-(2-pyridyl)sulfonyl carbazoles and indolines ... 218

4.5. Conclusions ... 220

5. Aerobic copper-catalyzed ortho-halogenation of anilines ... 225

5.1. Introduction: sustainable catalytic C−H functionalization ... 225

5.2. Coupling reactions under aerobic conditions ... 225

5.3. Aerobic Cu-catalyzed C−H functionalization ... 227

5.3.1. Base-promoted Cu-catalyzed C−H functionalization ... 228

5.3.2. C−H activation of relatively inert aryl C−H bonds... 232

5.4. Ortho-halogenated reactions of anilines derivatives ... 241

5.5. Aim of the project... 248

5.6. Results and discussion ... 249

5.6.1. First attempts in Cu-catalyzed ortho-halogenation of anilines... 249

5.6.2. Development of a more benign copper-catalyzed protocol for the ortho-halogenation of anilines 253 5.6.3. Evaluation of the effect of the N-directing/protecting group ... 258

5.6.4. Structural versatility of the aniline in the ortho-chlorination reaction ... 260

5.6.5. Expanding the reaction to bromination and iodination ... 265

5.6.6. Ortho-substituted substrates: Development of the N-(2-pyrimidyl)sulfonyl directing group 269 5.6.7. Deprotection ... 274

5.6.8. Application to indole synthesis... 274

5.7. Conclusions ... 278

6. Experimental section ... 285

6.1. Catalytic oxidative homocoupling of N-(2-pyridyl)sulfonylindoles: synthesis of 2,2’-biindoles .... 285

6.1.4. Synthesis of 2,3’-biindoles via Pd^II-catalyzed dehydrogenative homocoupling ... 292

6.1.5. Deprotection of N,N’-bis(2-pyridilsulfonyl)-2,2’-biindolyl (2) to afford free NH-biindole 41.293 6.1.6. Intramolecular homocoupling reaction ... 294

6.2. C−H olefination of anilines and arylalkylamines ... 297

6.2.1. General methods ... 297

6.2.2. Typical procedure for N-sulfonylation of anilines ... 298

6.2.3. Synthesis of the starting functionalized N-alkyl anilines: ... 300

6.2.4. General procedure for N-sulfonylation of N-methyl-N-(2-pyridyl)sulfonyl arylalkylamines 304 6.2.5. General procedure for the C−H alkenylation reaction ... 309

6.2.6. General procedure for the Zn-promoted reductive N-desulfonylation: ... 325

6.2.7. Synthesis of indoles from N-(methoxycarbonyl)methyl-substituted olefinated adducts: cyclization-deprotection-aromatization. ... 326

6.3. C−H di ortho-olefination of carbazoles ... 329

6.3.1. General methods ... 329

6.3.2. Synthesis of the starting carbazoles and derivatives ... 329

6.3.3. C−H alkenylation reaction ... 335

6.3.4. Zn-promoted reductive N-desulfonylation ... 342

6.3.5. Mg-promoted reductive N-desulfonylation ... 343

6.3.6. Oxidative aromatization ... 344

6.4. Aerobic copper-catalyzed ortho-halogenation of anilines ... 345

6.4.1. General methods ... 345

6.4.2. Typical procedure for the N-sulfonylation of anilines. ... 346

6.4.3. General procedures for the copper-catalyzed ortho-halogenation ... 354

6.4.4. Typical procedure for the Mg-promoted N-desulfonylation ... 369

6.4.5. Typical procedure for the synthesis of 2-substitued NH-indoles from ortho-bromo- substituted N-(2-pyridil)sulfonyl anilines: Sonogahira coupling/cyclization/deprotection. ... 370

6.4.6. Intramolecular isotopic kinetic effect ... 371

Appendix I: Publications...377

And in the CD attached:

Appendix II: NMR spectra collection Appendix II-A: NMR spectra chapter 2 Appendix II-B: NMR spectra chapter 3 Appendix II-C: NMR spectra chapter 4 Appendix II-D: NMR spectra chapter 5

Standard Abbreviations and Acronyms

Standard Abbreviations and Acronyms

Ac: acetyl

AcOH: acetic acid Ac2O: acetyl anhydride Ar: aryl

Bn: benzyl.

BQ: 1,4-benzoquinone CAN: ceric ammonium nitrate δδδδ: chemical shift in parts per million

DCE: 1,2-dichloroethane DCM: dicloromethane

DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DMA: dimethylacetamide

DMAP: 4-(N,N-dimethylamino)pyridine DMF: dimethylformamide

DMSO: dimethyl sulfoxide EI: electron impact EM: elemental mass ESI: electrospray ionization EWG: electron-withdrawing group

[F⁺]: N-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate FAB: fast atom bombardment

GC: gas chromatography HQ: hydroquinone

Hz: hertz

M: molar (moles per liter)

MS: mass spectrometry; molecular sieves NBS: N-bromosuccinimide

NCS: N-chlorosuccinimide NIS: N-iodosuccinimide

Ns. 4-nitrobenzenesulfonyl (nosyl) SET: single electron transfer TAA: tert-amyl alcohol

TBHP: tert-butyl hydroperoxide TBPB: tert-butyl perbenzoate temp: temperature

TEMPO: 2,2,6,6-trimethylpiperidin-1-oxyl Tf: trifluoromethanesulfonyl (triflyl) TFA: trifluoroacetic acid

THF: tetrahydrofuran

TLC: thin-layer chromatography Ts: para-toluenesulfonyl (tosyl)

Chapter 1:

Introduction

1. Introduction

1.1. Importance and challenges of C

The ultimate aim of Organic Synthesis is to assemble a given organic compound (target molecule) from readily available starting materials and reagents in the most efficient way.¹ Consequently, o

increase efficiency and minimiz coined to describe such a goal.

transformation of a non-activated C−heteroatom bond. Non-activated C

Therefore, the development of selective, energy of C−H bonds into useful functional groups Synthesis (Scheme 1.1).³ The

fascinating from the notion that a C equivalent of an active functional group.

often requires numerous chemical operations to link two molecules together, catalyzed C−H functionalization has tremendous potential in

synthesis of complex molecules.

1 K. C. Nicolaou, J. S. Chen in Classics Wiley-VCH, Weinheim, 2011.

2 B. M. Trost, Acc. Chem. Res. 2002,

3 R. G. Bergman, Nature 2007, 446, 391

4 For reviews on the application of C a) K. Godula, D. Sames, Science 2006 Rev, 2011, 40, 1885; c) D. Y.-K. Chen

Importance and challenges of C−−−−H functionalization

of Organic Synthesis is to assemble a given organic compound ) from readily available starting materials and reagents in the most Consequently, one of the main goals in modern organic chemistry is to ze chemical waste. The term atom economy has been coined to describe such a goal.² One of the most atom economic processes is the activated carbon-hydrogen (C−H) bond into a C−C or activated C−H bonds are ubiquitous in organic molecules the development of selective, energy-efficient chemistry for the conversion H bonds into useful functional groups is leading to a paradigm shift in Organic

he application of C−H functionalization technologies from the notion that a C−H bond can be viewed as a latent functional

active functional group. In contrast to conventional synthesis that often requires numerous chemical operations to link two molecules together, metal

functionalization has tremendous potential in streamlining the complex molecules.⁴

Scheme 1.1

Classics in Total Synthesis III: Further Targets, Strategies, Methods

, 35, 695.

, 391.

For reviews on the application of C−H functionalization to the total synthesis of complex molecules:

2006, 312, 67; b) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc.

K. Chen, S. W. Youn, Chem. Eur. J. 2012, 18, 9452.

of Organic Synthesis is to assemble a given organic compound ) from readily available starting materials and reagents in the most ne of the main goals in modern organic chemistry is to e chemical waste. The term atom economy has been One of the most atom economic processes is the C or molecules.

chemistry for the conversion leading to a paradigm shift in Organic H functionalization technologies is functional that metal- streamlining the

in Total Synthesis III: Further Targets, Strategies, Methods;

of complex molecules:

Chem. Soc.

The functionalization of unactivated C−H bonds, however, remains a tremendous challenge.⁵ This is due to: (1) The high pKa values (>35) and bond dissociation energies (375 – 440 kcal/mol) of typical unfunctionalized C−H bonds, as well as their

“paraffin” nature, as they possess neither low lying HOMOs nor high lying LUMOs; (2) Over-oxidation of functionalized products is often thermodynamically favored; (3) Difficulty in functionalizing a single C−H bond with high regiocontrol within a complex structure which contains many types of C−H bonds.

This is a very large, diverse, and highly active field. As consequence, the aim of this introductory chapter is not to provide a comprehensive sampling of the vast literature. Several excellent general review articles have been published on various aspects of this field, some fairly recently.⁶ Our goal in this chapter is to convey some general background and insight to help the reader to appreciate and put into context the research of this thesis. Subsequent chapters of this manuscript provide a wider coverage of the current state of art of the particular reaction that has been studied.

Therefore, in this chapter we place our emphasis on C−H functionalization of arenes, a common feature of the research described in this manuscript, with discussion of C(sp³)−H and other C−H bonds being outside of the general scope of this Thesis.

5 For a review on direct transformations of sp² C−H bonds: a) D.-G. Yu, B.-J. Li, Z.-J. Shi,Tetrahedron 2012, 68, 5130. See also: b) B. A. Arndtsen, R. G. Begman, T. A. Mobley, T. H. Peterson, Acc.

Chem. Res. 1995, 28, 154; c) M. Tobisu, N. Chatani, Angew. Chem. Int. Ed. 2006, 45, 1683.

6 For general reviews on metal-catalyzed C−H functionalization: a) W. D. Jones, Science 2000, 287, 1942; b) J. A. Labinger, J. E. Bercaw, Nature 2002, 417, 507. See also the February 2010 and March 2011 issues of Chem. Soc. Rev., the April 2011 issue of Chem. Rev. and the June 2012 issue of Acc.

Chem. Res. For selected reviews: c) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885. d) J. Wencel-Delord, T. Dröge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740. e) K. M.

Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788. f) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879; g) J. J. Mousseau, A. B. Charette, Acc. Chem. Res.

2013, 46, 412.

1.2. General approaches for catalytic C−−−−H Functionalization

Different transition metal complexes are capable of catalytic activation/functionalization of C−H bonds. These catalysts can operate within two very different general mechanistic manifolds: (1) Cleaving unactivated C−H bonds to furnish carbometallated intermediates (C−[M]), which can be then transformed into the desired products (C−FG) by treatment with appropriate reagents (R−X, Scheme 1.2, a); (2) Cleaving the C−H bond by insertion of metal-oxo or metal- carbenoid/nitrenoid species⁷ (Scheme 1.2, b). In the latter case, a C–H bond within the substrate is not converted into a C–[M] bond for its subsequent functionalization.

Rather these processes rely on the formation of high energy species on the metal center, which are then able to insert into the C–H bonds of the substrate.

Scheme 1.2

The research discussed in this thesis focuses mainly on the first method. Hence, the discussion hereafter is focused in that area. The latter approach is outside of the scope of this thesis and will thus not be discussed.

7 For reviews on catalytic C–H functionalization by metal carbenoid and nitrenoid insertion, see: a) H.

M. L. Davies, J. R. Manning, Nature 2008, 451, 417; b) H. M. L. Davies, D. Morton, Chem. Soc. Rev.

2011, 40, 1857.

1.3. C−−−−H functionalization via aryl-metal intermediates: use of directing groups

In 1968, Fujiwara and Moritani disclosed the first catalytic C−H activation reaction with Pd(OAc)₂ in which benzene (as solvent) was added to styrene to afford diphenylethylene (Scheme 1.3).^8,9

Cu(OAc)₂or AgOAc (10 mol%) Ph

Ph +

Pd(OAc)₂(10 mol%)

O₂(50 atm), AcOH, 80 ºC 45%

H

Scheme 1.3

As shown in Scheme 1.4a, the mechanism involved the electrophilic palladation of arene ring with a Pd^II catalyst to generate the arylpalladium intermediate I.

Subsequent carbopalladation of the olefin led to the alkylpalladium complex II that underwent syn-β-H elimination to yield the styrenyl product and Pd⁰. The final step of the catalytic cycle was oxidation of Pd⁰ to Pd^II using Cu salts, Ag salts, benzoquinone, O2, and peroxides, among other oxidants examined. In an alternative mechanism, the Pd^II catalyst was proposed to coordinate to the olefin, which enhanced its electrophilicity and propensity to undergo nucleophilic addition with electron-rich aromatic rings (Scheme 1.4b).¹⁰ The resulting intermediate II was intercepted in this pathway.

8 a) Y. Fujiwara, I. Moritani, M. Matsuda, S. Teranishi, Tetrahedron Lett. 1968, 9, 3863; b) Y.

Fujiwara, I. Moritani, S. Danno, R. Asano, S. Teranishi, J. Am. Chem. Soc. 1969, 91, 7166.

9 For previous studies using stoichiometric Pd^II, see: a) I. Moritani, Y. Fujiwara, Tetrahedron Lett.

1967, 8, 1119; b) Y. Fujiwara, I. Moritani, M. Matsuda, Tetrahedron, 1968, 24, 4819; c) Y. Fujiwara, I.

Moritani, M. Matsuda, S. Teranishi, Tetrahedron Lett. 1968, 9, 633.

10 E. M. Beck, M. J. Gaunt, Top. Curr. Chem. 2010, 292, 85.

Scheme 1.4

This early report by Moritani and Fujiwara demonstrated the impressive reactivity of palladium(II) in activating aryl C−H bonds. However, two major drawbacks largely hampered the application of this catalytic reaction. First, a large excess of the arene was required (often used as the solvent). Second, there was a lack of control in the regioselectivity when monosubstituted benzene derivatives such as toluene or

anisole were used, generally resulting in the formation of undesirable mixtures of regioisomeric products (Scheme 1.5).¹¹

Scheme 1.5

In response to these problems, the development of ligand-directed C−^H activation6^,12 has proved to be essential to address the challenges of improving reactivity and controlling regioselectivity.¹³ This strategy involves the use of

11 Y. Fujiwara, I. Moritani, R. Asano, Tetrahedron 1969, 25, 4815.

12 For a recent account on controlling regioselectivity in C−H bond functionalization: a) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936. For a recent review on removable directing groups in metal catalysis: b) G. Rousseau, B. Breit, Angew. Chem., Int. Ed. 2011, 50, 2450.

13 Another mode of substrate-controlled regioselectivity involves the activation of C−H bonds in substrates containing halogen substituents. The transition metal catalysts are brought adjacent to the C−H bond of interest for selective cleavage via oxidative addition of the carbon-halogen (C−X) bond, thereby generating organometallic intermediates as the requisite active catalysts prior to C−H. For selected reviews, see: a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174; b) M.

Catellani, E. Motti, N. Della Ca, Acc. Chem. Res. 2008, 41, 1512. A dramatic example on the efficient application of this strategy was described by Fagnou and co-workers in the total synthesis of Allocolchicine (see Scheme below).

substrates bearing a coordinating functional group (L in Scheme 1.6) that can reversibly chelate to the transition metal and brings it in proximity to the unactivated C−H bond, thereby facilitating its cleavage (activation). The resulting cyclometalated complex II formed upon C−H cleavage could then react with proper reagents to afford ortho-functionalized products.

Scheme 1.6

The first report of ligand-directed C−H functionalization appeared in 1963 using stoichiometric amounts of the transition metal. Kleiman and Dubeck discovered that Cp2Ni could activate C–H bonds in azobenzene (Scheme 1.7).¹⁴ In 1965, Cope and Siekman demonstrated that PdCl2 and K2PtCl4 showed an analogous reactivity.¹⁵

This total synthesis was based on a Pd-catalyzed intramolecular biaryl forming step between an aryl halide and a donor Ar−H species. The in situ generated catalytic Pd⁰ species undergoes oxidative addition to the aryl halide to form the Pd^II-aryl species that facilitates the activation of the aryl C−H donor to assemble the biaryl–Pd^II intermediate prior to reductive elimination. See also: c) L.-C.

Campeau, M. Parisien, M. Leblanc , K. Fagnou, J. Am. Chem. Soc. 2004, 126, 9186; d) M. Leblanc, K. Fagnou, Org. Lett. 2005, 7, 2849; e) L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am.

Chem. Soc. 2006, 128, 581. For a review of C−H functionalization in natural product synthesis: f) L.

McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885. For another example of a total synthesis, e.g. Trauner’s synthesis of rhazinilam, see: g) A. L. Bowie Jr., C. C. Hughes, D. Trauner, Org. Lett. 2005, 7, 5207; h) A. L. Bowie Jr., D. Trauner, J. Org. Chem. 2009, 74, 1581.

14 J. P. Kleiman, M. Dubeck, J. Am. Chem. Soc. 1963, 85, 1544.

15 A. C. Cope, R. W. Siekman, J. Am. Chem. Soc. 1965, 87, 3272.

Scheme 1.7

The pioneering catalytic directed C−H functionalization was reported by Murai and co-workers, who 30 years later demonstrated that [Ru(PPh3)3(CO)2] and [Ru(PPh3)3(CO)H2] were able to catalyze the insertion of olefins into the ortho-C−H bonds of aromatic ketones (Scheme 1.8).¹⁶

Scheme 1.8

As shown in Scheme 1.9, the reaction mechanism proposed by Murai involved the chelation-directed C−H bond activation by the ketone group to form the cyclometallated ruthenium(0) hydride complex III, followed by olefin insertion and reductive elimination to yield the product.¹⁷

16 S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda, N. Chatani, Nature 1993, 366, 529.

17 a) M. Sonoda, F. Kakiuchi, A. Kamatani, N. Chatani, S. Murai, Chem. Lett. 1996, 109; b) F.

Kakiuchi, H. Ohtaki, M. Sonoda, N. Chatani, S. Murai, Chem. Lett. 2001, 918; c) F. Kakiuchi, S.

Murai, Acc. Chem. Res. 2002, 35, 826.

Scheme 1.9

Since this initial report, many groups have expanded the scope of this strategy to include a variety of directing groups, which can be classified conventionally as belonging to one of two principal classes: removable or non-removable (auxiliary) groups.

1.3.1. Non-removable directing groups

In particular, nitrogen and oxygen-bearing structural units have been most extensively utilized for transition-metal catalyzed C−H bond cleavage (Scheme 1.10).

Scheme 1.10

Especially, nitrogen played a vital role in chelation-induced activation reactions.

For example, pyridine was one of the classic directing groups, and the types of reactions performed on 2-phenylpyridines range from C−C bond forming reactions

such as arylation with aryl halides,¹⁸ hypervalent iodine reagents¹⁹ or arenes,²⁰ oxidative Heck reactions or alkylation with organoboron,²¹ to carbon-heteroatom (C−X) bond formation such as halogenation,²² acetoxylation²³ or fluorination.²⁴ For example, the pyridine moiety in 2-phenylpyridine was discovered by Sanford and co- workers to be an efficient directing group for Pd(OAc)2-catalyzed ortho-acetoxylation using PhI(OAc)2 as stoichiometric oxidant (Scheme 1.11).²³ This reaction was proposed to proceed through a Pd^II/Pd^IV catalytic cycle where the hypervalent iodine reagent oxidized a cyclometallated Pd^II intermediate to Pd^IV species from which C−O beyond-forming reductive elimination released the product.

18 a) D. Shabashov, O. Daugulis, Org. Lett. 2005, 7, 3657; b) L. Ackermann, A. Althammer, R. Born, Synlett 2007, 2833.

19 D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford, J. Am. Chem. Soc. 2005, 127, 7330.

20 K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904.

21 a) X. Chen, C. E. Goodhue, J. Q. Yu, J. Am. Chem. Soc. 2006, 128, 12634; b) B. F. Shi, N. Maugel, Y. H. Zhang, J. Q. Yu, Angew. Chem., Int. Ed. 2008, 47, 4882.

22 a) A. R. Dick, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2004, 126, 2300; b) D. Kalyani, M. S.

Sanford, Org. Lett. 2005, 7, 4149; c) D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford, Org. Lett.

2006, 8, 2523; d) D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford, Tetrahedron 2006, 62, 11483.

23 A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62, 2439.

24 a) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem. Soc. 2006, 128, 7134. For a review on catalysis for C−H fluorination and trifluoromethylation, see: b) T. Furuya, A. S. Kamlet, Tobias Ritter, Nature, 2011, 471, 470.

Scheme 1.11

1.3.2. Removable, auxiliary directing groups

The use of pyridine and similar structures as directing group to functionalize C−H bonds is restricting from a practical standpoint since many molecules of interest do not contain such directing group or its further manipulation requires extensive destruction of the core structure.²⁵ To overcome this problem, temporary auxiliary directing groups that are easily removable after C−H functionalization have recently emerged.

Important criteria for the efficiency of such catalyst-directing groups are: i) ease of installation of the directing group; ii) efficient control over the reactivity/selectivity;

and iii) ease of removal from the substrate.

To avoid or minimize the impact of the requirement of two extra unproductive steps involving the installation and removal of the directing group from the substrate, in some cases the directing group is also a protecting group (with dual protecting/directing role) or a source of chemical diversity, allowing its further transformation into new functionalities. This concept will be illustrated below with some remarkable examples extracted from the literature.

25 A. M. Kearney, C. D. Vanderwal, Angew. Chem., Int. Ed. 2006, 45, 7803.

Daugulis and co-workers have demonstrated that a carboxylate substituent may be used as a directing group in the direct palladium-catalyzed ortho-arylation of free benzoic acids (Scheme 1.12).²⁶ The possibility of a subsequent decarboxylation step makes this sequence synthetically equivalent to the regioselective arylation of unfunctionalized arenes. Likewise, it offers the possibility of a tandem reaction development by using carboxylate functionality in subsequent Heck and Suzuki couplings.

Scheme 1.12

The use of an aryl iodide as the coupling partner required stoichiometric amounts of silver acetate for iodide removal in acetic acid as solvent. This method was applicable to the arylation of electron-rich to moderately electron-poor benzoic acids and tolerated chloride and bromide substituents on both coupling partners. This method most likely proceeded through a Pd^II-Pd^IV coupling cycle.

The coupling with aryl chlorides was effected in the presence of cesium carbonate as base, n-butyl-di-1-adamantylphosphine as ligand (BuAd2P), in DMF as solvent. This protocol was suitable for both electron-rich and electron-poor benzoic

26 H. A. Chiong, Q.-N. Pham, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 9879.

acids and mechanistic studies pointed toward the heterolytic C−H bond cleavage as the turnover-limiting step.

Importantly, it was demonstrated that the arylation products could be decarboxylated using the method developed by Goossen and co-workers,²⁷ in the presence of CuO/quinoline in NMP (Scheme 1.13).

Scheme 1.13

Yu and co-workers as well as Miura and co-workers have also used carboxylic acids and their salts as highly effective directing groups for both Pd- and Rh- catalyzed C−H activation.²⁸

The dialkylhydrosilyl function has been devised by Hartwig and Boebel as an auxiliary directing group in the Ir-catalyzed ortho-borilation of arenes, phenols and N- alkylanilines.²⁹ The reaction occurs with complete ortho-regiocontrol in all cases under the conditions depicted in Scheme 1.14. The mechanism implied the formation of an Ir−Si bond rather than the formation of a silaborane intermediate. The directing group could be removed upon exposure to a source of fluoride ions.

27 a) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662: For a review, see: b) L. J.

Goossen, N. Rodríguez, Chem. Soc. Rev. 2011, 40, 5030.

28 a) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B. Saunders, J.-Q Yu, J. Am. Chem.

Soc. 2007, 129, 3510; b) A. Maehara, H. Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008, 10, 1159; c) M.

Yamashita, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2009, 11, 2337; d) S. Mochida, K. Hirano, T.

Satoh, M. Miura, Org. Lett. 2010, 12, 5776; e) S. Mochida, K. Hirano, T. Satoh, M. Miura, J. Org.

Chem. 2011, 76, 3024.

29 T. A. Boebel, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 7534.

Scheme 1.14

Also related to this strategy, the groups of Gevorgyan³⁰ and shortly after Ge³¹ reported independently the use of Si−OH group in directed oxidative C−H alkenylation. Gevorgyan and co-workers equipped phenols with a silanol group and the Pd^II-catalyzed ortho-alkenylation proceeded in good to excellent yields adopting the previously described Yu’s conditions (Scheme 1.15).³² The silanol group was removed with TBAF to afford ortho-alkenylated phenols. Owing to the steric demand of the silicon atom decorated with two tert-butyl groups, the regioselectivity was complete even for unsymmetrically substituted phenols. Not surprisingly, electron-rich arenes and electron-poor alkenes were the optimal combination.

30 a) C. Huang, B. Chattopadhyay, V. Gevorgyan, J. Am. Chem. Soc. 2011, 133, 12406. For a silanol- directed C−H oxygenation, see: C. Huang, N. Ghavtadze, B. Chattopadhyay, V. Gevorgyan, J. Am.

Chem. Soc. 2011, 133, 17630.

31 C. Wang, H. Ge, Chem. Eur. J. 2011, 17, 14371.

32 Y. Lu, D.-H. Wang, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 5916.

Scheme 1.15

Ge and co-workers described a related Pd^II-catalyzed alkenylation of toluene- derived silanols (Scheme 1.16).³¹ Yields were generally good and the scope ranged from electron-rich to electron-poor arenes. The reaction worked efficiently when electron-poor alkenes were used as coupling partners. Smooth “deprotection” of the alkenylated benzylic silanols yielded the parent toluenes.

Scheme 1.16

Directing groups based in a coordinating nitrogen-atom are very common in C−H functionalization reactions. For example, 2-pyrazol-5-ylaniline (pza-H2) has been used as an easily attachable and detachable directing group for the ortho-C−H functionalization of aromatic organoboronic acids. Suginome and co-workers reported a one-pot procedure for the Ru-catalyzed ortho-C-H silylation of arylboronic acids with triethylsilane. The reaction took place with good yields and complete regiocontrol (Scheme 1.17).³³ It tolerated aromatic systems bearing both electron-donating or electron-withdrawing substituents. The auxiliary directing group was easily introduced by condensation of the boronic acid with the 2-pyrazol-5-ylaniline and was efficiently removed from the final products under acidic conditions.

Scheme 1.17

In 2006, Sames and co-workers described a ruthenium-catalyzed α-arylation of 2-substituted pyrrolidines and piperidines with aryl boronic esters based on the use of an amidine directing group (Scheme 1.18).³⁴

33 H. Ihara, M. Suginome, J. Am. Chem. Soc. 2009, 131, 7502.

34 S. J. Pastine, D. V. Gribkov, D. Sames, J. Am. Chem. Soc. 2006, 128, 14220.

Scheme 1.18

The directing group facilitated the insertion of the ruthenium metal into the C(sp³)−H bond. The resulting metal hydride was then transformed into the corresponding metal-aryl complex via a metal-alkoxide intermediate (Scheme 1.19).

The final reductive elimination generated the C−C bond in the product and regenerated the ruthenium catalyst. A wide range of aryl and heteroaryl boronic esters were compatible with the reaction conditions employed. Although good yields and diastereoselectivities were obtained with pyrrolidine substrates, extension of this method to piperidine systems was less successful. Removal of the amidine function from the product was possible although using rather harsh conditions.

Scheme 1.19

The metal-coordinating 2-pyridyl unit has been widely employed as directing group in many transition metal-catalyzed transformations.³⁵ For example, Yoshida and co-workers has shown the efficiency of the dimethyl(2-pyridyl)silyl group in a vast variety of functionalizations.³⁶ More recently, Gervorgyan and co-workers have illustrated that the pyridyldiisopropylsilyl (PyDipSi) group was an efficient silicon- tethered directing group to allow the efficient palladium(II)-catalyzed functionalization of aromatic C−H bonds (Scheme 1.20).

In particular, it proved to be very efficient in the ortho-acetoxylation/pivaloxylation and ortho-halogenation of arenes. The reaction in the presence of 2.0 equiv of PhI(OR)₂ (R = Ac, Piv), in combination with AgOAc as bystanding oxidant system, provided a variety of acetoxylated and pivaloxylated aromatic compounds in good yields and excellent regiocontrol (Scheme 1.20a).³⁷ On the other hand, the combination of PhI(OAc)2 (1.5 equiv) with 2.0 equiv of NXS (X = Cl, Br, I) furnished the corresponding ortho-halogenated arenes with excellent levels of reactivity and selectivity (Scheme 1.20b).³⁸ This directing group could efficiently be “traceless”

cleaved by treatment with AgF in methanol, or converted into a variety of other functional groups such as iodide or boronates. Also, the pyridyldiisopropylsilyl (PyDipSi) group was used in the Hiyana-Denmark-type cross-coupling reaction with iodoarenes, providing the access to biaryl derivatives.

35 For selected examples related to 2-pyridyl protecting group in transition metal-catalyzed reactions, see: a) S. Nakamura, H. Nakashima, H. Sugimoto, N. Shibata, T. Toru, Tetrahedron Lett. 2006, 47, 7599; b) S. Nakamura, H. Sano, H. Nakashima, K. Kubo, N. Shibata, T. Toru, Tetrahedron Lett. 2007, 48, 5565; c) H. Tatamidani, K. Yokota, F. Kakiuchi, N. Chatani, Org. Lett. 2006, 8, 2519; d) P. H. Bos, A. J. Minnaard, B. L. Feringa, Org. Lett. 2008, 10, 4219; e) P. H. Bos, B. Macia, M. A. Fernández- Ibáñez, A. J. Minnaard, B. L. Feringa, Org. Biomol. Chem. 2010, 8, 47; f) J.-N. Desrosiers, W. S.

Bechara, A. B. Charette, Org. Lett. 2008, 10, 2315.

36 For a general review: a) K. Itami, K. Mitsudo, T. Nokami, T. Kamei, T. Koike, J.-I. Yoshida, J.

Organomet. Chem. 2002, 653, 105. For recent examples: b) T. Kamei, K. Itami, J.-I. Yoshida, Adv.

Synth. Catal. 2004, 346, 1824; c) K. Itami, Y. Ohashi, J.-I. Yoshida J. Org. Chem. 2005, 70, 2778.

37 N. Chernyak, A. S. Dudnik, C. Huang, V. Gevorgyan, J. Am. Chem. Soc. 2010, 132, 8270.

38 A. S. Dudnik, N. Chernyak, C. Huang, V. Gevorgyan, Angew. Chem. Int. Ed. 2010, 49, 8729.

Scheme 1.20

As another example of a directing group bearing a pyridine unit, Chatani and co- workers reported the first example of a catalyst system based on nickel that took advantage of chelation assistance. This work described the use of the N-(2- pyridyl)methyl directing group in the Ni-catalyzed oxidative cycloaddition of aromatic amides with alkynes (Scheme 1.21, a).³⁹ The same concept has been extended to the carbonylation of non-activated C(sp³)−H of aliphatic amides, in this case using Ru₃(CO)₁₂ as the catalyst (Scheme 1.21, b).⁴⁰ The activation of methyl groups was favoured over methylenes, and the reaction featured a wide functional group tolerance. In both transformations, the 2-pyridylmethylamino unit was crucial for the reaction to proceed due to its coordination to the metal through the nitrogen atoms of both pyridyl and amide functions. The final removal of the directing group was effected by reaction with LDA followed by bubbing O2 and hydrolysis to afford the NH- quinolone.

39 H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2011, 133, 14952.

40 N. Hasegawa, V. Charra, S. Inoue, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2011, 133, 8070.

Scheme 1.21

More recently, in 2012, Huang and co-workers reported that triazenes were a class of effective directing groups for oxidative Heck coupling reactions (Scheme 1.22).⁴¹ The presence of two electronegative nitrogen atoms contiguous to the C−N bond attached to the arene attenuates the directing group-substrate bonding, thereby allowing its easy cleavage under ambient conditions and enabling a number of synthetic manipulations.^42,43 Removal of this directing group was achieved by

41 C. Wang, H. Chen, Z. Wang, J. Chen, Y. Huang, Angew. Chem. Int. Ed. 2012, 51, 7242.

42 For an account on this chemistry, see: C. Wang, Y. Huang, Synlett 2013, 24, 145.

43 Independently, the ortho-selective trifluoromethylation of phenyltriazenes with AgCF3 has been recently reported: A. Hafner, S. Bräse, Angew. Chem. Int. Ed. 2012, 51, 3713.

treatment with BF3

.OEt2 at room temperature, yielding the corresponding Ar−H in quantitative yields.

Scheme 1.22

1.4. Precedents of our research group

In 2004 our research group started a new research line oriented to explore the potential of heteroarylsulfonyl groups (especially the 2-pyridylsulfonyl group) as temporary auxiliary directing groups in transition metal-catalyzed reactions. It was rapidly found that this group promoted a dual effect: i) it usually enhanced the reactivity and selectivity of the process by means of pre-association of the metal- catalyst to the N-pyridyl unit, and ii) after the reaction, the sulfonyl group could be readily removed under mild conditions.

Along this line, a pioneering example was the development of a chelation- assisted, transition metal-catalyzed protocol for the sequential multiarylation of cyclic allyl sulfones. As shown in Scheme 1.23, the metal-coordinating ability of the 2- pyridyl group on the sulfone promoted the otherwise difficult intermolecular Heck monoarylation and diarylation of trisubstituted alkenes, as well as the copper- catalyzed allylic arylation with Grignard reagents.^44,45 The role of the metal

44 T. Llamas, R. Gómez Arrayás, J. C. Carretero, Adv. Synth. Catal. 2004, 346, 1.

coordinating 2-pyridylsulfonyl group was crucial to accomplish this goal, as proven by the fact that the corresponding tosyl or phenyl sulfonyl derivatives were inert in this reaction, even under harsh reaction conditions.

Scheme 1.23

On the other hand, combining the N-(2-pyridyl)sulfonyl group as directing group with a chiral organometallic catalyst has led to the development of new asymmetric catalytic processes. Thus, our research group described in 2004 the first catalytic protocol for the enantioselective conjugated addition of carbon nucleophiles to α,β- unsaturated sulfones.⁴⁶ An exhaustive screening of different directing groups confirmed that N-(2-pyridyl)sulfonyl was optimal for the Rh-catalyzed conjugated addition of boronic acids to vinyl sulfones using (S,S)-Chiraphos as the most appropriate chiral ligand. The products were all isolated with excellent yields and high enantiomeric excesses (76-92% ee, Scheme 1.24). The method could be applied to E- and Z-substrates and tolerated a wide variety of substituents at the β-position to

45 For the Heck arylation of α,β-insaturated 2-(N,N-dimethylamino)phenyl sulfones, see: a) P.

Mauleón, I. Alonso, J. C. Carretero, Angew. Chem. Int. Ed. 2001, 40, 1291; b) P. Mauleón, A. A.

Nuñez, I. Alonso, J. C. Carretero, Chem. Eur. J. 2003, 9, 1511; c) I. Alonso, M. Alcami, P. Mauleón, J.

C. Carretero, Chem. Eur. J. 2006, 12, 4576. For the reaction of N-(2-pyridyl)sulfonyl azabenzonorbornadienes with cuprates, see: d) R. Gómez Arrayás, S. Cabrera, J. C. Carretero, Org.

Lett. 2005, 7, 219; e) R. Gómez Arrayás, S. Cabrera, J. C. Carretero, Synthesis 2006, 1205.

46 a) P. Mauleón, J. C. Carretero, Org. Lett. 2004, 6, 3195; b) P. Mauleón, I. Alonso, M. Rodríguez Rivero, J. C. Carretero, J. Org. Chem. 2007, 72, 9924.

the sulfone, as well as in the boronic acid. The elimination of the 2-pyridylsulfonyl group through a Julia-Kocienski-type reaction opened a new path to optically active alkenes substituted at the allylic position. This methodology has been extended to the construction of stereogenic quaternary centers through the enantioselective addition of boronic acids to α,β-unsaturated-β,β-disubstituted-(2-pyridyl)sulfones (88-99%

ee).⁴⁷

Scheme 1.24

Another important reaction that rivalizes with the asymmetric conjugate addition is the Cu-catalyzed conjugate reduction of β,β-disubstituted Michael-type acceptor olefins. Since the first protocol described by Buchwald and workers in 1999,⁴⁸ this reaction has experienced a dramatic growth, being applied to a variety of α,β^- unsaturated carbonyl compounds.⁴⁹ Our group has been pioneer on incorporating vinyl sulfones into the arsenal of electrophiles that efficiently participates in this process.⁵⁰ Again, the use of the N-(2-pyridyl)sulfonyl group was key to overcome the weaker Michael acceptor character that characterizes the vinyl sulfones in comparison to the corresponding α,β-unsaturated dicarbonylic compounds (Scheme

47 P. Mauleón, J. C. Carretero, Chem. Commun. 2005, 4961.

48 D. H. Apella, Y. Moritani, R. Shintani, E. M. Ferreira, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 9473.

49 For a review in the topic, see: S. Rendler, M. Oestreich, Angew. Chem. Int. Ed. 2007, 46, 498.

50 T. Llamas, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2007, 46, 3329.

1.25). In fact, analogues phenyl vinyl sulfones proved to be inert under the optimized reaction conditions. The use of CuCl/tBuONa/(R)-BINAP as the chiral catalytic system (5 mol%) and PhSiH3 as hydride source allowed the reduction of a broad range of β^-alkyl-β-aryl-substituted and β,β-dialkyl-substituted α,β-unsaturated 2- pyridylsulfones in excellent chemical yields and with excellent enantioselectivities (typically 90–94% ee). These enantioenriched sulfones were versatile intermediates in the preparation of a wide variety of functionalized chiral compounds.

Scheme 1.25

This concept has been extended to reactions of coordinating N- (heteroaryl)sulfonyl imines. These new electrophiles have proven to be extremely reactive compared to traditional N-tosyl imines. An example of this strategy has been the development of a very general protocol for the synthesis of diaryl amines and dialkyl amines based on the Friedel-Crafts reaction of N-(2-pyridyl)sulfonyl imines with electron-rich aromatic and heteroaromatic compounds (Scheme 1.26).⁵¹ In this reaction, the presence of the coordinating group was essential for stopping the process in the mono-addition product, whereas the analogue N-Ts or N-aryl imines provided exclusively the double addition products under identical conditions.⁵² The scope of the reaction was very broad with regard to both imine and nucleophile

51 J. Esquivias, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2006, 45, 629.

52 For selected examples, see: a) J. Hao, S. Taktak, K. Aikawa, Y. Yusa, M. Hatano, K. Mikami, Synlett 2001, 1443; b) B. Ke, Y. Qin, Q. He, Z. Huang, F. Wang, Tetrahedron Lett. 2005, 46, 1751.

components, tolerating a wide variety of aromatics and heteroaromatics derivatives.

The deprotection of the sulfonamides was very efficient under mild conditions.

This method allowed an in situ second electrophilic aromatic substitution with a different nucleophilic arene species (Ar³−H) promoted by the same Lewis acid catalyst. This sequential addition of two arenes to the N-(2-pyridyl)sulfonyl imine constituted the first one-pot synthesis of unsymmetrical triarylmethanes. DFT theoretical studies of the second Friedel-Crafts reaction have shown that the different reactivity of the N-(2-pyridyl)sulfonyl imine could be due to the different coordinating mode of this imine to the metal, in comparison to the typical N-tosyl derivatives.⁵³

Scheme 1.26

The same strategy has been applied to the development of the first general protocol for the direct alkylation of imines with alkylzinc halides.⁵⁴ This type of alkylating reagents is very attractive because of their easy preparation, high compatibility with a wide variety of functional groups and easy availability. However,

53 I. Alonso, J. Esquivias, R. Gómez-Arrayás, J. C. Carretero, J. Org. Chem. 2008, 73, 6401.

54 J. Esquivias, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2007, 46, 9257.

their attenuated nucleophilic character has hampered their addition to imines.⁵⁵ In the presence of a catalytic amount of Cu(OTf)2 (1-5 mol%) the N-(2-pyridyl)sulfonyl imines of aromatic and heteroaromatic aldehydes shown unprecedented high reactivity towards the direct addition of a wide variety of alkyl zinc bromide reagents (Scheme 1.27). The N,N-bidentate character of 2-pyridylsulfonyl imines with respect to metal coordination was proven by an X-ray crystallographic study of the Cu^I complex of the N-(2-pyridyl)sulfonyl imine of chalcone, and it was suggested as the origin of the exceptional reactivity displayed by these substrates. The deprotection of the sulfonamide group took place under mild reductive conditions, compatible with many sensitive functional groups.

Scheme 1.27

The high reactivity offered by the N-(8-quinolyl)sulfonyl group led to the development of the first example of catalytic asymmetric inverse-electron-demand

55 Our group has also described the copper-catalyzed asymmetric conjugate addition of dialkyl zinc reagents with α,β−insaturated ketimines (80-90% yield, 70-80% ee): J. Esquivias, R. Gómez Arrayás, J. C. Carretero J. Org. Chem. 2005, 68, 8120.

Diels-Alder reaction of N-sulfonyl-1-aza-1,3-dienes.⁵⁶ Up to that date, this reaction required harsh conditions (high temperatures and high pressure) due to the low reactivity of the 1-azadienes. This hampered the development of asymmetric versions.⁵⁷ Among the numerous chiral catalysts employed, the combination of Ni(ClO4)2·6H2O/DBFOX-Ph (10 mol%) provided the best results, affording the corresponding piperidines in good yields, with excellent endo-selectivity and high enantioselectivities (typically in the range of 80-91% ee, Scheme 1.28).

Scheme 1.28

The Cu^I-Fesulphos-catalyzed (10 mol%) asymmetric Mannich reaction of glycinate Schiff bases with N-(8-quinolyl)sulfonyl imines was reported by our group as an efficient approach to α,β−diamino esters (Scheme 1.29).⁵⁸ This type of amino acids are very attractive targets in organic synthesis because of their wide range

56 J. Esquivias, R. Gómez Arrayás, J. C. Carretero, J. Am. Chem. Soc. 2007, 129, 1480.

57 The presence of an ester group in the 4-position of the 1-azadiene has allowed the development of a catalytic versión of the process using chiral auxiliaries: R. C. Clark, S. S. Pfeiffer, D. L. Boger, J.

Am. Chem. Soc. 2006, 128, 2587.

58 J. Hernández-Toribio, R. Gómez Arrayás, J. C. Carretero, J. Am. Chem. Soc. 2008, 130, 16150.

biological significance and high versatility as synthetic building blocks.⁵⁹ A thorough study on the influence of the imine protecting group in the reaction outcome revealed the superiority of the 8-quinolylsulfonyl group over the N-Boc and other N-arylsulfonyl or N-heteroarylsulfonyl moieties.

Up to date, a major limitation of the previous approaches was that they were applicable only for the selective preparation of syn-configured products. This important limitation was solved independently by the group of Hou⁶⁰ and ours. An additional distinctive feature of our catalyst system was that it allowed the construction of α,β-diaminoacids with a tetrasubstituted carbon stereocenter at C-α in a highly diastereo- and enantiocontrolled manner. A variety of aryl and heteroaryl aldimines, including the challenging imine derived from 3-pyridinecarboxaldehyde, proved to be excellent electrophilic substrates. The sequential amino deprotection of the α,β-aminoester adducts could be effected under mild conditions and reasonable yields.

Scheme 1.29

59 a) A. Viso, R. Fernández de la Pradilla, A. García, A. Flores, Chem. Rev. 2005, 105, 3167; b) A.

Ting, S. E. Schaus, Eur. J. Org. Chem. 2007, 5797; c) R. Gómez Arrayás, J. C. Carretero, Chem.

Soc. Rev. 2009, 38, 1940.

60 X.-X. Yan, Q. Peng, Q. Li, K. Zhang, J. Yao, X.-L. Hou, Y.-D. Wu, J. Am. Chem. Soc. 2008, 130, 14362.

The modification of the steric and electronic properties of the α-iminoester used as starting materials made possible the inversion of the diastereoselectivity (from anti to syn), keeping the high asymmetric induction of the process. Accordingly, it was achieved the access to α,β-diamino acid derivatives of syn configuration with high diastereoselectivities and enantiomeric excesses, starting from ketimines (instead of aldimines) from the glycinate derivatives of benzophenones poor in electrons (Scheme 1.30).⁶¹

Scheme 1.30

Very recently, our group has demonstrated that the activating effect of the 2- pyridylsulfonyl unit (and related sulfur-based groups) in metal-mediated reactions could be applied to challenging Pd-catalyzed C−H activation processes. This concept was first investigated in the Pd^II-catalyzed regioselective C2-alkenylation of N-(2- pyridyl)sulfonyl indoles and pyrroles.⁶² The coordinating ability of the N-(2- pyridyl)sulfonyl group was critical for inducing C−H activation with complete regiocontrol at the less favoured C2-position, likely through formation of the palladacycle I (Scheme 1.34). For instance, the N-Ts protected indole led to less than 20% conversion under identical conditions, whereas the low conversion and

61 J. Hernández-Toribio, R. Gómez Arrayás, J. C. Carretero, Chem. Eur. J. 2010, 16, 1153.

62 A. García-Rubia, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2009, 48, 6511.

regiocontrol observed for the 3-pyridylsulfonyl group made unlikely the high reactivity and selectivity observed to originate from electronic effects.

Both, electron-poor and non-activated alkenes were applicable, with the participation of 1,2-disubstituted alkenes and 1,3-dienes being particularly noteworthy. On the other hand, both electron-withdrawing and electron-donating substituents were tolerated at different positions of the indole core (Scheme 1.31)

Scheme 1.31

This method was also applicable to the functionalization of pyrroles (Scheme 1.32). Monosubstituted, disubstituted, as well as unsymmetrical 2,5-disubstituted pyrroles could be obtained by small variations in the reaction conditions (temperature and reaction time).

Scheme 1.32

Removal of the N-(2-pyridyl)sulfonyl group from indoles and pyrroles was readily achieved by reductive cleavage with Zn or Mg to give 2-alkenyl- or 2-alkyl-substituted heteroarenes, respectively (Scheme 1.33).

Scheme 1.33

In an attempt to isolate the presumed palladacycle intermediate (type I or related species), the N-(2-pyridyl)sulfonyl indole 1 was heated (60 ºC) with 1.2 equiv of

Pd(OAc)2 in AcOH for 18 h. Instead of the palladacycle, the 2,2’-biindolyl 2 was cleanly formed and isolated in 71% yield (Scheme 1.34). We speculated that due to the facile C2-palladation in the absence of the alkene component, the palladacycle I evolved by formation of a C2-palladated bi-indolyl intermediate II which would afford 2 via reductive elimination.

Scheme 1.34