Catalyzed Carbon-Heteroatom Bond Formation E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 620

Veröffentlichungsjahr: 2010

Beschreibung

Written by an experienced editor widely acclaimed within the scientific community, this book covers everything fromo9xygen to nitrogen functionalities.

From the contents:

• Palladium-Catalyzed Syntheses of Five-Member Saturated Heterocyclic and of Aromatic Heterodynes
• Palladium-Catalysis for Oxidative 1, 2-Difunctionalization of Alkenes
• Rhodium-Catalyzed Amination of C-H-Bonds
• Carbon-Heteroatom Bond Formation by RH(I)-Catalyzed Ring-Opening Reactions
• Transition Metal-Catalyzed Synthesis of Lactones and of Monocyclic and Fused Five-Membered Aromatic heterocycles
• the Formation of Carbon-Sulfur and Carbon-Selenium bonds by Substitution and Addition reactions catalyzed by Transition Metal Complexes
• New Reactions of Copper Acetylides
• Gold Catalyzed Addition of Nitrogen, Sulfur and Oxygen Nucleophiles to C-C Multiple Bonds.

The result is an indispensable source of information for the Strategic Planning of the Synthetic routes for organic, catalytic and medicinal chemists, as well as chemists in industry.

Leseprobe

The Editor

Prof. Andrei K. Yudin

University of Toronto

Department of Chemistry

St. George Street 80

Toronto, ON M5S 3H6

Canada

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ISBN: 978-3-527-32428-6

Further Reading

Nugent, T. C. (Ed.)

Chiral Amine Synthesis

Methods, Developments and Applications

2010

ISBN: 978-3-527-32509-2

Ricci, A. (Ed.)

Amino Group Chemistry

From Synthesis to the Life Sciences

2008

ISBN: 978-3-527-31741-7

Bäckvall, J.-E. (Ed.)

Modern Oxidation Methods

2011

ISBN: 978-3-527-32320-3

Bandini, M., Umani-Ronchi, A. (Eds.)

Catalytic Asymmetric Friedel-Crafts Alkylations

2009

ISBN: 978-3-527-32380-7

Bullock, R. M. (Ed.)

Catalysis without Precious Metals

2010

ISBN: 978-3-527-32354-8

Drauz, K., Gröger, H., May, O. (Eds.)

Enzyme Catalysis in Organic Synthesis

2011

ISBN: 978-3-527-32547-4

Royer, J., Husson, H. P. (Eds.)

Asymmetric Synthesis of Nitrogen Heterocycles

2009

ISBN: 978-3-527-32036-3

Dupont, J, Pfeffer, M. (Eds.)

Palladacycles

Synthesis, Characterization and Applications

2008

ISBN: 978-3-527-31781-3

Plietker, B. (Ed.)

Iron Catalysis in Organic Chemistry

Reactions and Applications

2008

ISBN: 978-3-527-31927-5

Contents

Cover

Title Page

Copyright

Further Reading

Preface

List of Contributors

1 Synthesis of Saturated Five-Membered Nitrogen Heterocycles via Pd-Catalyzed C–N Bond-Forming Reactions

1.1 Introduction

1.2 Pd-Catalyzed Amination of Aryl Halides

1.3 Synthesis of Saturated Nitrogen Heterocycles via Alkene, Alkyne, or Allene Aminopalladation Reactions

1.4 Synthesis of Nitrogen Heterocycles via Intermediate π-Allylpalladium Complexes

1.5 Synthesis of Nitrogen Heterocycles via Pd-Catalyzed 1,3-Dipolar Cycloaddition Reactions

1.6 Synthesis of Nitrogen Heterocycles via Carbonylative Processes

1.7 Summary and Future Outlook

References

2 Transition Metal Catalyzed Approaches to Lactones Involving C–O Bond Formation

2.1 Introduction

2.2 Synthesis of Lactones Involving CO

2.3 Synthesis of Lactones via C=C and C≡C Addition

2.4 Synthesis of Lactones via C=O Hydroacylation

2.5 Miscellaneous Syntheses of Lactones

2.6 Conclusions and Outlook

References

3 The Formation of Csp2–S and Csp2–Se Bonds by Substitution and Addition Reactions Catalyzed by Transition Metal Complexes

3.1 Introduction

3.2 Catalytic Cross-Coupling Reactions

3.3 Catalytic Addition of RZ–ZR Derivatives to Alkynes (ZS, Se)

3.4 Catalytic Addition of RZ-H Derivatives to Alkynes (ZS, Se)

3.5 Conclusions

References

4 Palladium Catalysis for Oxidative 1,2-Difunctionalization of Alkenes

4.1 Introduction

4.2 Palladium-Catalyzed 1,2-Difunctionalization Reactions: Halogenation

4.3 Aminohalogenation Reactions

4.4 Dialkoxylation

4.5 Aminoacetoxylation Reactions

4.6 Diamination Reactions

4.7 Conclusion

References

5 Rhodium-Catalyzed C–H Aminations

5.1 Metal Nitrenes from Iminoiodinanes

5.2 Metal Nitrenes from N-Tosyloxycarbamates

References

6 The Palladium-Catalyzed Synthesis of Aromatic Heterocycles

6.1 Introduction

6.2 Palladium π-Lewis Acidity: Intramolecular Nucleophilic Attack on Unsaturated Bonds

6.3 Palladium-Catalyzed Carbon–Heteroatom Bond Forming Reactions

6.4 Palladium-Catalyzed Carbon–Heteroatom Bond Formation with Alkynes

6.5 Heck Cyclizations

6.6 Palladium Catalyzed C–H Bond Activation

6.7 Multicomponent Coupling Reactions

6.8 Summary and Outlook

References

7 New Reactions of Copper Acetylides: Catalytic Dipolar Cycloadditions and Beyond

7.1 Introduction

7.2 Azide–Alkyne Cycloaddition: Basics

7.3 Copper-Catalyzed Cycloadditions

References

8 Transition Metal-Catalyzed Synthesis of Monocyclic Five-Membered Aromatic Heterocycles

8.1 Introduction

8.2 Monocyclic Five-Membered Heterocycles

8.3 Conclusion

8.4 Abbreviations

References

9 Transition Metal-Catalyzed Synthesis of Fused Five-Membered Aromatic Heterocycles

9.1 Introduction

9.2 Fused Five-Membered Heterocycles

9.3 Conclusion

9.4 Abbreviations

References

10 Carbon–Heteroatom Bond Formation by RhI-Catalyzed Ring-Opening Reactions

10.1 Introduction

10.2 Ring-Opening meso-Oxabicyclic Alkenes with Oxygen-Based Nucleophiles

10.3 Ring-Opening meso-Oxabicyclic Alkenes with Nitrogen-Based Nucleophiles

10.4 Ring-Opening meso-Azabicyclic Alkenes with Nitrogen-Based Nucleophiles

10.5 Ring-Opening meso-Oxabicyclic Alkenes with Sulfur-Based Nucleophiles

10.6 Mechanistic Model

10.7 Ring-Opening Unsymmetrical Oxa- and Aza-bicyclic Alkenes with Heteroatom Nucleophiles

10.8 Ring-Opening of Vinyl Epoxides with Heteroatom Nucleophiles

10.9 Conclusion

Acknowledgment

References

11 Gold-Catalyzed Addition of Nitrogen and Sulfur Nucleophiles to C–C Multiple Bonds

11.1 Introduction

11.2 Addition of Nitrogen Nucleophiles to Alkynes

11.3 Hydroamination of Allenes

11.4 Hydroamination of Alkenes and Dienes

11.5 Addition of Sulfur Nucleophiles to C–C Multiple Bonds

References

12 Gold-Catalyzed Addition of Oxygen Nucleophiles to C–C Multiple Bonds

12.1 Introduction

12.2 Addition to Alkynes

12.3 Addition to Allenes

12.4 Addition to Alkenes

References

Index

Preface

Metal catalyzed carbon-heteroatom bond forming processes constitute a vibrant area of research that continues to serve as an unmatched source of challenges. The cover of the book you hold in your hands provides a pictorial representation of a typical landscape in transition metal catalysis. The roads connecting the carbon center with heteroatoms depict catalyzed pathways. These roads are often indirect, they go via valleys and they climb over steep hills. There is almost always more than one way to connect the nodes on this map. Continuing effort in this important area is a testament to how difficult finding an optimal solution to a given bond forming reaction really is. I owe a great deal of gratitude to an outstanding cast of authors who wrote 11 outstanding chapters you will find in this book. I am grateful to these individuals for agreeing to participate in this important undertaking and for delivering superb and comprehensive chapters. I would also like to express gratitude to my students, Igor Dubovyk and Lawrence Cheung, for proof reading some of the chapters.

Andrei Yudin

May 2010

Toronto, Canada

List of Contributors

Valentine P. Ananikov

Russian Academy of Sciences

Zelinsky Institute of Organic Chemistry

Leninsky Prospect 47

Moscow 119991

Russia

Bruce A. Arndtsen

McGill University

Department of Chemistry

801 Sherbrooke Street

West Montreal, QC H3A 2K6

Canada

Irina P. Beletskaya

Lomonosov Moscow State University

Chemistry Department

Vorob'evy gory

Moscow 119899

Russia

Vy M. Dong

University of Toronto

Department of Chemistry

80 St. George Street

Toronto, Ontario

Canada M5S 3H6

Peter K. Dornan

University of Toronto

Department of Chemistry

80 St. George Street

Toronto, Ontario

Canada M5S 3H6

Alexander S. Dudnik

University of Illinois at Chicago

Department of Chemistry

845 West Taylor Street, 4500 SES,

M/C 111

Chicago, IL 60607-7061

USA

Matthew J. Fleming

Solvias AG

Chemical Development and Catalysis Dept.

P.O. Box

4002

Basel

Switzerland

Valery V. Fokin

The Scripps Research Institute

Department of Chemistry

10550 North Torrey Pines Road

La Jolla, CA 92037

USA

Vladimir Gevorgyan

University of Illinois at Chicago

Department of Chemistry

845 West Taylor Street, 4500 SES,

M/C 111

Chicago, IL 60607-7061

USA

Béatrice Jacques

University of Strasbourg

Institut de Chimie, UMR 7177

4 Rue Blaise Pascal

67000 Strasbourg Cedex

France

Mark Lautens

University of Toronto

Department of Chemistry

Devenport Chemical Laboratories

80 St. George St.

Toronto, Ontario M5S 3H6

Canada

Hélène Lebel

Université de Montréal

Département de Chimie

2900 Boul Edouard Montpetit

Montreal, Quebec H3T, J4

Canada

Yingdong Lu

McGill University

Department of Chemistry

801 Sherbrooke Street

West Montreal, QC H3A 2K6

Canada

Duy H. Mai

University of Michigan

Department of Chemistry

930 N. University

Ann Arbor, MI 48109-1055

USA

Kilian Muñiz

ICIQ - Institut Català d'Investigació

Química

Avgda. Països Catalans 16

43007 Tarragona

Spain

Joshua D. Neukom

University of Michigan

Department of Chemistry

930 N. University

Ann Arbor, MI 48109-1055

USA

Feijie Song

Duke University

French Family Science Center

Durham, NC 27708-0346

USA

Ross A. Widenhoefer

Duke University

French Family Science Center

Durham, NC 27708-0346

USA

John P. Wolfe

University of Michigan

Department of Chemistry

930 N. University

Ann Arbor, MI 48109-1055

USA

Charles S. Yeung

University of Toronto

Department of Chemistry

80 St. George Street

Toronto, Ontario

Canada M5S 3H6

1

Synthesis of Saturated Five-Membered Nitrogen Heterocycles via Pd-Catalyzed C–N Bond-Forming Reactions

John P. Wolfe, Joshua D. Neukom, and Duy H. Mai

1.1 Introduction

Saturated five-membered nitrogen heterocycles, such as pyrrolidines, indolines, and isoxazolidines, appear as subunits in a broad array of biologically active and medicinally significant molecules [1]. As such, the synthesis of these compounds has been of longstanding interest. Many classical approaches to the construction of these heterocycles involve the use of C–N bond-forming reactions such as reductive amination, nucleophilic substitution, or dipolar cycloaddition for ring closure [2]. Although these methods have proven quite useful, their substrate scope and functional group tolerance is often limited.

In recent years, a number of powerful new transformations have been developed that involve the use of palladium-catalyzed C–N bond-forming reactions for construction of the heterocyclic ring [3]. These transformations frequently occur under mild conditions, tolerate a broad array of functional groups, and proceed with high stereoselectivity. In addition, the use of palladium catalysis allows for highly convergent multicomponent coupling strategies, which generate several bonds and/or stereocenters in a single process. This chapter describes recent approaches to the synthesis of saturated five-membered nitrogen heterocycles via Pd-catalyzed C–N bond forming reactions.

1.2 Pd-Catalyzed Amination of Aryl Halides

One of the most versatile and widely employed methods for the construction of aryl C–N bonds is the palladium-catalyzed cross coupling of amines with aryl halides and related electrophiles [4]. These reactions are believed to occur as shown in Scheme 1.1, with the coupling initiated by oxidative addition of the aryl halide to a Pd0 complex. The resulting intermediate 1 is converted to a palladium(aryl)(amido) complex 2 through reaction with the amine substrate in the presence of base. Finally, C–N bond-forming reductive elimination affords the desired aniline derivative with concomitant regeneration of the palladium catalyst.

Scheme 1.1

Although these reactions are most commonly used for intermolecular C–N bond formation, intramolecular versions of these reactions have occasionally been employed for the synthesis of saturated nitrogen heterocycles [5]. For example, Buchwald has described the synthesis of oxindoles and indolines through intramolecular reactions of aryl halides bearing pendant amines or amides (Eq. (1.1)) [6]. The conditions are amenable to the generation of indoline derivatives bearing amide, carbamate, or sulfonamide protecting groups. A two-flask sequence involving a four-component Ugi reaction followed by an intramolecular N-arylation that affords 3-amino oxindoles has also been developed (Eq. (1.2)) [7], and a number of other nitrogen heterocycles including ureas [8] and indolo[1,2-b]indazoles [9] have been prepared using this method.

(1.1)

(1.2)

Intramolecular Pd-catalyzed or -mediated N-arylation reactions have been employed in the synthesis of several natural products [5]. For example, pyrroloindoline 4, which represents the mitomycin ring skeleton was generated via the intramolecular N-arylation of 3 (Eq. (1.3)) [10]. Other targets generated using this strategy include asperlicin [11], the cryptocarya alkaloids cryptaustoline and cryptowoline [12], and the CPI subunit of CC-1065 [13].

(1.3)

A number of interesting one-pot or two-pot sequences of Pd-catalyzed reactions have been developed that involve intramolecular N-arylation processes [14]. For example, a two flask sequence of Negishi coupling followed by intramolecular C–N bond formation has been employed for the synthesis of substituted indolines (Eq. (1.4)) [14a]. Lautens has recently described an elegant one-flask sequence of intermolecular C–H bond functionalization followed by intramolecular N-arylation for the preparation of substituted indolines [14b]. As shown below (Eq. (1.5)), the Pd-catalyzed coupling of 2-iodotoluene with 2-bromopropylamine 5 in the presence of norbornene provided indoline 6 in 55% yield.

(1.4)

(1.5)

1.3 Synthesis of Saturated Nitrogen Heterocycles via Alkene, Alkyne, or Allene Aminopalladation Reactions

A number of approaches to the synthesis of saturated five-membered nitrogen heterocycles involve alkene, alkyne, or allene aminopalladation as a key step [2b,g]. The aminopalladation step can occur by either outer-sphere anti-aminopalladation or via inner-sphere syn-aminopalladation, and the mechanism can be dependent on substrate structure and reaction conditions. The anti-aminopalladation processes generally involve coordination of the unsaturated moiety to PdII, followed by external attack by a pendant nitrogen nucleophile (e.g., Scheme 1.2, 7 to 8). In contrast, the syn-aminopalladations occur via formation of a palladium amido complex (e.g., 9), which then undergoes migratory insertion of the alkene into the Pd–N bond to provide 10. Heterocycle-forming reactions that proceed via aminopalladation of an unsaturated group can be broadly classified into four categories: (i) oxidative amination reactions of alkenes; (ii) hydroamination reactions of alkenes and alkynes; (iii) carboamination reactions of alkenes, alkynes, and allenes; and (iv) haloamination and diamination reactions of alkenes.

Scheme 1.2

1.3.1 PdII-Catalyzed Oxidative Amination of Alkenes

The first examples of Pd-catalyzed oxidative amination reactions of alkenes were described by Hegedus in 1978 for the construction of indoles [15], and dihydropyrrole derivatives [16]. Although these reactions proceed in good yield with catalytic amounts of palladium, a stoichiometric amount of a co-oxidant, such as benzoquinone (BQ) or CuCl2, was required to facilitate catalyst turnover. In recent years, several groups have explored the extension of this chemistry to the synthesis of saturated nitrogen heterocycles, with a focus on the use of O2 as a mild, environmentally benign co-oxidant. Early advances in this area were reported independently by Larock and Andersson [17]. For example, treatment of 11 with a catalytic amount of Pd(OAc)2 in the presence of O2 in DMSO solvent afforded pyrrolidine 12 in 93% yield (Eq. (1.6)). The oxidative amination reactions are believed to proceed via either syn- or anti-aminopalladation to provide 13, which then undergoes β-hydride elimination to afford the heterocyclic product. The Pd(H)X intermediate is converted to a Pd0 complex via loss of HX, and is then subsequently re-oxidized to PdII by oxygen in the presence of DMSO. This method has also been employed for the generation of indolines and bicyclic pyrrolidines bearing sulfonyl or carbamate protecting groups (Eq. (1.7)) [17, 18].

(1.6)

(1.7)

In recent years, there has been a considerable focus on the development of new reaction conditions that use only molecular oxygen as the co-oxidant and do not require DMSO solvent [19]. Considerable progress has been made through the use of palladium catalysts supported by pyridine or N-heterocyclic carbenes as ligands. For example, Stahl has demonstrated that the 2-allylaniline derivative 14 is transformed to indoline 15 in 79% yield upon treatment with 5 mol% IMesPd(TFA)2 and 10 mol% benzoic acid (Eq. (1.8)) [19d]. Stoltz has reported the conversion of amide 16 to lactam 17 under similar reaction conditions (Eq. (1.9)) [19b]. Through elegant mechanistic studies Stahl has shown that the stereochemistry of the aminopalladation step is dependent on reaction conditions, and both syn- and anti-aminopalladation mechanistic pathways are accessible in oxidative amination reactions [20].

(1.8)

(1.9)

A related approach to the synthesis of nitrogen heterocycles also proceeds via PdII-catalyzed alkene aminopalladation, but involves substrates bearing allylic acetates or allylic hydroxy groups [21, 22]. In contrast to the oxidative amination reactions described above, these transformations are terminated by β-elimination of the acetate or hydroxy group (rather than β-hydride elimination). This approach alleviates the need for added oxidants, but does require the use of slightly more complex substrates. Nonetheless, this method is quite useful, and has been applied to the synthesis of several natural products [23]. In addition, a very interesting approach to the asymmetric synthesis of oxazolidinones involves treatment of tosylcarbamate 18 (generated in situ from the corresponding alcohol) with a catalytic amount of chiral PdII catalyst 21 (Eq. (1.10)) [24]. This reaction affords 19 in 81% yield and 91% ee by way of intermediate 20.

(1.10)

This strategy has also been employed for the synthesis of pyrrolidines [25]. For example, treatment of 22 with 15 mol% PdCl2(PhCN)2 afforded 23 in 77% yield as a single diastereomer (Eq. (1.11)) [25b]. The mild reaction conditions allow cyclization without epimerization of the amino ester stereocenter.

(1.11)

1.3.2 Pd-Catalyzed Hydroamination Reactions of Alkenes and Alkynes

The hydroamination of alkenes and alkynes has been of longstanding interest in organometallic chemistry [26]. Much of the early work in this area focused on early transition metal or lanthanide metal catalyst systems. However, much recent progress has been made in late-metal catalyzed hydroamination chemistry, and several interesting hydroamination reactions that afford nitrogen heterocycles have been developed using palladium catalysts.

Palladium-catalyzed intramolecular hydroamination reactions of alkynes that afford pyrrolidine derivatives were initially reported by Yamamoto in 1998 [27] and have been the subject of detailed investigation over the past ten years [28]. In a representative example, alkyne 24 was converted to 25 in 86% yield upon treatment with Pd(PPh3)4 as catalyst (Eq. (1.12)) [28c]. This transformation has been employed in the synthesis of the natural product indolizidine 209D [29], and asymmetric variants have also been developed that afford pyrrolidine products with up to 95% ee [30]. A related hydroamidation that affords lactam products has also been described [31], and hydroamination reactions of amines bearing tethered allenes are also known [32].

(1.12)

Although Pd-catalyzed intramolecular hydroamination reactions of alkynes have been known for ten years, analogous transformations of unactivated alkenes have only recently been developed [33]. Key to the success of these studies was the use of a cationic palladium complex bearing a pyridine-derived P–N–P pincer ligand (29). For example, treatment of 26 with catalytic amounts of 29, AgBF4, and Cu(OTf)2 led to the formation of pyrrolidine 27 in 88% yield with 4: 1 dr (Eq. (1.13)). Detailed mechanistic studies have indicated these transformations proceed via alkene coordination to the metal complex followed by outer-sphere aminopalladation to provide 28. Protonolysis of the metal–carbon bond with acid generated in situ leads to formation of the product with regeneration of the active catalyst.

(1.13)

An interesting tandem intermolecular/intramolecular hydroamination reaction of cycloheptatriene with substituted anilines has been developed by Hartwig for the synthesis of tropene derivatives [34]. As shown in Eq. 1.14, the coupling of 30 with 31 provided 32 in 73% yield. The mechanism of this transformation is believed to involve acid-assisted formation of an η3-pentadienylpalladium complex 33, which is then captured by the aniline nucleophile to afford the allylpalladium intermediate 34. Intramolecular attack of the aniline nitrogen on the allylpalladium moiety affords the observed heterocycle.

(1.14)

1.3.3 Pd0-Catalyzed Carboamination Reactions of Alkenes

Over the past several years our group has been involved in the development of new Pd0-catalyzed carboamination reactions between aryl or alkenyl halides and alkenes bearing a pendant nitrogen functionality [35, 36]. In a representative example, treatment of Cbz-protected amine 35 with 3-bromopyridine and a catalytic amount of Pd(OAc)2/Dpe-Phos in the presence of Cs2CO3 afforded pyrrolidine 36 in 74% yield with >20 : 1 dr (Eq. (1.15)) [36e]. This method has been applied to a stereocontrolled synthesis of (+)-preussin [37], and is also effective with substrates bearing disubstituted alkenes (Eq. (1.16)) [36f]. The reactions appear to proceed via an unusual mechanism involving intramolecular syn-aminopalladation of a palladium(aryl)(amido) complex (e.g., 37) followed by C–C bond-forming reductive elimination of the resulting intermediate 38. Intramolecular variants of this transformation in which the aryl halide is appended to the alkene have also been described [38], and a one-flask tandem Pd-catalyzed N-arylation/carboamination reaction sequence has been developed for the conversion of primary amine substrates to N-aryl-2-arylmethyl indoline and pyrrolidine derivatives [39].

(1.15)

(1.16)

In addition to providing stereoselective access to substituted pyrrolidines, this method has been employed for the construction of a number of different nitrogen heterocycles including imidazolidin-2-ones (Eq. (1.17)) [40], and isoxazolidines [41]. A highly stereoselective synthesis of cis- and trans-3,5-disubstituted pyrazolidines has been developed in which the presence or absence of an N-1 protecting group controls product stereochemistry [42]. For example, treatment of 39 with 4-bromobiphenyl and a palladium catalyst in the presence of NaOtBu affords the trans-disubstituted product 41 (Eq. (1.18)), whereas subjection of 40 to similar reaction conditions affords the cis-disubstituted product 42 (Eq. (1.19)).

(1.17)

(1.18, 1.19)

Balme has reported a one-pot three-component alkene carboamination between propargylic amines, alkylidene malonates, and aryl halides [43]. For example, treatment of N-methyl propargylamine (2 equiv), dimethyl benzylidene malonate (2 equiv) and 1,4-diiodobenzene (1 equiv) with n-BuLi and a palladium catalyst provided 43 as a single diastereomer (Eq. (1.20)) [43a]. The formation of the C–N bond in this process does not appear to be metal catalyzed. Instead, initial conjugate addition of the nitrogen nucleophile to the activated alkene affords a malonate anion, which undergoes carbopalladation followed by reductive elimination to afford the pyrrolidine product.

(1.20)

1.3.4 PdII-Catalyzed Carboamination Reactions of Alkenes

Two recent reports have described PdII-catalyzed carboamination reactions involving two alkenes that afford pyrrolidine products. Building on early work by Oshima that employed stoichiometric amounts of palladium [44], Stahl has developed an intermolecular Pd-catalyzed coupling of N-allylsulfonamide derivatives with enol ethers or styrene derivatives that affords substituted pyrrolidines in high yields with moderate diastereoselectivity [45]. For example, treatment of 44 with styrene in the presence of PdII and CuII co-catalysts, with methyl acrylate added for catalyst stability, provided 45 in 97% yield with 1.9: 1 dr (Eq. (1.21)). This reaction proceeds through intermolecular aminopalladation of styrene to afford 46. Intramolecular carbopalladation then provides intermediate 47, and subsequent β-hydride elimination yields product 45.

(1.21)

Yang has reported a related tandem cyclization for the synthesis of pyrroloindoline derivatives that also proceeds though a mechanism involving alkene aminopalladation followed by carbopalladation of a second alkene [46]. As shown below, the 2-allylaniline derivative 48 was converted to 49 in 95% yield through treatment with a catalyst composed of Pd(OAc)2 and pyridine (Eq. (1.22)). Use of (−)-sparteine as a ligand in this reaction provided 49 with up to 91% ee.

(1.22)

1.3.5 Pd-Catalyzed Carboamination Reactions of Alkynes, Allenes, and Dienes

A few examples of Pd0-catalyzed carboamination reactions between alkyne-tethered amines and aryl halides have also been reported [28, 47]. For example, treatment of amino ester derivative 50 with PhI in the presence of K2CO3 using Pd(PPh3)4 as catalyst led to the formation of 51 in 80% yield with complete retention of enantiomeric purity (Eq. (1.23)) [28d]. In contrast to the Pd0-catalyzed carboamination reactions of alkenes with aryl halides described above, the reactions of alkynes usually proceed via anti-aminopalladation, although products resulting from syn-aminopalladation have been obtained in some cases [48]. In addition to carboamination reactions that employ aryl halides as coupling partners, several transformations involving other electrophiles, such as acrylate derivatives, have been described (Eq. (1.24)) [49].

(1.23)

(1.24)

Several examples of Pd0-catalyzed carboamination reactions between allenes and aryl or alkenyl halides have been reported [50]. For example, treatment of allene 52 with iodobenzene in the presence of K2CO3 and 2 mol% Pd(PPh3)4 afforded pyrrolidine 53 in 78% yield (Eq. (1.25)) [50a]. Mechanisms involving alkene aminopalladation (similar to the reactions of alkynes and alkenes noted above) have occasionally been invoked to explain these reactions. However, in many instances these transformations may involve intermediate π-allylpalladium complexes. Due to this mechanistic ambiguity, these transformations have been included in this section for comparison with the related reactions of alkenes and alkynes. Similar reactions involving allylic halides have also been described (Eq. (1.26)) [51].

(1.25)

(1.26)

Cross-coupling carboamination reactions between allenes and 2-haloaniline derivatives or halogenated allylic amines have also been employed for the generation of substituted indolines, and use of an appropriate chiral catalyst for these transformations leads to formation of enantioenriched products [52]. For example, Larock has described the synthesis of indoline 56 via the Pd-catalyzed reaction of aryl iodide 54 with allene 55 (Eq. (1.27)) [52a]. The best asymmetric induction was obtained using chiral bisoxazoline ligand 57. These reactions appear to proceed via intermediate π-allylpalladium complexes [53].

(1.27)

Ma has developed a three-component allene carboamination reaction for the stereoselective synthesis of 2,5-cis-disubstituted pyrrolidine derivatives [54]. A representative transformation involving allene 58, 4-iodoanisole, and imine 59 that generates 60 in 90% yield is shown below (Eq. (1.28)). The reaction is believed to proceed through the intermediate π-allylpalladium complex 62, which is formed by carbopalladation of the alkene to give 61 followed by addition of the malonate anion to the activated imine. Intramolecular capture of the allylpalladium moiety by the pendant nitrogen nucleophile affords the pyrrolidine product. A related asymmetric synthesis of pyrazolidines that employs azodicarboxylates as one of the electrophilic components has also been reported [55]. The pyrazolidine products are obtained with up to 84% ee when chiral bis oxazolines are employed as ligands.

(1.28)

An interesting Pd-catalyzed diene carboamination reaction that involves urea-directed C–H activation was recently reported [56]. For example, treatment of N-aryl urea 63 with an activated diene in the presence of 10 mol% Pd(OAc)2, 50 mol% TsOH, Ac2O, and benzoquinone provided 64 in 90% yield (Eq. (1.29)). The transformation is initiated by directed palladation of the arene by a palladium tosylate complex (formed in situ) to yield 65. Carbopalladation of the diene generates allylpalladium complex 66, which is then trapped by the urea to afford the observed product.

(1.29)

1.3.6 Vicinal Difunctionalization of Alkenes and Allenes

Reactions that effect addition of two heteroatoms across an alkene are very powerful methods for the generation of heterocycles, and have significant potential synthetic utility. Several important advances in this area that involve the use of palladium catalysts have recently been reported [57]. Interestingly, many of these may involve high oxidation state PdIV complexes as intermediates.

Palladium-catalyzed intramolecular aminobromination and aminochlorination reactions of alkenes have been employed for the conversion of unsaturated amides, carbamates, and sulfonamides to indolines and pyrrolidines [58]. As shown below (Eq. (1.30)), treatment of 67 with 10 mol% Pd(TFA)2 in the presence of excess CuBr2 or CuCl2 affords 68 and 69 in moderate to good yields [58a]. In some cases superior results are obtained using PdCl2(CH3CN)2 as the catalyst and NCS as the stoichiometric oxidant, as demonstrated in the conversion of 70 to 71 in 90% yield (Eq. (1.31)) [58]. The alkene aminohalogenation reactions are believed to proceed via initial aminopalladation of the substrate followed by oxidative halogenation of the resulting alkylpalladium complex.

(1.30)

(1.31)

Related aminohalogenation reactions of allenes, such as the conversion of 72 to 73, can be effected under similar reaction conditions (Eq. (1.32)) [59]. However, these latter transformations appear to proceed via a different mechanism involving allene bromopalladation followed by nucleophilic trapping of the resulting π-allylpalladium intermediate (e.g., 74).

(1.32)

A very interesting PdII-catalyzed aminoacetoxylation reaction of alkenes was recently developed jointly by the Sorensen and Lee groups [60]. In a representative example, treatment of 75 with Pd(OAc)2 and PhI(OAc)2 provides oxazolidinone 76 in 65% yield with >20: 1 dr (Eq. (1.33)). This transformation is believed to proceed via a PdII/PdIV catalytic cycle that is initiated by anti-aminopalladation of the alkene to afford 77. The intermediate PdII complex is then oxidized by PhI(OAc)2 to alkyl PdIV intermediate 78, which undergoes C–O bond-forming reductive elimination to afford 76.

(1.33)

Three different approaches to the synthesis of five-membered cyclic ureas have recently been described that involve Pd-catalyzed alkene diamination reactions. In a series of very interesting papers, Muniz has described the conversion of alkenes bearing pendant ureas to imidizolidin-2-one derivatives using catalytic amounts of Pd(OAc)2 in the presence of an oxidant such as PhI(OAc)2 or CuBr2 [61, 62]. For example, these conditions were used to effect the cyclization of 79 to 80 in 78% yield (Eq. (1.34)) [62a]. These reactions proceed via a mechanism similar to that shown above in Eq. 1.33, except that the heteropalladation may occur in a syn- rather than anti- fashion, and the reductive elimination occurs with intramolecular formation of a C–N bond rather than intermolecular formation of a C–O bond. The alkene diamination reactions have also been employed for the synthesis of bisindolines (Eq. (1.35)) [63] and bicyclic guanidines (Eq. (1.36)) [64].

(1.34)

(1.35)

(1.36)

The intermolecular diamination of 1,3-dienes with acyclic ureas to provide monocyclic or bicyclic urea derivatives has been achieved by Lloyd-Jones and Booker-Milburn through use of a palladium catalyst combined with either benzoquinone or O2 as an oxidant [65]. For example, diene 81 was converted to urea 82 in 82% yield (Eq. (1.37)). These transformations are mechanistically distinct from the reactions described above, and appear to involve intermediate π-allylpalladium complexes.

(1.37)

A much different strategy was developed by Shi for the conversion of 1,3-dienes or trienes to cyclic ureas [66]. As shown below, treatment of conjugated diene 84 with di-t-butyldiaziridinone 83 and in the presence of Pd(PPh3)4 as catalyst led to the formation of 85 in 94% yield with >20: 1 dr (Eq. (1.38)). This reaction is believed to occur via oxidative addition of 83 to Pd0 to generate 86, which undergoes aminopalladation to afford allylpalladium complex 87. Reductive elimination from 87 affords the urea product. An asymmetric variant of this transformation that provides products with up to 95% ee has also been reported [67].

(1.38)

The scope of this chemistry has recently been extended to terminal alkene substrates [68]. For example, 1-hexene was transformed to 88 in 68% yield under solvent-free conditions using Pd(PPh3)4 as catalyst (Eq. (1.39)). Asymmetric induction has also been achieved in these reactions, and ees of up to 94% have been obtained with a catalyst supported by a chiral phosphoramidite ligand [68c]. The mechanism of the terminal alkene diamination reactions has not yet been fully elucidated, but it appears likely that allylic C–H activation/amination is involved.

(1.39)

1.4 Synthesis of Nitrogen Heterocycles via Intermediate π-Allylpalladium Complexes

The intramolecular addition of nitrogen nucleophiles to intermediate π-allylpalladium complexes is a valuable method for the synthesis of saturated nitrogen heterocycles [69]. A number of different strategies have been employed for the generation of the reactive intermediate π-allylpalladium complexes, such as oxidative addition of alkenyl epoxides, allylic acetates, allylic carbonates, and related electrophiles to Pd0. These intermediates have also been accessed through carbopalladation or heteropalladation reactions of allenes (as described above), vinyl cyclopropanes, or 1,3-dienes, and recent approaches involving allylic C–H activation have also been developed.

1.4.1 Reactions Involving Oxidative Addition of Allylic Electrophiles

One of the most common methods employed for the generation of allylpalladium complexes involves oxidative addition of allylic electrophiles to Pd0. This transformation has been explored by several groups, and has been the topic of recent reviews [69]. A representative example of this process was demonstrated in a recent total synthesis of (+)-Biotin [70]. The key step in the synthesis was an intramolecular amination of 89, which provided bicyclic urea derivative 90 in 77% yield (Eq. (1.40)). In contrast to the PdII-catalyzed reactions of allylic acetates bearing pendant amines described above (Eq. (1.10)), which proceed via alkene aminopalladation, Pd0-catalyzed reactions of these substrates occur via initial oxidative addition of the allylic acetate to provide an intermediate π-allylpalladium complex (e.g., 91). This intermediate is then captured by the pendant nucleophile (e.g., 91 to 90) in a formal reductive elimination process to generate the product and regenerate the Pd0 catalyst. Both the oxidative addition and the reductive elimination steps occur with inversion of configuration when soft nucleophiles are employed, which results in overall retention of configuration at the carbonate-bearing carbon stereocenter. Related transformations of propargylic electrophiles have also been reported [71].

(1.40)

A number of studies have focused on the development and application of asymmetric versions of Pd-catalyzed allylic alkylation reactions [72]. Trost has developed a class of ligands, including 94 and 95, that provide excellent yields and enantioselectivities for many of these reactions. For example, treatment of allylic acetate 92 with 1 mol% of allylpalladium chloride and 3 mol% of ligand 94 led to the formation of 93 in 97% yield and 91% ee (Eq. (1.41)) [73]. Asymmetric desymmetrization reactions of meso-bis-carbamates that provide heterocyclic products have also been described [74].

(1.41)

Recently, Trost has employed this methodology in a tandem one-pot ene–yne coupling/enantioselective allylation process [75]. This transformation was used for the construction of pyrrolidine 99, an intermediate in a formal synthesis of kainic acid [75b]. As shown below (Eq. (1.42)), ruthenium-catalyzed coupling of 96 with 97 provided intermediate allyl ether 98. Addition of 2 mol% of allylpalladium chloride and 6 mol% of chiral ligand 94 to the reaction vessel led to the formation of 99 in 92% yield and 94% ee.

(1.42)

Alkenyl epoxides and aziridines have also been widely utilized as electrophiles in reactions that proceed via intermediate π-allylpalladium complexes [69], including reactions that form five-membered nitrogen heterocycles [76]. In a representative transformation, alkenyl epoxide 100 was coupled with isocyanate 101 in the presence of a catalyst generated in situ from Pd2(dba)3 and P(Oi-Pr)3 to afford oxazolidin-2-one 102 in quantitative yield (Eq. (1.43)) [76b]. The reaction is initiated by oxidative addition of 100 to Pd0 to afford 103, which reacts with the isocyanate to yield 104. The product is then generated by trapping the allylpalladium complex with the pendant carbamate anion. Related transformations involving the use of imines in place of isocyanates allow the construction of 1,3-oxazolidines [77], and syntheses of substituted pyrrolidines from 2-vinyloxiranes bearing tethered nitrogen nucleophiles have also been reported [78].

(1.43)

Related reactions of vinylaziridines [79] or activated vinylcyclopropanes [80] with isocyanates and other heterocumulenes have been developed for the construction of cyclic ureas and similar heterocycles. For example, Trost has recently described a dynamic kinetic asymmetric reaction of aziridine 105 with phenylisocyanate that affords urea 106 in 82% yield with 99% ee (Eq. (1.44)) [81]. The interconversion of stereoisomers occurs via η3–η1–η3 isomerization processes after oxidative addition of the aziridine to Pd0.

(1.44)

A related strategy has been used for the conversion of 5,5-divinyl oxazolidinones to highly substituted pyrrolidines [82]. For example, treatment of 107 with a Pd0 catalyst in the presence of activated alkene 108 provides 109 in 95% yield (Eq. (1.45)). The reaction proceeds via oxidative addition followed by decarboxylation to afford the allylpalladium complex 110. Intermolecular conjugate addition to give 111, followed by intramolecular trapping of the allylpalladium moiety, affords the observed products.

(1.45)

1.4.2 Reactions Involving π-Allylpalladium Intermediates Generated via Alkene Carbopalladation

A number of approaches to the generation of intermediate allylpalladium complexes in heterocycle synthesis involve initial Heck-type carbopalladation of an alkene with an alkenyl halide, followed by rearrangement of the resulting alkylpalladium species via reversible β-hydride elimination processes [83, 84]. For example, treatment of alkenyl sulfonamide 112 with 1-iodocyclopentene in the presence of catalytic amounts of Pd(OAc)2 and P(o-tol)3 provided pyrrolidine 113 in 93% yield (Eq. (1.46)) [84a]. The C–N bond forming step occurs from the π-allylpalladium complex 116, which results from β-hydride elimination of 114 followed by hydridopalladation of 115. This strategy has also been employed for the synthesis of lactams from ω-olefinic amides [83b]. In addition, intramolecular versions of the pyrrolidine-forming reactions have been developed, such as the conversion of 117 to 118 (Eq. (1.47)) [84b,c].

(1.46)

(1.47)

Another approach to the construction of five-membered nitrogen heterocycles by way of intermediate π-allylpalladium complexes involves carbopalladation reactions of 1,3- or 1,4-dienes [85]. For example, Larock has described the coupling of N-tosyl-2-iodoaniline with 1,3-cyclohexadiene, which affords 119 in 87% yield (Eq. (1.48)). The allylpalladium complex 120 is a key intermediate in this transformation. Asymmetric versions of these reactions that generate pyrrolidine products have also been described [86]. Related Heck reactions that employ vinylcyclopropanes as diene surrogates have also been reported, although lengthy reaction times (3–4 days) are often required for transformations of these substrates [87].

(1.48)

The use of Heck reactions of dienes for the construction of nitrogen heterocycles has been applied to an elegant synthesis of (−)-spirotryprostatin B [88]. As shown below (Eq. (1.49)), the intramolecular Heck reaction of 121 afforded the complex pentacycle 122, which was converted to the natural product after cleavage of the SEM protecting group.

(1.49)

1.4.3 Reactions Involving Aminopalladation of 1,3-Dienes

Blsquäckvall and coworkers have developed a stereoselective palladium catalyzed 1,4-addition to cyclic 1,3-dienes that produces pyrrolidine [89a] or lactam products [89b]. For example, treatment of 123 with catalytic Pd(OAc)2 and excess LiCl affords 125 (Eq. (1.50)). Alternatively, treatment of 123 with catalytic Pd(OAc)2 and excess LiOAc affords 127 (Eq. (1.50)). Both reactions proceed via anti-aminopalladation to afford an allylpalladium complex (124 or 126), which is then captured by an external nucleophile. Outer-sphere attack of chloride ion on 124 results in net syn-addition to the diene to give 125, whereas inner-sphere attack of acetate results in anti-addition to provide 127.

(1.50)

1.4.4 Generation of Allylpalladium Intermediates through C–H Activation

A recent example of isoxazolidine synthesis that involves generation of an allylpalladium complex via allylic C–H activation was reported by the White group [90]. As shown below (Eq. (1.52)), treatment of homoallylic carbamate 128 with Pd(OAc)2 in the presence of sulfoxide ligand 130 and phenylbenzoquinone (PhBQ) provided 129 in 72% yield with 6: 1 dr. A related transformation that affords indoline products has been described by Larock [17a].

(1.52)

1.5 Synthesis of Nitrogen Heterocycles via Pd-Catalyzed 1,3-Dipolar Cycloaddition Reactions

Although the use of 1,3-dipolar cycloaddition reactions that form carbon–heteroatom bonds is fairly common using traditional synthetic methods [2], palladium-catalyzed dipolar cycloaddition reactions of this type are rather rare. However, a few reports have described an interesting and synthetically useful approach to the synthesis of pyrrolidines via Pd-catalyzed [3 + 2] cycloaddition reactions of trimethylenemethane with imines [91]. In very recent studies, Trost has developed an asymmetric variant of these reactions that provides access to enantioenriched pyrrolidine derivatives [92]. For example, treatment of trimethylenemethane precursor 131 with imine 132 proceeds to afford 133 in 84% yield and 91% ee when a catalyst composed of Pd(dba)2 and ligand 134 is used (Eq. (1.53)).

(1.53)

Although many Pd-catalyzed [3 + 2] cycloaddition reactions employ 131 as a trimethylenemethane precursor, readily available 2-methylenepropane-1,3-diols and their corresponding benzyl ethers have also been used as sources of trimethylenemethane [93]. This approach allows construction of more highly substituted pyrrolidine derivatives than can be generated from 131. For example, treatment of 135 with 136 in the presence of diethylzinc and a palladium catalyst afforded pyrrolidine 137 in 92% yield as a single diastereomer (Eq. (1.54)).

(1.54)

An unusual class of Pd-catalyzed [3 + 2] cycloaddition reactions between activated aziridines and heterocumulenes such as isocyanates and carbodiimides has been extensively examined by Alper and coworkers [94]. These transformations led to the preparation of ureas, carbamates, and other heterocycles in good yields. For example, treatment of 138 with phenylisocyanate afforded urea 139 in 72% yield (Eq. (1.55)) [94a]. The mechanism of these reactions presumably involves oxidative addition of the aziridine to Pd0, followed by insertion of the isocyanate into the Pd–N bond and C–C bond-forming reductive elimination (similar to the reactions of vinylaziridines described in the section above, although allylpalladium intermediates are obviously not involved).

(1.55)

1.6 Synthesis of Nitrogen Heterocycles via Carbonylative Processes

Many of the concepts and strategies outlined above have been employed in carbonylative processes, which provide more highly functionalized heterocyclic products through incorporation of one or more units of CO [95]. Palladium-catalyzed carbonylative transformations that afford saturated five-membered nitrogen heterocycles can be broadly divided into three major categories: (i) processes involving CO insertion into a Pd–CAr or Pd–CAlkenyl bond, followed by intramolecular capture by a pendant nucleophile; (ii) transformations involving CO insertion into a Pd– heteroatom bond; and (3) Wacker-type processes wherein anti-heteropalladation of a carbon–carbon multiple bond precedes CO insertion.

1.6.1 Transformations Involving CO Insertion into Aryl or Alkenyl Pd-Carbon Bonds

Palladium-catalyzed carbonylative reactions of aryl or alkenyl bromides bearing pendant nitrogen nucleophiles have been studied for over 30 years, and have proven useful for the construction of a variety of different heterocyclic compounds [96]. For example, treatment of 140 with catalytic amounts of Pd(OAc)2 and PPh3 in the presence of Bu3N under an atmosphere of CO afforded lactam 141 in 65% yield (Eq. (1.56)) [96a]. This transformation presumably occurs via oxidative addition of the aryl bromide to Pd0 to provide 142, which undergoes insertion of CO into the Pd–C bond to yield 143. Intramolecular capture of the acylpalladium intermediate 143 by the tethered amine gives the desired heterocyclic product.

(1.56)

The insertion of CO into Pd–carbon bonds has also been employed in several tandem/cascade reactions that afford five-membered nitrogen heterocycles [97]. A representative example of this approach to the construction of heterocycles involves synthesis of isoindolinones via the Pd-catalyzed coupling of 2-bromobenzaldehyde with two equivalents of a primary amine under an atmosphere of CO [97b]. As shown below (Eq. (1.57)), this method was used for the preparation of 144 in 64% yield. The mechanism of this reaction is likely via initial, reversible condensation of 2-bromobenzaldehyde with 2 equiv of the amine to form an aminal 145. Oxidative addition of the aryl bromide to Pd0 followed by CO insertion provides the acylpalladium species 146, which is then captured by the pendant aminal to afford the observed product. An alternative mechanism involving intramolecular imine insertion into the Pd–C bond of a related acylpalladium species, followed by formation of a palladium-amido complex and C–N bond-forming reductive elimination has also been proposed [97b].

(1.57)

A sequence involving intermolecular Pd-catalyzed carbonylative amidation followed by intramolecular Michael addition has been employed for the construction of isoindolin-1-ones [97d]. For example, treatment of 147 with 4-methoxyaniline under standard conditions for Pd-catalyzed carbonylative coupling gave isoindolinone 148 in 79% yield (Eq. (1.58)). This transformation is effective with a wide array of primary aliphatic and aromatic amine nucleophiles.

(1.58)

A synthesis of phthalimides via double carbonylative coupling of ortho-diiodo arenes with anilines has also been reported [98]. The conversion of 149 to 150 proceeded in good yield using a Pd/PPh3-based catalyst system (Eq. (1.59)).

(1.59)

1.6.2 Transformations Involving CO Insertion Into a Pd–Heteroatom Bond

A number of interesting methods for the synthesis of heterocycles that employ palladium carbonylation chemistry involve formal CO insertion into a Pd–heteroatom bond via either an inner-sphere or outer-sphere mechanism [99]. Several groups have employed this strategy for the generation of isoxazolidines and ureas via Pd-catalyzed carbonylation reactions of 1,2-amino alcohols or 1,2-diamines [100]. For example, Gabriele and coworkers have synthesized oxazolidin-2-ones in high yields using a PdI2/KI/air catalyst system [100b]. Oxazolidin-2-one 152 was obtained in 96% yield from amino alcohol substrate 151 using only 0.05 mol% of PdI2 (Eq. (1.60)). In a similar fashion, diamine 153 was transformed to 1,3-dihydrobenzoimidazol-2-one 154 in 70% yield (Eq. (1.61)) [100d]. The first carbon heteroatom bond is formed by CO insertion into the palladium amido complex 155, followed by intramolecular trapping of the resulting acylpalladium intermediate 156 with the second heteroatom. This leads to reduction of the PdII catalyst to Pd0, and the presence of air (oxygen) is required to regenerate the catalytically active PdII species.

(1.60)

(1.61)

Several transformations involving CO insertion into a Pd–heteroatom bond have been developed that lead to incorporation of two molecules of CO into the heterocyclic product. This approach to heterocycle synthesis is exemplified by a synthesis of dihydroindolones reported by Gabriele [101]. As shown below, treatment of ortho-alkynyl aniline 157 with a PdII catalyst under CO in methanol afforded 158 in 50% yield (Eq. (1.62)). A similar strategy has been employed for the conversion of alkene 159 to pyrrolidinone 160 (Eq. (1.63)) [102].

(1.62)

(1.63)

1.6.3 Wacker-Type Carbonylative Processes

Pd-catalyzed carbonylative processes that involve Wacker-type anti-aminopalladation of alkenes, alkynes or allenes have been widely employed in the construction of nitrogen heterocycles. Early studies using stoichiometric amounts of palladium to effect intramolecular alkene aminopalladation followed by carbonylation were reported by Danishefsky in 1983 [103]. A number of elegant studies by Tamaru subsequently led to the development of catalytic versions of these reactions, and extended the scope of this chemistry to allow the generation of a wide array of nitrogen heterocycles, including oxazolidin-2-ones, imidazolidin-2-ones, pyrrolidines, and isoxazolidines [104]. For example, treatment of carbamate 161 with 5 mol% PdCl2 in the presence of CuCl2 under CO using trimethyl orthoacetate as solvent provides oxazolidin-2-one 162 in 70% yield with >20: 1 dr (Eq. (1.64)) [104e]. The mechanism of this reaction involves anti-aminopalladation of the alkene to afford 163, which undergoes CO insertion to form 164. Capture of the acylpalladium intermediate 164 with methanol (formed in situ from trimethyl orthoacetate) gives the heterocyclic product.

(1.64)

This strategy has been used for the construction of bridged bicyclic nitrogen heterocycles, and has been applied to a formal total synthesis of the alkaloid natural product (±)-ferruginine [105]. In addition, an asymmetric variant of this reaction has been developed by Sasai and coworkers. As shown below (Eq. (1.65)), use of a catalyst composed of Pd(TFA)2 and spiro bis(isoxazoline) ligand 167 effected the conversion of sulfonamide 165 to pyrrolidine 166 in 95% yield and 60% ee [106]. Although this transformation requires high catalyst loadings and very long reaction times (7 days), it is clear that there is potential for achieving asymmetric induction in these systems, and development of new catalysts for these reactions is likely to be an area of future investigation.

(1.65)

Alkene aminopalladation/carbonylation has also been employed in the synthesis of fused bis(heterocycles) [107]. As shown below, treatment of 168 with 10 mol% PdCl2 in the presence of CuCl2 under CO provided 169 in 66% yield (Eq. (1.66)) [107a]. This strategy has been used for the preparation of 1,4-iminoglycitols [107b], and has been applied to a concise synthesis of the Geissman–Waiss Lactone, which is a key intermediate in the synthesis of necine bases [107c].

(1.66)

A number of Pd-catalyzed carbonylative processes have employed allenes as substrates for the synthesis of nitrogen heterocycles [108]. For example, subjection of substituted allene 170 to reaction conditions similar to those employed in related reactions of alkenes led to the formation of pyrrolidine 171 in 68% yield with 2: 1 dr (Eq. (1.67)) [108d]. Modest asymmetric induction has been achieved in these transformations using simple chiral auxiliaries [108b,d]. This strategy was employed in an asymmetric synthesis of pumiliotoxin 251 D, which involved the aminocarbonylation of allene 172 to pyrrolidine 173 as a key step (Eq. (1.68)) [108b].

(1.67)

(1.68)

1.7 Summary and Future Outlook

Over the past several decades, research in the field of palladium catalysis has resulted in the development of a myriad of transformations that provide access to saturated nitrogen heterocycles. Many of these transformations effect the formation of several bonds, and/or proceed with good to excellent levels of stereocontrol. Despite the many advances made in this field, discoveries of new reactivity are still being reported with great frequency, and this promises to remain a fruitful area of research for many years to come. In particular, the development of new palladium catalysts will likely lead to improvements in the scope of existing transformations, and will also open up new reaction pathways that can be applied to unsolved problems in heterocyclic chemistry.

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