Palladium-Catalyzed C-H Amination of C(sp ) and C(sp )-H Bonds

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Palladium-Catalyzed C-H Amination of C(sp) and C(sp)-H Bonds: Mechanism and Scope for N-Based Molecule Synthesis Yam N. Timsina, B. Frank Gupton, and Keith C. Ellis ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01168 • Publication Date (Web): 08 May 2018 Downloaded from http://pubs.acs.org on May 8, 2018

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Palladium-Catalyzed C-H Amination of C(sp2) and C(sp3)-H Bonds: Mechanism and Scope for N-Based Molecule Synthesis Yam N. Timsina, † B. Frank Gupton, ‡ and Keith C. Ellis†,§,∥, * †

Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298-0540, United States. ‡ Department of Chemical and Life Sciences Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia 23284, United States. § The Institute for Structural Biology, Drug Discovery, and Development, Virginia Commonwealth University, Richmond, Virginia 23219, United States. ∥Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298-0037, United States.

ABSTRACT: Nitrogen containing compounds are the most common structural architectures in drug candidates, natural and biological products, and small molecule therapeutics. Within the body of work of transition metal-catalyzed direct C-H amination reactions, palladium remains in the forefront and has been established as one of the most useful transition metals for C-N bond formation. The fundamental organometallic reactivity of palladium in its 0, I, II, III and IV oxidation states make it special and useful in challenging carbon-heteroatom bond formation reactions. Palladium undergoes facile formation of chelation-assisted palladacycle and palladium-nitrenoid intermediates that opens the avenue for new bond formation. It has been utilized in various new synthetic approaches towards both intermolecular and intramolecular CN bond formation reactions that employ nitrogen sources ranging from free, unprotected amines to electrophilic nitrogen sources. Palladium’s compatibility with various functional groups and oxidants as well as the mild reaction conditions (temperature and air atmosphere) used with this metal have attracted many scientists to the area and will continue to advance new mechanistic insights and opportunities to explore palladium catalysis for C-N bond synthesis. Here, we summarize the progress of Pd-catalyzed C-N bond advances involving both the reaction development and mechanisms in numerous synthetically useful intra- and intermolecular C-H catalytic aminations. NHCOR N

(PhO2S)2N

N

(PhO2S)2N CO2Me R

N R1

N

O

DG C(sp2)-H

Pd C(sp3)-H NR1R2

Ts

CH3

O

R2 NHR

N N

N

N

CH3

KEYWORDS: palladium, oxidation, chelation, palladacycle, intermolecular, intramolecular, amination, amine * Corresponding Author: Keith C. Ellis ([email protected])

ACS Paragon Plus Environment

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1. INTRODUCTION Both aliphatic and aryl amines are important components of privileged-structures in biologicallyactive molecules, agrochemicals, pharmaceuticals, and other supramolecular materials.1-4 The nitrogen atoms contained in these molecules are essential for their biological activity, as nitrogen can hold a positive charge as well as act as both hydrogen bond donor and hydrogen bond acceptor, with pKas comparable to physiological pH. These features are significant for the interaction between medicinal agents and their molecular targets. The majority of amine synthesis methods involve direct reaction of a nitrogen-based nucleophile with an electrophilic carbon center. Traditionally, electrophilic aromatic nitration followed by reduction is the only widely-used synthetic method to install amino groups into arenes.5 The requirement of strong acidic or oxidizing reaction conditions severely limits its use on substrates with sensitive functional groups. To overcome this limitation, metal-catalyzed coupling reactions have been developed for the construction of aryl amines. Examples of metal-catalyzed coupling reactions include the Ullmann-Goldberg condensation6-7 and Chan-Lam coupling,8-9 which both utilize copper, as well as the palladium-catalyzed Migita-Kosugi reaction10 and Buchwald-Hartwig amination11-12 (Scheme 1). The Buchwald-Hartwig reaction is the first palladium catalyzed amination extensively studied and used where pre-activated electrophiles (aryl halides) are reacted with amines in presence of palladium catalyst and base.11-12 Typically, C(sp2)-N reductive elimination is the final product forming step in these reactions, transforming aromatic and vinylic C(sp2)-X into C(sp2)-N bonds. Many chemists have studied this Pd(0)/(II) catalyzed amination of aryl halides or pseudohalides (pre-activated electrophiles) to understand the nature of catalyst and mechanism as well as to expand the scope of reaction.13 Among many limitations, synthesis of metal reagents, aryl halides or pseudohalides as well as managing inevitable undesired waste byproducts is expensive and cumbersome. As the Buchwald-Hartwig reaction is well-studied and there are numerous published reviews on it, this reaction will not be part of this review.14-20 Scheme 1. Historic C-N Cross-Coupling Reactions Ullmann and Goldberg Coupling Reaction X

NH 2 R2

+

R1

H N

Cu(0) or Cu(I) catalyst R1

R2

base

Buchwald and Hartwig Coupling Reaction H N

X R1

+

R2

R3

Pd(0) or Pd(II) catalyst R3

N R1

PR 3 and base

Chan and Lam Coupling Reaction

R1

H N

B(OH) 2 +

R2

R3

Cu(0) or Cu(I) catalyst R3

R2

N R1

R2

base

Despite enormous progress in C-N bond formation using metal-catalyzed couplings, the search has continued for a more ideal amination reaction: highly selective and efficient direct aminations utilizing unfunctionalized starting materials such as arenes, heterocycles, or sp3(C)-H


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bond containing compounds. This amination version of a C-H activation reaction offers the same advantages as known C-H activation reactions that directly form C-O, C-C, and C-Halogen bonds. C-H activation reactions are atom-economical processes that have several advantages including elimination of the need for pre-functionalization of substrates and eliminating the generation of undesired by-products. Collectively, these advantages offer both a decrease in cost and reduced impact on the environment, further incentivizing the development of C-H activation technologies.21-42 Recently, numerous C-H activation reactions have been reported in mild conditions that can be used as efficient synthetic tools in the late stage functionalization of complex molecules,43 including the synthesis of numerous nitrogen containing natural products and pharmaceuticals.44-46 Recyclable heterogeneous catalysts for C-H activation reactions have also been reported as a means of enhancing catalytic activity and further reducing the environmental impact of the technology.47-50 The published literature using C-H activation reactions to construt C-N bonds, which is the subject of this reiew, have shown that there are many challenges in developing direct amination reactions, including: (a) the inert nature of most C-H bonds because of a large kinetic barrier with the C-H bond cleavage (85-105 kcal/mol), (b) achieving energetically demanding C-N bond formation while avoiding homo-dimerization, (c) chemoselectivity in amine nucleophiles with similar pKas, and (d) control of chemo-, regio-, and stereoselectivity in many C-H bonds. The site selectivity is generally approached either through substrate control (with directing group) or catalyst control (using ligands).51 Ideally, finding energetic amine sources or efficient catalysts to either increase the thermodynamic favorability of the reaction or decrease the activation barrier remain the prime concern in C-N bond formation. There are mainly two approaches practiced in solving these challenges: (a) C-H insertion via outer-sphere pathway utilizing nitrene transfer to the targeted C-H bonds or (b) C-H activation via inner-sphere pathway converting the C-H bond to a C-M bond in presence of directing group or coordinating ligand followed by reaction with aminating reagents (Scheme 2). Palladium metal not only promotes the rate of reactions of C-H bonds but also can cyclometallate to many directing groups or coordinating ligands to promote C-H activation at both sp2 and sp3 C-H bonds.52 Moreover, palladium is compatible with many oxidants and additives along with air and moisture in comparison to other transition metals. In addition, the easy electronic tuning of Pd (electrophilic or nucleophilic) has attracted numerous chemists in frontiers of C-H activation. Scheme 2. Current Approaches of Pd-catalyzed C-H Amination C-H Amination via C-H Insertion (Pd-nitrene) R3

R2 +

R1

R3

PdLn, Oxidant

H R

NH2 via Pd-nitrene R N=PdLn

NHR R2

R1

C-H Amination via C-H Activation (Directing Group Controlled)

H R1

N

+ R2

DG

PdLn, Oxidant

X

DG

R3

via Palladacycle

NR2R3 R1

X = H or other groups

Despite many reviews on C-H amination by various transition metals,53-66 there is no thorough, concise, and comprehensive review on C-H activation using palladium metal for the formation of


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C-N bonds. This review covers the recent advancements on C-N bond formation in terms of intermolecular, intramolecular, and direct C(sp3)-H bond activation catalyzed by palladium metal catalysts that are useful in the field of organic synthesis. It will also cover allylic aminations and direct amination reactions in association with other coupling reagents in brief. We will cover reaction development as well as mechanisms and substrate scope for reactions published through 2017. The organization of the review is based on mechanistic parameters such as nature of palladacycles, directing groups, and low vs. high valent Pd-pathways. We hope this review will be a guide and inspiration for additional discoveries with palladium metal in this rapidly progressing field of C-H bond amination.

2. INTERMOLECULAR C-N BOND FORMATION Intermolecular direct amination reactions would be a powerful and useful synthetic tool because the synthetic steps required to make the substrates are not needed. Cross-dehydrogenative coupling for the formation of C-N bond remains the most ideal because it avoids prefunctionalization steps and rquires only an oxidant to consume the formal H2 by-product in C-N bond formation step. Due to many difficulties, the intermolecular process suffers from limited catalysts and substrate scope. Palladium is a unique and powerful catalysts for this transformation not only because it is capable of forming geometrically organized palladcycle intermediates but also because is catalyzes energetically uphill intermolecular C-N bond formation. Most of the C-N bond forming reactions are initiated by C-H activation to form organometallic palladacycle intermediates. Selectivity is controlled by steric effects, proximity to the directing group and length of the tether rather than strength of C-H bonds. Chemists around the globe have reported the conversion of C-H bonds into amines utilizing various kinds of catalysts with efficiency and waste-free techniques. 2.1. Mechanistic insight Mechanistically, there are four pathways commonly encountered for the intermolecular C-N bond formation: 1) putative Pd-nitrene formation (Scheme 3, Path A); 2) Pd(II/0) reduction (Scheme 3, Path B); 3) two electron oxidation (Scheme 3, Path C); and 4) one electron oxidation (Scheme 3, Path D). In the vast majority of the literature these reactions are substrate-dependent, with the chelating atom in the directing group of the substrate coordinating with the palladium metal assisted by the supporting ligands. Subsequent ortho-C-H activation occurs to give the five or six membered intermediate palladacycle 1. Cyclopalladation remains the rate-limiting step in the majority of the intermolecular amination reactions. Nitrogen sources now coordinate to the palladium center either by maintaining the same oxidation state or higher oxidation state. The Path A route (Scheme 3) suggests that free-nitrene insertion may not be kinetically competitive so that putative Pd-nitrene species is proposed. As shown in Path A, a Pd-nitrene species is formed by the transference of nitrene moiety of nitrogen source to the Pd-center. The stereoelectronic properties of the putative Pd-nitrene mainly controls the selectivity of C-H insertion, especially at the tertiary, allylic or benzylic positions. A recent study67 shows that a metal-nitrene cleaves the inert C-H bond either by a concerted C-H insertion or a stepwise hydrogen atom abstraction (HAA) and subsequent radical recombination. Generally, carbamate or sulfonamide type nitrogen sources are potential nitrene generating agents and maintain the same oxidation state. Therefore, the palladacyclic complex reacts with nitrene forming sources


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like carbamate or sulfonamide anion to form an N-anchored complex which generally undergoes migratory insertion to the Pd-C bond via a putative Pd-nitrene species. This species ultimately furnishes the amination product. In a second mechanistic pathway, as shown in Path B in Scheme 3, the Pd(II/0) catalytic cycle undergoes series of steps C-H activation, ligand exchange and reductive elimination to give the product with concomitant release of Pd(0). The Pd(0) is oxidized to Pd(II) for the continuation of the catalytic cycle. Another possible pathway involves the direct electrophilic cleavage with no change in palladium oxidation state. The remaining two mechanistic pathways for palladacyclic complex is the formation of high valent Pd complexes – Pd(III) or Pd(IV) – either by oxidative addition of aminating reagent or by addition of external one electron or two electron oxidants (Path C and D in Scheme 3). Sometimes external ligand helps to accelerate the oxidative addition as well as reductive elimination. In some cases, external oxidant is added in the reaction to increase the efficiency of the reaction even if Pd(IV) is formed by the aminating reagent, which probably re-oxidizes the Pd(0) produced by off-cycle pathways. The C-N reductive elimination from Pd(IV) species affords the amination product as well as regenerates the Pd(II) catalyst. Scheme 3. General Schematic Mechanism of Intermolecular C-N Bond Formation by C-H Activation Concerted C-H Insertion

DG

Putative Pd-nitrene Intermediate Path A

LnPd

Oxidant Nitrogen Source

C-H activation DG C H H+

C

DG

PdLn II

DG = Directing Group

1

DG DG

C N

DG

C

DG

C N

PdLn

DG

R

H C N

R

CH3

Path B Modern 2 Electron Oxidation

Reductive Elimination

PdLn

Path C

Modern 1 Electron Oxidation Path D

DG

C N

DG

C N

IV PdIII dimer

or PdIII

2.2.

N R

Hydrogen Atom Abstraction

or Traditional Direct Electrophilic Functionalization

PdLn

H Radical Combination

Stepwise

PdII/0 Reductive Cycle

+

R

PdLn

R N

LnPd

N

LnPd

CH

DG

H

C H

C

DG

Reductive Elimination

PdLn

III

Common Nitrogen Sources

The ideal nitrogen sources consist of common amines and amides without pre-synthesis. These reagents are used in presence of external oxidants for Pd-catalyzed C-H amination. The nitrogen atom in these nitrogen sources is mostly nucleophilic in character, which can be converted to electrophiles (umpolung) such as N-halides, N-carboxylate and N-tosylate. This is an important approach for aromatic C-H amination strategy. In most of the cases, carbon-palladium metal intermediate acts as a nucleophile so that aminating agent needs to be an electrophile. In many cases, this N-X polarized bond not only cleaves oxidatively in presence of palladium but also serves as an internal oxidant for C-H amination. The common nitrogen sources used in palladium catalysis are shown in Figure 1.


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O O H 2N R Che, 2006 Liu, 2011 O

R

H 2N S O

NH 2

NaN 3

R Che, 2006 Liu, 2011

Jiao, 2013 Buchwald, 2011 X

PhO 2S N F

HN

OEt

PhO 2S

O Hartwig, 2013

R1 N SO2Cl R2 Chen, 2012

O

HN X = OMes or ONs

Zhang, 2010, 2011 Alvarez and Muniz, 2012 Ritter, 2013 Liu, 2017

Yu, 2010, 2012

R1

R1 N OBz

Ts

R2 Yu, 2011, 2015 Qin, 2015

N Cl

PhI=NTs

Sanford, 2007

Liang, 2011

Figure 1. Common Nitrogen Sources in Pd-Catalyzed C-H Amination Reactions 2.3. Pd-Nitrene Pathway In 1980, Breslow and Gellman demonstrated the metal-catalyzed reaction of tosylimidophenyliodinane (TsN=IPh) to generate a metal nitrene that aminated cyclohexane.68-69 Since this pioneering work, nitrene insertion has become a common strategy for metal catalyzed C-H activation. In comparison to rhodium and ruthenium, there are limited number of reports indicating the formation of nitrenoid intermediates with Pd-catalysts.70-72 Che and coworkers pioneered various nitrene sources like carbamates, acetamides, sulfonamides, and cinnamides in the intermolecular amination reaction of O-methyl oximes (Scheme 4).73 Treatment of these substrates with a catalytic amount of Pd(OAc)2 (5 mol %), nitrogen source (1.2 equiv), oxidant K2S2O8 (5 equiv), and MgO (2 equiv) in 1,2- dichloroethane at 80 oC gave excellent yields of C(sp2)-H activated products. The complete manipulations of reaction conditions do not require air- or moisture-free conditions. This direct cross-dehydrogenative coupling (CDC) without prefunctionalized substrates is a prime example of a practical and environmentally benign amination process.74-76 The authors propose that the reaction proceeds through the five-membered chelation directed palladacycle 2 (Scheme 5) via cyclopalladation on treatment with palladium acetate. The nitrene then inserts into the Pd-C bond to give the amidation product (Scheme 5). The nature of active nitrene species – either free or palladium bound – involved in the reaction remains unclear.


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Scheme 4. Palladium catalyzed Direct Intermolecular ortho-C-H Amidation of Aromatic Oximes Pd(OAc) 2 (10 mol %) Amides (1.2 equiv) N

R1

NHR

K 2S2O8 (5 equiv) DCE, 80 oC, 14-20 h

R = CO 2CH 3 = COCF 3 9 examples 87-96%

Selected substrate scope CH 3

CH 3 OCH 3

N

NHCO 2CH 3

I

H 3CO

Br

OCH 3

N

NHCOCF 3

H 3CO

92%

N

H 3CO

OCH 3

NHCO 2CH 3

87%

OCH 3

N

NHCO 2CH 3

93%

N

OCH 3

N

R1

OCH 3

OCH 3

H 3CO

N

NHCO 2CH 3

NHCOCF 3

96%

94%

94%

Scheme 5. Proposed Mechanism of ortho-C-H Amidation of Aromatic Oximes

N

OCH3

NHCO 2CH 3 Pd(OAc) 2

N

OCH 3

Cyclopalladation NH 2CO2CH 3

nitrene insertion into Pd-C bond or Pd(II) nitrene

N

OCH 3

Pd AcO 2 2

Yu and coworkers have reported the reaction of a palladium catalyst and N-nosyloxycarbamates to form intermolecular C-N bonds employing anilides as substrates via a directing group in the ortho position (Scheme 6).77 While a two-step pre-synthesis of N-nosyloxycarbamates is required, no external oxidant or base are utilized in this transformation. The authors are able to demonstrate the versatility of this C-H activation reaction by showing different substrates with electron donating and withdrawing groups. The vinyl and ester group containing pivalanilide shows selective N-H bond formation only ortho to the anilide directing group. The proposed mechanism shows formation of palladacycle 3 (rate-determing step; kinetic isotope effect, kH/kD = 3.7) and nitrene insertion via a metal-nitrene pathway for C-N bond formation (Scheme 7). This mechanistic proposal is based on similar reactions with ruthenium and rhodium, where this type of insertion of a monovalent nitrogen (nitrene) to a C-H bond coordinated to a metal


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complex forms a C-N bond.78 However, in Yu’s amidation of anilides by N-nosyloxycarbamates there is equal possibility of involvement of Pd(IV) or a dimeric Pd(III) complexes and their subsequent reductive elimination to form the desired C-N bond formation. Scheme 6. Palladium-Catalyzed ortho-C-H Amidation of Anilides by N-Nosyloxycarbamate H N R H

O

R1

+

NsO

O

O

N H

Pd(OTs) 2(MeCN) 2 (10 mol %)

R2

R O

R 2 = Et = Troc = benzyl

R1

O NH

Dioxane, 80 oC, 6 h

(1.2 equiv) R 1 = tBu = Me = Ph

H N

O R2

21 examples 45-87%

Selected substrate scope O

H N

tBu

O NH O

O

84% H N

O CCl 3 87%

CO 2Bu

O NH O

O

O Et 85%

tBu

tBu

O NH

Me

NH

O Et

R

Me H N

N

H N

O Et

tBu

H N

tBuO2C

O NH

R = OMe; 45% = OCHF 2; 60% = F; 66% = Br; 68%

O

tBu

O NH

O Et

O

O Et

50%

50%

Scheme 7. Proposed Mechanism of Intermolecular ortho-C-H Amidation H N

H N

O NH O

H

O

OEt Pd(II)

nitrene insertion or via Pd(III) or Pd(IV) species

TsOH H N II O Pd

N-CO2Et nitrene by NsO-NHCO2Et

TsO 2 6-membered palladacycle

3


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The carboxylate group has been recognized as an important assisting group in metal-catalyzed CH functionalization reactions.79 Yu’s group has also reported a direct ortho-C-H amidation of benzoic acids using ethyl mesitylsulfonyloxycarbamate as a nitrogen source for the synthesis of anthranilic acids (Scheme 8).80 Lithium carboxylate (due to its hard Lewis acidity) and potassium acetate in dioxane gave the best results with numerous substituted benzoic acids. The authors proposed the carboxylate-assisted formation of the ortho-C-H palladation complex 4 as the rate limiting step (kinetic isotope effect, kH/kD = 2.6). The reversible deprotonation of carbamate with potassium acetate affords the N-mesitylsulfonyloxycarbamate anion and reacts with palladacyclic complex to generate arylpalladium(II) complex 5. This intermediate undergoes migratory insertion to the Pd-C bond either through a putative Pd-nitrene species or concerted aryl migration with the departure of the sulfonate group. Another molecule of acetic acid generates amidated product with the release of active catalytic species (Scheme 8). Scheme 8. Palladium catalyzed Direct Intermolecular ortho- C-H Amidation of Benzoic Acid and Proposed Mechanism

R1

CO2-Li+

Pd(OAc)2 (10 mol %) KOAc (1 equiv)

H +

N

MesO

H

CO2-Li+

R1

CO2Et

NHCO2Et

dioxane, 90 oC, N2, 6 h

(1.5 equiv)

13 examples 21-73%

CO2H NHCO2Et CO2-Li+ H AcOH

Pd(OAc)2 Cyclopalladation O-Li+ C O Pd

O-Li+ OAc

N

C O

L

CO2Et

Pd AcO

O-Li+ C

or concerted aryl migration

2

MesO

O N

N

CO2Et

K + HOAc

O-Li+

Pd L

C O Pd L

CO2Et via putative Pd-nitrene

4

MesO

H N

CO2Et + KOAc

KOAc

N MesO

CO2Et

Arylpalladium (II) Complex 5

2.4. Oxidative High-Valent Pd Pathway Catalysis by low-valent palladium [Pd(0)/(II)] is well studied and synthetically useful crosscoupling reactions of pre-functionalized substrates but suffers from several limitations including high susceptibility of decomposition (β-hydride elimination) and difficulty in forming carbonheteroatom bonds. After Canty and coworker’s report81 of Pd(IV), high-valent palladium


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[Pd(II)/(III) or (IV)] catalysis systems have been developed with wide substrate scope and mild reaction conditions. Chemo, regio and site-selectivity is profoundly increased in comparison to traditional, more common low-valent palladium complexes even though there is a challenge in achieving selective reductive elimination from high valent metal species.82 In most cases, C-H activation (cleavage) of the substrate occurs upon treatment with Pd(II), followed by oxidation to Pd(IV) or Pd(III) dimer leading to product forming reductive elimination. But recently, it has also been shown that C-H activation (cleavage) can occur at Pd(IV) after oxidation which releases a product through reductive elimination.83 In 2007, Sanford and coworkers reported a stoichiometric reaction for the conversion of C-H bonds into amines using palladacyclic intermediates.84 Palladium(II) complexes possessing bidentate cyclometalated C-N chelating ligands react with PhI=NTs, where NTs inserts in the Pd-C bond (Scheme 9). The authors proposed two possible mechanisms for this reaction: a concerted process or a stepwise process. In the concerted process, the coordination of iminoiodinane to the Pd metal produces the intermediate 6 that initiates the loss of iodobenzene and the insertion of a sulfonamide moiety into the Pd-C bond simultaneously to give the product. In the stepwise process, the coordination of iminoiodinane to the Pd metal produces iodobenzene first to provide Pd(IV)-imido complex 7 where NTs subsequently inserts into Pd-C bond to give the desired product. The final aminated compound is produced from the metal complex by treating with trifluoroacetic acid or hydrochloric acid. Cundari and Ke utilized density functional theory (DFT) studies to understand the mechanism and intermediates of Pd-catalyzed cascade C-H activation/C-N bond formation by using the reaction system (benzo[h]quinoline)Pd(II)(Cl)Py and PhINTs as a nitrogen source.85 Their work revealed that the stepwise mechanism is the lower energy pathway compared to both concerted PhINTs transfer mechanism or free nitrene insertion mechanism. Scheme 9. Stoichiometric Palladium-Mediated C-H Amination 1.

(8 equiv)

1. HCl (8 equiv)

N

N

N Cl

Pd

Pd NTs

2. PhI = NTs (1.3 equiv), rt Cl

2

N TsHN

Py 99 % 78 % X-ray analysis

or N

N Pd Cl

NTs Py IPh

concerted intermediate 6

Cl

Pd Py

N Ts

stepwise intermediate 7

Yu and coworkers reported amide directed C-N bond formation by a catalytic method based on Pd(OAc)2, AgOAc and benzoyl hydroxylamine (Scheme 10).86 O-Acetyl and O-benzoyl hydroxylamines were effective amine sources but N-chloroamine remained ineffective. The authors reported the necessity of using CONHAr {Ar = (4-CF3)C6F4}, a fluorine containing auxiliary, in the amide substrate. Dichloroethane remains the best solvent for the broader scope of electron neutral and rich substrates to provide good isolated yields (56-89%). Electrondeficient substrates required α,α,α-trifluorotoluene as the solvent for the best yields. The


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tolerance of bromo-group in the substrate is important as further derivatization following amination is possible via cross-coupling. Scheme 10. Amination Reaction of N-Aryl Benzamides with O-Benzoyl hydroxylmorpholine F

F O C R

F

CF3

N H

F

OBz N

+

R O

F

H

F

Pd(OAc) 2 (10 mol %), AgOAc (1 equiv), CsF (2 equiv) DCE, 130

oC,

18 h

CF 3

O CN H N

F F O

(2 equiv)

12 examples 56-89% Selected substrate scope F

F F

Br

F

CF3

O CN H N

O CN H N

F F

F 3C

F

MeO

O

O

F F

CF3 F F O

O

56%

75%

F Me O CN H N

CF3

O CN H N

F F

F

F CF3

89%

88%

In the extension of this reaction, many O-benzoyl hydroxylamines synthesized from simple dialkylamines gave good yields of products (73-97%) (Scheme 11). The mechanism for this transformation is unclear as multiple reactive pathways are available. The authors proposed Pd(II) cyclic salt 8 as an intermediate after the deprotonation of the acidic amide with CsF. The resultant arylpalladium(II) intermediate could either oxidize to Pd(IV) species 9 and subsequently undergoes reductive elimination to furnish the product. However, authors have not ignored the possibility that the cyclic arylpalladium(II) intermediate 8 may directly react with the aminating agent via electrophilic amination pathway to give the amination product (Scheme 12). The role of Ag oxidant in this transformation is not clear. Interestinlgy, Pd(dba)2 is also effective catalyst with 96% yield clearly indicating the possibility of Pd(0)/Pd(II) catalysis. Scheme 11. Scope of O-Benzoyl Hydroxylamine Substrates in Amination F

F O C t-Bu

H

F N H

CF3 F F

+ R1

OBz N 2 R

(2 equiv)

F

Pd(OAc) 2 (10 mol %), AgOAc (1 equiv), CsF (2 equiv) DCE, 130

oC,

O CN H t-Bu

18 h

N

CF3 F F

R2

R1 N

N R2

N

N

N

97%

80%

73%

N CO2t-Bu

=

N R1


78%

75%

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 12. Proposed Reaction Mechanism in Amination NHAr C

O

+ CsF

H O C

Pd(II) NHAr

N R2 Cs

ArN

R1

C reductive elimination

electrophilic amination (R1R2NOBz)

ArH2N C

O PdII Ln arylpalladium(II) intermediate 8

Cs

O Ln PdIV 1R2RN OBz 9

Oxidative Addition

OBz R

1N

R2

The Yu group has also reported the use of a ligand in the development of Pd(II)-catalyzed C-H aminations. Use of 2,4,6-trimethoxy pyridine as a Pd ligand gave ortho-C-H aminated products employing triflyl-protected benzylamines and benzamides with O-benzoyl hydroxyl morpholine as a nitrogen source (Scheme 13).87 Silver acetate acted as the best oxidant with binary bases (Na2CO3+K3PO4) in the reaction. Electron donating groups at the -ortho, -meta, and -para positons as well as electron withdrawing fluoro, chloro, bromo and trifluoromethyl groups are compatible with this amination reaction. In case of benzamides, the amination proceeds only on a specific type of p-trifluoromethyltetrafluoro benzamide (Scheme 14). This amination protocol is equally feasible for other amine donors like piperidine, piperazine and dialkylamine. The authors proposed the catalytic cycle where triflyl-protected amine coordinates to the Pd(II) center after deprotonation by the base as a neutral sulfonimidate. This is followed by ortho-C-H activation and oxidation by aminating reagent to give Pd(IV) species 10 (Scheme 15). Finally, selective reductive elimination leads to amination product with regeneration of Pd(II) catalyst. The authors proposed that the trimethoxy pyridine ligand promotes both oxidation as well as reductive elimination and that AgOAc is helpful for the re-oxidation of Pd0 produced by off-cycle pathways. Schaefer and coworkers studied the role of AgOAc in a palladium acetatecatalyzed ortho-C–H bond activation reaction using density functional theory. Their findings supported Yu’s Pd(II)/(IV) catalytic cycle and proposed a heterobimetallic Pd(µ-OAc)3Ag as an active species over traditional monometallic Pd(OAc)2.88-89 A cooperative interaction between Pd(II) and Ag(I), as well as the additive CsF, help to stabilize transition states and intermediates in the catalytic cycle.


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ACS Catalysis


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 97

Scheme 13. Ligand promoted ortho-C-H Amination of Triflyl-protected Benzylamines Pd(OAc) 2 (10 mol %) AgOAc (2 equiv) L (20 mol %)

OBz N

NHTf

R1

+

H

NHTf

R1 N

O

Na 2CO 3 (2 equiv) K 3PO 4 (1 equiv) 4A MS, C6F 6, 130 oC, 24 h

(2 equiv)

O 15 examples 61-93%

OMe L= MeO

N

OMe

Selected substrate scope CH 3

CF3

OMe NHTf

NHTf

NHTf

N

N

N

O

O

O

85%

72%

90%

NHTf Br

NHTf

N

CH3

H 3C

NHTf

N

O

N

O

61%

O

82%

93%

Scheme 14. Ligand promoted ortho-C-H Amination of Benzamides F O R1

F

CF 3

N H

F

H

OBz N +

F

R2

O

CsF (2 equiv) DCE, 130 oC, 18 h OMe

F N H

R1

R3

(2 equiv)

F

Pd(OAc) 2 (10 mol %) AgOAc (1 equiv) L (20 mol %)

N R2

CF3 F F

R3

15 examples 37-96%

L= MeO

N

OMe

Scheme 15. Proposed Mechanism of ortho-C-H Amination of Triflyl-protected Benzylamines

N

N H

NHTf R2

Tf + Base

H

R1

LPd(OAc) 2 Cyclopalladation

reductive elimination

N

Tf

Pd II IV Pd 2R1RN

10

Tf

N

L

L OBz

OBz N

R1

R2


Page 15 of 97 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Liu and coworkers reported the ortho-directed C-H amidation cross-dehydrogenative coupling (CDC) of aromatic ketones using sulfonamides and amides with an electron deficient Pdcomplex [Pd(OTf)2].90 In these substrates, the Lewis basic ketones are effective palladium chelators, even though they are weaker compared to nitrogen containing strong chelators. The use of ketone as directing group has been continuously applied in organic synthesis because of their ubiquitous presence in various molecules.91 In these reactions. the combination of palladium acetate (10 mol %) with triflic acid (0.5 equiv) is an equally competent catalyst system as the pre-synthesized complex of Pd(OTf)2. The use of fluorocompounds, (N-fluoro-2,4,6trimethylpyridinium triflate), Selectfluor, or Na2S2O8 are crucial as an oxidant for this amidation reaction (Scheme 16). The use of F+ oxidants are beneficial (despite the high costs of these reagents) because coordination of the fluorine to the Pd complex biases the reductive elimination toward the formation of C-N bonds, as the reductive elimination to a form C-F bond is quite difficult. Electron rich ketones perform better as substrates not only for sulfonamides, but also for selected amides and N-methyl sulfonamides as the N-source in the reaction. To demonstrate the utility of this transformation in organic synthesis, the authors applied this procedure to synthesize repaglinide, a drug for type II diabetes. To understand the mechanism of this amidation reaction, authors isolated and characterized (by X-ray crystallography) the Pd(II) palladacycle dimer 11 as well as the ketone- and sulfonamide-coordinated Pd(II) palladacycle 12. These palladacycle dimers gave no C-H amidation product on treatment with nitrene precursor 4-Cl-C6H4SO2N=IPh. Moreover, N-methyl aryl sulfonamides as N-source furnish the C-H amidation products in satisfactory yields indicating that this C-H amidation mechanism does not go through nitrene intermediate as N-methyl aryl sulfonamides cannot produce any nitrene intermediate. Observing all the experimental facts, authors proposed the mechanism where C-H activation step to form ketone chelated 5-member palladacyle 11 is rate-limiting step. The Pd(II)palladacycle 11 coordinates to sulfonamide to give sulfonamide coordinated neutral Pd(II) palladacycle 12. This is followed by oxidation where Pd(IV) imido complex 13 is formed and undergoes selective reductive elimination to furnish the amidated product with release of an active Pd(II) species (Scheme 17).


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Scheme 16. Catalytic Ortho-C-H Amidation of Aromatic Ketones O O R1

R2 R3

Pd(OAc) 2 (10 mol %) HOTf (0.5 equiv)

O

+

R3

R1

NH O S O

S NH 2 F + or Na 2S 2O8 (2-4 equiv) DCE, 80 oC, 8 h

O (2 equiv)

or Selectfluor

F+ =

N

Selected substrate scope

F

O

R2

OTf

O O

NH O S O

Br

NH O S O

Cl 82%

NH O S O

Cl 66%

Cl 66% Me O

O NH O S O

NH O S O

OMe

CF 3

46%

Me

O

82%

NH O S O

Cl 38%


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ACS Catalysis

Scheme 17. Proposed Mechanism of Catalytic Ortho- C-H Amidation of Aromatic Ketones O R NH O S O

O R


+ HOTf

Pd(OAc) 2 Cyclopalladation

R C Pd

O IV

R C O

HN O S O

Pd TfO 2

X-ray crystallography 11

13

R C O

oxidant

II Pd OTf H 2N O S O

O S NH 2 O

X-ray crystallography 12

2-Amino-substituted indoles are biologically and pharmaceutically important compounds. They can be formed by the C-H amination reaction of 5-membered heteroarenes with amines having a leaving group on nitrogen. The Liu group utilized the direct amination of N-methylindole with N-chloro-N-alkyl–benzenesulfonamide as a nitrogen source that gave good yields of 2aminoindole products.92 The use of Pd(OAc)2 (5 mol %), Cu(acac)2 (10 mol %), 2,2’-bipyridine (10 mol %), and Na2CO3 (2 equiv) in dioxane is the best combination for the transformation (Scheme 18A). This room temperature direct amination reaction gave 3-chloro-2-aminoindole product in the absence of 2,2’-bipyridine (Scheme 18B). Possibly, chlorosulfonamide undergoes oxidative addition to the Pd(0) and produces electrophilic Pd(II) intermediate. The species attacks C-3 position of indole and gives C-2 palladated intermediate via C3-C2 migration. Finally, 2-aminoindole product is released by the reductive elimination. Hocek and coworkers extended this amination to 7-deazapurines, pyrrolo[2,3-d]pyrimidine for the synthesis of 8(arylsulfonyl)methylamino-7-deazapurines using the Liu’s Pd-Cu catalysis.93 For these substrates, a large excess of chlorosulfonamide (5 equiv) and base Na2CO3 (7 equiv) are required for reasonable 68 % yield of the aminated product during the extended reaction time of 72 h (Scheme 18C).


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 18. Palladium-Copper Catalyzed Direct Amination and Chloroamination Scheme 18A Pd(OAc) 2 (5 mol %) Cu(acac)2 (10 mol%) bpy (10 mol %)

Cl R1

+

N

Ts

R2

N

R3 R1

N N

R3 Na 2CO 3 (2 equiv) dioxane, rt, N 2, 14 h

(2 equiv)

Ts

R2 13 examples 68-92%

Scheme 18B

Pd(OAc) 2 (2.5 mol %) CuCl (10 mol%) Ag2CO 3 (2 equiv)

Cl R1

+

N

Ts

R2

N

Cl R1 N

CH 3

LiCl (2 equiv) dioxane, rt, N 2, 14 h

(3 equiv)

CH 3 N Ts


Selected substrate scope CH3

CH 3 N

N

N N

Ts

CH 3

CH 3

CH 3

N

Ts

MeO 2C

N

92%

Ts

CH3

CH3

68%

82%

Cl

CH3 N N

N N

Ts

Ph

CH 3 N

N

Ts

Ts

CH3

69%

73%

80%

Scheme 18C Pd(OAc) 2 (5 mol %) Cu(acac) 2 (10 mol%) bpy (10 mol %)

Ph Cl

N N

N Bn

+

ArO2S

N

CH 3

Ph

N N

Na 2CO3 (7 equiv) dioxane, rt, Ar, 72 h

CH 3

N N Bn

SO2Ar

68%

Chen and coworkers have reported the desulfination of sulfamoyl chloride in the direct amination reaction through C-H bond cleavage of benzoxazole followed by C-N bond formation.94 The ideal reaction includes bipyPdCl2 (10 mol %), CuCN (20 mol %) in presence of oxidant K2Cr2O7 (1 equiv), and K2CO3 base (2 equiv) in chlorobenzene solvent. The presence of 4Å molecular sieve accelerated the yield of the reaction (Scheme 19). The possible mechanism for this transformation is a Pd(II/IV) catalytic cycle where initial cupration of benzoxazole is essential for the smooth catalytic transformation (Scheme 20). Transmetallation of Cu(I) to Pd followed by oxidative addition of sulfamoyl chloride leads to Pd(IV) species 14. This species releases SO2 and palladium(IV) species 15, which contains a dimethylamine ligand. Finally, reductive elimation from Pd(IV) N-ligand species gives the amine product along with regeneration of the Pd(II) species for re-entry into the catalytic cycle. The authors have not ignored the possibility of Pd(0/II) mechanism for this tranformation.


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ACS Catalysis

Scheme 19. Palladium-Copper Catalyzed Direct Amination of Benzoxazole with Dimethylsulfamoyl Chloride

R1

H3C

O +

N

BipyPdCl2 (10 mol %) CuCN (20 mol %)

O N S

H3C

O

R1

Cl

N N

K2Cr2O7 (1 equiv) K2CO3 (2 equiv), 4Å MS, chlorobenzene, 150 oC, 24 h

O

CH3 CH3

12 examples 48-91%

Selected substrate scope O O N N

O2N

O

CH3

N N

t-Bu

CH3

CH3

N N

CH3

H3C

O

CH3 CH3

91%

70%

76%

O O N N

EtO2C

O

CH3

N N

CH3 F3C

80%

N

CH3 CH3

N H3COC

CH3 CH3

48%

86%

Scheme 20. Proposed Mechanism of Palladium-Copper Catalyzed Direct Amination of Benzoxazole with Dimethylsulfamoyl Chloride O N O N N

CH3

CuCN

CH3

O Cu(I) N Pd(II)

reductive elimination transmetallation

CH3

H3C O N

N

O Pd(II)

Pd(IV)

N

Cl

15 H3C SO2

CH3 N

O S O O Pd(IV) N Cl

H3C

O N S

H3C

Cl

O

oxidative addition

14

Azides are very reactive as nitrogen sources in C-H activation, but overall are milder reagents than the oxidants typically used in these reactions because they release only N2 as a by-product. Many organic azides are considered as electrophilic nitrene precursors as they generate a reactive nitrene intermediate, which inserts into the C-M bond to create a new C-N bond. While azides have seen extensive use as nitrogen sources in ruthenium-, rhodium-, and iridium-catalyzed C-H amination, their use in pd-catalyzed C-H amination reaction has been limited.95 Jiao and


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

coworkers reported the installation of one N-atom from sodium azide through C-H activation in 2-arylpyridines.96 This Pd-catalyzed direct C-H azidation was followed by spontaneous N-N bond formation and provides an alternative route to synthesize bioactive pyrido[1,2-b]-indazoles (Scheme 21). For the best result, Ce(SO4)2 oxidant with FeCl2 additive under O2 (1 atm) is required and the reaction requires extended reaction times (79-82 h) at 100 oC for completion. Possible mechanism involves a N-chelated cyclopalladium (II) dimeric intermediate 16 formed by the involvement of rate-limiting C-H bond cleavage (kinetic isotope effect, kH/kD = 4.0). After ligand exchange with the azide group and oxidation by Ce(SO4)2; azido Pd(IV) species 17 is formed (Scheme 22). This intermediate undergoes reductive elimination to give azide product, which spontaneously cyclized to pyrido[1,2-b]-indazole releasing N2 gas. The final step of forming cyclized product with release of N2 does not involve the catalyst. Scheme 21. Palladium-Catalyzed Tandem C-H Azidation and N-N Bond Formation of Arylpyridines

R2 N

R1

Pd(OAc) 2 (15 mol %) Ce(SO 4)2 (2 equiv)

(2 equiv)

R2

R1

+ NaN 3

N

FeCl 2 (20 mol %) DMSO, 100 oC, O2 (1 atm), 79-82 h

N

27 examples 35-77%

Scheme 22. Proposed Mechanism of Palladium-Catalyzed Tandem C-H Azidation and N-N Bond Formation of Arylpyridines

N

N N

- N2 Pd(OAc)2 N N3 reductive elimination

N Pd OAc 16

N IV Pd Ln N3 OAc 17

2 cyclopalladium (II) dimeric intermediate

N3 followed by Ce(SO4)2 oxidation

2.5. NFSI (N-Fluorobenzenesulfonimide) in C(sp2)-H Intermolecular Amination Zhang and coworkers reported a highly chemoselective intermolecular amide directed C-H amination reaction of anilides by using the non-nitrene nitrogen source N-


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ACS Catalysis

Fluorobenzenesulfonimide (NFSI).97 The common base sodium bicarbonate (2 equiv) in 1,2dichloroethane works well for the reaction (Scheme 23). Depending on the substrate, this reaction can be extended to afford the para-aromatic C-H amination product if one or both ortho-positions are blocked (Scheme 24); this is the first example of a reaction of this type. 2-and 4-substituted acetanilide do not give the desired products as 4-substituted acetanilide gives the unseparated mixture of side products without major products. The authors proposed in situ generation of F-Pd(II)N(SO2Ph)2 18 by the oxidative addition of Pd(0) to the N-F bond of NFSI (Scheme 24). This intermediate coordinates with the arene to form a dearomatized spiropalladacycle 19. The intermediate 19 undergoes nucleophilic amination followed by hydrogen elimination to release ortho- or para-amination product depending on the electronic and steric effect of the arene substituents. If one or both ortho-positions are blocked, the para amination product is predominant. Scheme 23. Ortho- C-H Amination with NFSI

R1

Pd(OAc) 2 (10 mol %) NaHCO 3 (2 equiv)

F

NH

2 C R O

+ PhO 2S

N

SO2Ph DCE, 80

oC,

N(SO 2Ph) 2

R1

1.5 - 13 h

(2 equiv)

NH C R2 O

17 examples 44-90% Selected substrate scope N(SO 2Ph) 2

N(SO 2Ph) 2

NH C

NH C O

FO

NH C O

MeO

59%

62%

NH C O

60% N(SO 2Ph) 2

N(SO 2Ph) 2

90%

N(SO 2Ph) 2

NH C O

O

58%

O C

N(SO 2Ph) 2

HN

NH C O 74%


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 97

Scheme 24. Para- C-H Amination with NFSI and Proposed Mechanism R1 NH

2 C R O

Pd(OAc) 2 (10 mol %) NaHCO 3 (2 equiv)

F + PhO 2S

N

R1 (PhO 2S)2N

SO2Ph

DCE, 80 oC, 3 h

(2 equiv)

NH 2 C R O 11 examples 71-94%

F

OCH 3 (PhO2S)2N

Pd[II]

NH 2 C R O

Pd[0]

PhO 2S

N

SO2Ph

oxidative addition

-HF FPdN(SO 2Ph) 2

(PhO 2S) 2N H

18

OCH 3 H N

OCH 3 NH C O

C Pd O OCH 3

F

NH OCH3 H N

N(SO 2Ph) 2

F

C Pd O N(SO 2Ph)

C Pd O F deromatized spiropalladacycle 19

2.6. Simple Arenes in Intermolecular C-H Amination Hartwig and coworkers have developed an oxidative amination of mono-, di-, and trisubtituted arenes without a directing group with phthalimide as a nitrogen source (Scheme 25).98 Reactions without a directing group are challenging because the catalyst is not pre-coordinated to the substrate and there is no high local concentration in close proximity to the metal.99 The sterically-control amination of arenes is one best option to generate various protected anilines from different aromatic compounds with moderate to high yields. For the best result, sequential addition of oxidant PhI(OAc)2 is required. Various reactions of 1,2,3-trisubstituted and symmetric 1,2-disubstitued arenes produce the less hindered products as the major constitutional isomer. Unsymmetrical 1,2-disubstituted arenes provide good yields of the two amination products possessing the phthalimide group meta to both substituents. Arenes with carbonhalogen bonds were tolerated without amination at the site of the halogen or protondehalogenation. The authors proposed that amination mechanism proceeds through an irreversible C-H bond cleavage (kinetic isotope effect, kH/kD = 4.1) and is different from acetoxylation of arenes by concerted metalation-deprotonation (CMD) sequence.


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ACS Catalysis

Scheme 25. Intermolecular C-H Amination of Toluene by Phthalimide O Me

Pd(OAc) 2 (10 mol %) t-Bu 3P (10 mol %)

HN

+

O (0.1 mmol scale)

O Me N O

PhI(OAc) 2 (4 equiv) toluene (1 mL), 100 oC 33 h

70% o:m: p=1:9:8

Ritter and coworkers has reported arenes as the limiting reagent in catalytic intermolecular C-H imidation that employs an amine-N-oxide-ligated palladium complex with a silver co-catalyst (Scheme 26).100 The nitrogen source N-fluorobenzenesulfonimide (NFSI) reacts with a variety of arenes without coordinating directing groups to afford good yields of imidated products. Various arenes including N- and S-heteroarenes give good yields. Selectivity is mostly substrate based and electron-rich arenes also give constitutional isomer products due to amidation at different site of the arene ring. The authors proposed the mechanism in which amine-N-oxide ligated palladium oxidizes to Pd(IV) species 20 by N-Fluorobenzenesulfinimide as a turnover-limiting oxidation (Scheme 27). The Pd(IV) intermediate complex undergoes single electron reduction by Ag(bipy)2+ followed by arene association to provide Pd(III) species 21. This intermediate transfers sulfonimidyl radical to bound arene to provide a delocalized radical 22 with release of Pd-catalyst. The arene radical is oxidized by Ag(bipy)2+ followed by deprotonation leads to imidated product. The interesting aspect of this mechanism is formation of C-N bond without involvement of C-H palladation. Scheme 26. Aryl C-H Imidation with Arene as the Limiting Reagent Ag(bipy)2ClO4 (10 mol %) Pd complex ( 2 mol %)

F Ar-H

N

+

(1 equiv)

PhO2S

Ar-N(SO2Ph)2

SO2Ph

MeCN, 23 oC, 24 h

(2 equiv)

N N O Pd O N N

Pd complex =

27 examples 45-99%

(OTf)2

Selected substrate scope N(SO2Ph)2

MeO2C

N(SO2Ph)2

O2N

N(SO2Ph)2 OMe

OMe 76%

99%

99% O N(SO2Ph)2

O (PhO2S)2N

O

OMe

O2N 89%

CO2Me NC

MeO 81%

S

N(SO2Ph)2

84%


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 27. Prosposed Mechanism of Aryl C-H Imidation with Arene as the Limiting Reagent 2 F (PhO2S)2N

N N O Pd N O N

H .

22

N SO2Ph

PhO2S

turnover limiting

resting state

2 IV Pd N(SO2Ph)2 F

20 + Ag I

F

III Pd NH(SO2Ph)2 F

21

2.7. Aromatic Nitration by C-H Bond Activation To make the traditional electrophilic nitration more broad and efficient in organic synthesis,5 Liu and coworkers introduced a chelation-assisted, site-regiospecific nitration of aromatic C-H bonds using AgNO2 as a nitrating reagent.101 The authors reported that Pd(OAc)2 (10 mol %) in combination with K2S2O8 (2 equiv) in AgNO2 (2 equiv) reacts with 2-phenylquinoxaline at 130 o C to give ortho-nitration product (Scheme 28). Various quinoxaline derivatives give orthonitration products in moderate to high yields (35-93%), with electron rich aryl substrates affording the better results. The nitration of more challenging substrate like 2,3diphenylquinoxaline required more catalyst loading, nitrating agent, and oxidant to furnish double nitration product 23 in 55 % yield. The authors are also able to nitrate many aromatic ketones using O-methyl oximes as a reasonable N-donor tethered aromatics (Scheme 29). In contrast to quinoxaline derivatives, O-methyl oximes give better results employing Pd(OCOCF3)2 (10 mol %) at lower temperature 110 oC (Scheme 29). Likewise, substrates having electron withdrawing groups give better results than those having electron donating groups. Due to this electronic differentiation in reaction pattern of quinoxaline and O-methoxy oxime, the authors proposed different reaction mechanisms, the former having electrophilic aromatic substitution and the later concerted metalation-deprotonation mechanism. They have isolated the binuclear palladacycle from quinoxaline but not from O-methoxy oxime. The later gives a mononuclear palladacycle 24. Possibly, quinoxaline-assisted reactions may proceed via a Agmediated radical mechanism with a binuclear palladacycle species. But O-methoxy oximeassisted reactions have high possibility of Pd(II)/(IV) catalytic cycle involving a mononuclear palladacycle 25 (Scheme 29). Wu and team reported a chelation-assisted ortho-nitration of 2arylbenzoxazoles using AgNO2 as a nitrogen source in presence of K2S2O8 oxidant under oxygen atmosphere (Scheme 30).102 A catalytic system of Pd(OAc)2 (10 mol %) in trichloropropane showed the best combination for a number of 2-arylbenzoxazole derivatives. These 2arylbenzoxazole substrates showed no electronic effect with substituents on the benzene ring, as both electron donating groups and electron withdrawing groups give high yields (80-97%). The


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ACS Catalysis

authors performed a radical trapping experiment with the radical scavenger TEMPO to confirm the involvement of the NO2 radical in the mechanism. Scheme 28. Pd-Catalyzed Ortho-Nitration of Quinoxaline Derivatives Pd(OAc) 2 (10 mol %) AgNO2 (2 equiv)

N

R3

R2 N

R1

N

R3

R2 N

R1

K 2S2O8 (2 equiv) DCE, 130 oC, 48 h

NO 2 15 examples 35-93%


NO 2 N

MeO

OMe

N

N

N

NO 2

NO 2

88%

N

F

93%

N

N

N

NO 2

NO 2

35%

23, 55%

Scheme 29. Palladium-Catalyzed Ortho-Nitration of O-methoxy oxime and Its Proposed Mechanism OMe N R1

R2

Pd(OCOCF3)2 (10mol%) AgNO2 (2 equiv) K2S2O8 (2 equiv) DCE, 110 oC, 48 h

NO2 N

OMe R2

R1

23 examples 42-91% OMe N

NO2 N

+

AgNO2

OMe L2Pd(II) CH3 reductive elimination N OMe

N OMe IV Pd NO2 NO2 25

Ag

II Pd L L 24 NO2 via Ag(I)NO2 + K2S2O8 radical entry


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 30. Chelation-Assisted ortho-C-H-Nitration of 2-Arylbenzoxazole Derivatives R2 O

R1

N

R2

Pd(OAc) 2 (10 mol %) AgNO2 ( 3 equiv)

O

R1

N O 2N

K 2S2O8 (2 equiv) TCP, 130 oC, O2, 42 h

16 examples 43-97%

2.8. Pd-Catalyzed Intermolecular Allylic Amination The synthesis of allylic amine compounds via intermolecular direct oxidative amination of simple and unactivated alkenes is significant and challenging.103-104 Generally allylic substitution requires a leaving group at the allylic position, but direct C-H activation avoids the necessity of pre-synthesis of the leaving groups. White and coworkers reported a successful allylic intermolecular C-H amination employing a heterobimetallic Pd(II)/Cr(III) catalytic system (Scheme 31).105 Silyl or benzyl ethers, Weinreb amides, Cbz- or Pht-protected amines are tolerated and provided high yields of linear allylic C-H amination products. It is believed that the Pd(II) catalyst activates the C-H bond and Cr(III) catalyst makes the π-allyl Pd-BQ complex more electrophilic. Scheme 31. Palladium(II)-Chromium(III)-Catalyzed Linear Allylic Amination

R

+

CO 2Me HN Ts

Pd(OAc) 2 (10 mol %) Cr(III)(salen)Cl (6 mol %) L (10 mol %) BQ, TBME, 45 oC, 72 h L=

O Ph

Selected Substrate Scope

O

CO 2Me N Ts

O 72%

CO 2Me N Ts

R

n-C 7H 15 59%

S

S

E:Z=20:1 Linear:Branched(20:1)

O Ph

CO2Me N Ts

CO2Me N Ts

BMBO NPht 65%

The White group extended the study using Bronsted bases like N,N-diisopropylamine, triethylamine and N,N-diisopropylethylamine to promote the scope of linear allylic amination.106 Authors proposed that Bronsted bases help the reactions by deprotonating the nitrogen atom. They improved this intermolecular linear allylic C-H amination (LAA) using a cobalt-mediated redox-relay cycle in presence of molecular oxygen as the terminal oxidant under mild conditions. The use of catalytic quantity of benzoquinone (BQ) improved the yields in comparison to the previously used excess stoichiometric benzoquinone oxidant even under reduced Pd-catalyst loadings. Their kinetic experiment showed that BQ has inhibitory effect on Pd(II) oxidative catalysis.107 Liu and co-workers utilized Pd(II)-catalyzed aerobic conditions for linear allylic amination of N-tosyl-carbamates.108 This reaction provided good yields, high regioselectivities and a tolerance of various functional groups on the alkene. Terminal olefins having benzyl ether, methyl aryl ether, ester, ketal and phthalimidyl groups gave direct oxidative linear amination


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ACS Catalysis

products in good yields (Scheme 32). Alkenes as the limiting reagent also provided modest to good yields. Authors prepared a π-allylpalladium complex and reacted with imide to support a mechanism in which allylic C-H activation proceeds with attack of nitrogen nucleophile at the terminal position of the π-allyl intermediate. Scheme 32. Palladium-Catalyzed Oxidative Allylic Amination of Alkenes Pd(OAc)2 (10 mol %) (MA) (40 mol %)

O R

+

NHTs

R1O

3 equiv

1 equiv

Ts N

R1OOC NaOAc (25 mol%) 4Å MS, O2 (6 atm) DMA, 35 oC

R + nonallylic isomers


MeOOC

Ts N

R tBuOOC

Ts N

87% (70:30)

OBn

MeOOC

Ts N

OMe O

83%

O

BnOOC

53%

Ts N

80%

In Liu’s subsequent work, they used soluble oxidant PhI(OCOtBu)2 to reduce the isomerization of the terminal double bond of the starting material as well as the isomerization of the products. This oxidant is also helpful to reduce the concentration of deleterious Pd(0) as well as reoxidation of it. The combination of PhI(OCOtBu) oxidant, substoichiometric amount of naphthoquinone and Bu4NOAc not only gave the high yields and excellent linear allylic amination selectivity but also significant improvements like olefin as limiting reagent, low catalyst loading (1-5 mol %) and shorter reaction time (5-8 h).109 Authors identified the role of naphthoquinone (NQ) in the reaction that leads rapid equilibration to afford a nitrogencoordinated olefin-Pd(NQ) complex which undergoes turnover-limiting allylic C-H bond activation to provide a π-allylpalladium complex. This mechanism involves irreversible allylic C-H bond activation with formation of π-allylpalladium complex followed by irreversible nucleophilic nitrogen attack on the basis of deuterium labeled and cross-over experiments. The fine-tuning of the electron density on the nitrogen atom is a key factor to facilitate allylic amination. Ishii and coworkers reported an aerobic linear allylic amination of simple alkenes using diphenylamine and Pd(OCOCF3) as a catalyst (Scheme 33).110 Scheme 33. Palladium(II)-NPMoV-Catalyzed Linear Allylic Amination of Alkenes with Diphenylamine

R

Pd(OCOCF3)2 (10 mol %) (NPMoV) (2 mol %)

H N + Ph

Ph R

Ph

N

Air (10 atm) Trifluorotoluene, 40 oC

Ph

NPMoV = [(NH4)5]H4PMo6V6O40.23H 2O Selected Substrate Scope Ph n-C5H11

N 52%

Ph

Ph Ph

n-C9H19 53%

N

Ph

Cy 73%

N

Ph Ph

Ph

N

75%


Ph

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 97

Baran and coworkers utilized Pd(OAc)2 as a redox-conserving route to synthesize N-tertprenylated indoles via C–H functionalization of 2-methyl-2-butene based on the allylic C-H amination (Scheme 34).111 The direct use of indoles as the amino coupling partner provides a significant advantage as many other methods utilize electron deficient amines. The authors proposed a π-allyl-Pd species as a key intermediate via allylic C(sp3)-H bond activation. Scheme 34. Palladium(II)-Catalyzed N-tert-Prenylation of Indoles Pd(OAc) 2 (40 mol %) AgOTFA (2 equiv)

R N H

R

+

N

Cu(OAc)2 (2 equiv) MeCN, 35 oC, 24 h

Selected Substrate Scope CO2Me

CO 2Me

CO 2Me

NHBoc

NPhth

NHFmoc

N

N

N

70 %

69 %

61 %

Zhang and coworkers reported the use of N-Fluorobenzenesulfonimide (NFSI) as a combined oxidant and nitrogen source efficiently to convert alkenes into respective allylic imides in presence of Pd(OAc)2 (10 mol %) and H2O (30 mol %) (Scheme 35).112 The authors proposed an intermediate Pd(II)-hydroxo complex which subsequently undergoes C-H activation. This species has two paths to accomplish the imide product either by reductive elimination and reoxidation of the Pd(0) species or by formation of a Pd(IV) species followed by subsequent reductive elimination.

Scheme 35. Palladium-Catalyzed Oxidative Allylic Amination Using NFSI

Pd(OAc) 2 (6 mol %) NFSI (1 equiv) R KF (2 equiv), H 2O (30 mol %) CCl 4, 60 oC, 24 h

H R

H O

SO2Ph [Pd]

N

SO2Ph

R N(SO 2Ph) 2 SO2Ph

54-88% [Pd]

N

SO2Ph

R

3. INTRAMOLECULAR C-N BOND FORMATION Palladium catalysts are very effective and successful in creating cyclometallation intermediates52 with various functional groups such as carbonyl compounds, nitrogen heterocycles and hydroxyl groups. In many cyclizations, the redox interchange between the two stable Pd(II)/Pd(0) oxidation states is responsible for the transformation and this redox chemistry is very compatible


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ACS Catalysis

with many organic functional groups. The Pd(II)/Pd(IV) redox mechanism has also been highly explored for the intramolecular formation of C-N bonds. In intramolecular C-N bond formation strategy, the palladacycle scaffold is generally recognized as the intermediate species stabilized by the intramolecular coordination of one neutral heteroatom donor, such as nitrogen or oxygen. The synthetic versatility, chemical stability, and mechanistic predictability of these palladacycle intermediates allow for a systematic and rational development of reactions to form C-N bonds. When palladium metal coordinates to a Lewis basic heteroatom, it lowers the entropic and enthalpic costs of the C-H bond cleavage as well as cyclization. The ring of palladacycle in C-H activation reactions generally vary between 4 and 7 atoms in size. In most cases, a kinetically favorable orientation for palladacycle through chelating the heteroatom leads to mainly either 5or 6-membered, which are thermodynamically stable palladacycles. Electrophilic aromatic substitution pathway is still the most favorable mechanism of cyclopalladation of aromatic compounds. The electronic and steric properties of the palladacycle is modulated by changing the size of the metallacyclic ring, the nature of the metallated C-atom (aliphatic or aromatic), the type of heteroatom donor group and its substituents, and the nature of associated ligands along with participated solvents. The intramolecular cyclization phenomenon remains a key factor to overcome the high energy barrier of product forming C(sp2)-N reductive elimination step. In some cases, reaction of the heteroatom directing group with the palladium leads to isomerization of the substrate, which then undergoes an intramolecular Pd-catalyzed C(sp2) amination process. A metal-nitrene reactive intermediate may react with the proximal arene or vinyl hydrogen to form C-N bond.113 For clarity here, the intramolecular C-N bond formation reactions via C-H activation are organized according to the size of the putative palladacycle ring. 3.1. Intramolecular Dehydrogenative C-H Amination The intramolecular dehydrogenative C-H amination (IDCA) is a very efficient way of combining N-H and C-H bonds to synthesize the desired C-N bond with a formal release of H2. The amine NH group of the substrate facilitates C-H activation by acting as a directing group and provides a palladacycle intermediate, a key step for C-N bond formation. 3.2. Intramolecular C-N Bond via Six-Membered Palladacycle 3.2.1. Pd(II)/Pd(0) Cycle In 2005, Buchwald and coworkers reported the directed C-H fuctionalization intramolecularly for the C-N bond formation leading to the construction of cabazoles.114 This inner sphere catalyst development for C-H bond amination is inspired by the seminal works of Tremont115 and Daugulis116. This is a powerful example of intramolecular cross-dehydrogenative coupling (CDC) for C-N bond formation and offer proof of principle of atom economy, efficiency and waste-free amination qualities of direct amination reactions. The conversion of 2acetaminobiphenyl to N-acetyl carbazole is achieved by using the combination of palladium precatalyst (5 mol %) and Cu(OAc)2 reoxidant (10 mol %) at 120 oC in presence of 1 atm of oxygen (Scheme 36). Using these conditions, various carbazoles could be synthesized tolerating electron-donating as well as electron-withdrawing groups. Initially, the authors proposed sixmembered palladacyclic intermediate species 26 through ortho-palladation reaction. This species on subsequent reductive elimination gave the carbazole product with release of Pd(0) species


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

which is re-oxidized to Pd (II) by Cu(OAc)2 to complete the catalytic cycle (Scheme 37). But later in 2008, the authors extended their work to study functional group compatibility and mechanism.117 The substrates containing sulfonamide as the amine protecting groups cleanly afforded acetamides as the cyclization product. But, carbamate-, benzoyl-, and perfluoropropanoyl N-protecting groups provided very low yields indicating that the acidity of the nitrogen-hydrogen bond is very important. The formation of acetylcarbazoles with various substitution patterns especially -ortho or -para positions to the biaryl axis can be obtained in excellent yields. The authors also applied this method for the synthesis of naturally occurring carbazoles. In their extensive experimental studies, their initial proposed mechanism remained inconsistent so that authors proposed a new mechanism invoking the formation of palladium amide intermediate 27 before C-H bond activation. This leads to two diastereomeric Pd(II) species 28 and 29 via Wacker- and Heck-type processes respectively. These palladium species undergo β-hydrogen elimination to provide carbazole product. The Pd(0) species re-oxidizes to Pd(II) by Cu(OAc)2 or oxygen to complete the catalytic cycle (Scheme 38). Scheme 36. Combined C-H Activation/C-N Bond Formation for the Synthesis of Carbazoles Pd(OAc) 2 (5 mol %) Cu(OAc) 2 ( 1 equiv)

O

R1 N H

R1

Me

Me

N O 2 (1 atm), toluene 120 oC, 12-24 h

R2

O

R2

18 examples 41-98%

Selected substrate scope Me Me

F 3C

Me

Me

N

Me

N

O

N O

O OMe 88%

92%

88%

F 3C Me

Me

Me

N

N

N

O

O

O

MeO t-Bu 92%

88%

41%


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ACS Catalysis

Scheme 37. Buchwald’s Initial Proposed Mechanism of Combined C-H Activation and C-N Bond Formation Cu(OAc) 2 O

Me re-oxidation

N

N H

O

Me

Pd(OAc) 2

LnPd(0) reductive elimination O N

Me

O H N

Pd

Me

Pd OAc OAc O H N HOAc

Me

Pd OAc

HOAc

six-membered palladacycle 26

Scheme 38. Proposed Mechanism of Combined C-H Activation and C-N Bond Formation via Heck- and Wacker-type Processes O Me

N H

Cu(OAc)2/O2 Pd(OAc)2 re-oxidation

HOAc

O

LnPd(0)

Me

N

HOAc

Pd OAc

27 PdH(OAc)

O N Me

O N

hydride elimination

or

H Me Pd OAc 29

O N H Me Pd OAc 28

distereomeric species


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 97

Inamoto and coworkers developed a catalytic C-H activation of hydrazone compounds by intramolecular amination using Pd(OAc)2 (10 mol %) (Scheme 39).118 The use of combination of oxidants Cu(OAc)2 and AgOCOCF3 is essential in C-H activation. The cyclization of either benzene ring largely depends on the electronic nature of the ring depending on the substituents. When the reactions of monosubstituted benzophenone tosylhydrazones of different E/Z-isomer ratios are used separately in the reaction, they gave similar conversions and yields indicating that isomerization of hydrazones occurs easily under the reaction conditions. Inamoto’s proposed mechanism is similar to Buchwald’s initial mechanism of carbazole synthesis where nitrogenchelated six membered palladacycle 30 reductively eliminates to give 3-arylindazole product. The regenerated Pd(0) is presumbly re-oxidized to Pd(II) by Cu(OAc)2 and AgOCOCF3. Inamoto’s group extended the study to synthesize 3-substituted indoles utilizing palladiumcatalyzed C-H activation via intramolecular amination of enamine compounds.119 A stoichiometric amount of Cu(OAc)2 and DMSO as solvent are crucial for this transformation (Scheme 40A). A single unsymmetric enamine isomer possessing differently substituted benzene rings gave regioisomeric mixture of two indoles indicating that the E/Z isomerization of the enamine occurs during this process (Scheme 40B).

Scheme 39. Aryl C-H Activation/C-N Bond Formation for the Synthesis of 3-Arylindazoles Pd(OAc) 2 (10 mol %) Cu(OAc)2 ( 1 equiv)

R1 N

R2

NHTs

R1

AgOCOCF3 (2 equiv) DMSO, 50 oC, 10-24 h

N

N N Ts

R2

Pd

NTs

30 16 examples 13-99%

6-membered palladacycle

Scheme 40. Aryl C-H Activation/C-N Bond Formation for the Synthesis of 3-Substituted Indoles Scheme 40A

R2

R1

Pd(OAc)2 (10 mol %) Cu(OAc)2 (1 equiv)

R1

NHTs

DMSO, 80-150 oC 5-24 h

R2

N H 6 examples 29-68%

Scheme 40B OMe

Pd(OAc)2 (10 mol %) Cu(OAc)2 (1 equiv) MeO

MeO

DMSO, 80 oC, 24 h NHTs

+ N H

N H (4.8:1)

single dissymmetric enamine

38%


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ACS Catalysis

Charette and coworkers utilized tosylhydrazonamide for intramolecular C-N bond forming reaction in the presence of Pd(OAc)2 (10 mol %) and CsOPiv (2 equiv) in toluene under air (Scheme 41).120 The authors reported this methodology in a two-step synthesis for the efficient conversion of readily available tertiary amides into diverse 3-aminoindazoles. Scheme 41. Palladium-Catalyzed Rapid Synthesis of 3-Aminoindazoles from Tertiary Amides

(1) (Tf) 2O (1.1 equiv) 2-Meo-Py (1.3 equiv)

O N

R1

R2

TsHN

N

R1

R3

Pd(OAc) 2 (10 mol %) CsOPiv (2 equiv)

N R2

N R1

R3

(2) TSNHNH2 (1.5 equiv) CH 2Cl 2, oC to rt, 3 h

TsN N

R2

R3

Toluene, air, 110 oC, 16 h 18 examples 15-70%

44-90%

N-Tosylphenylacetamide compounds are important because of their use in synthesizing heterocyclic cores in natural products and pharmaceuticals. The cyclization of these compounds via ortho-C-H bond activation and C-N bond formation is reported by Murakami and coworkers (Scheme 42).121 When N-tosyl-2-methyl-2-phenylpropanamide is treated with Pd(OAc)2 (10 mol %) in presence of Cu(OAc)2 under an O2 atmosphere, the corresponding oxindole is produced in 82 % yield. The authors proposed the six-membered ring palladacycle 31 which undergoes reductive elimination providing the oxindole product and Pd(0) species (Scheme 43). This Pd(0) species re-oxidizes to Pd(II) species in the presence of Cu(OAc)2 in O2 atmosphere. This cyclization reaction is limited because non-substituted derivatives on the methylene carbon do not work, most likely due to a gem-dialkyl effect. Scheme 42. Synthesis of Oxindoles by Palladium-Catalyzed C–H Bond Amidation R 2 R 3H N

R1

Pd(OAc) 2 (10 mol %) Cu(OAc)2 ( 1 equiv)

R2 R3 C O

R1

Ts

N

5A MS, p-xylene, O2 100 oC, 14 h

O

Ts 9 examples 58-84%


C O

C O

N

N

Ts

Ts

39%

84%

C O N

Cl

C O N

MeO

Ts

Ts 65%

61%


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 43. Proposed Mechanism of Oxindoles by Palladium-Catalyzed C–H Bond Amidation Me Me H N

Ts

O Cu(OAc)2/O2 Pd(OAc) 2 re-oxidation

HOAc

Pd(0)Ln Me

Ts Me Me N

Me N Ts

Pd(OAc)

O

C O reductive elimination

cyclopalladation Me Me

O

-HOAc

NTs Pd 31 palladacycle

Shi, Yang and coworkers utilized tetramethylthiourea (TMTU) for the first time as an additive for the intramolecular C-N bond formation via C-H activation methodology.122 TMTU has been used as a ligand in various transformations.123-124 Varieties of 1H-benzo[d]imidazoles are synthesized using [PdCl2(PhCN)2] as the catalyst and Cu(OAc)2/O2 as a co-oxidant employing N-phenylbenzimidamides in NMP solvent at 80-100 oC (Scheme 44). Only electron donating groups on phenyl rings containing the nitrile moiety afforded the products. This also applies to aniline derivatives which give better yields if the phenyl ring has electron donating groups. Both free NH groups are required for this cyclization as N-substituted N-phenylbenzimidamides do not afford the desired imidazole. The imino group directs ortho-cyclopalladation, affording the six-membered palladacycle dimer 32 (Scheme 45). The palladacycle coordinates to TMTU to give another intermediate species 33. Acetate ion acts as a base and removes proton from imino group and this intermediate undergoes reductive elimination to give desired imidazole product, releasing Pd(0) which re-oxidizes to Pd(II) by Cu(OAc)2/O2 (Scheme 45). The possible role for TMTU is to facilitate the reductive elimination. Reactions in absence of TMTU, which afford product by direct deprotonation followed by reductive elimination from six-membered palladacycle dimer, offer poor yields of product. In these reactions, there is also the possibility of Cu(OAc)2 acting as a catalyst.


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ACS Catalysis

Scheme 44. Direct Imidation by Pd(II)-Catalyzed C-H Activation Promoted by Thiourea H N

R1

PdCl 2(PhCN) 2 (10 mol %) Cu(OAc) 2 ( 1 equiv)

R2

H N N

TMTU (20 mol %) NMP, O 2, 80-100 oC, 24 h

NH

R2

R1

17 examples 40-75% Selected substrate scope H N

H N

N

N

60%

63%

Me Me

H N

MeO

H N

MeO

N 65%

H Me N

O

H N

N

O

N

OMe

N

53%

71%

75%

Scheme 45. Proposed Mechanism of Direct Imidation by Pd(II)-Catalyzed C-H Activation Promoted by Thiourea Cu(OAc) 2/O2 H N

H N

+ OAc NH

N

Pd (II) Pd(0) HOAc

reductive elimination H N

cyclopalladation

Ph

H N

N Pd L

Ph NH

TMTU

Pd L 2

AcOH

32 H N OAc

Ph NH

TMTU

Pd L

TMTU 33

Punniyamurthy and coworkers utilized an intramolecular C-H activation and C-N bond formation strategy for the synthesis of 1-aryl-1H-benzotriazoles.125 Importantly, 1Hbenzotriozole motifs possess anticancer and antibacterial activities. The reaction of aryl triazene compounds with Pd(OAc)2 (10 mol %), 2 equivalent Cs2CO3 base in DMF in the presence of 4Å molecular sieve at 110 oC under O2 atmosphere afforded the desired 1-aryl-1H-benzotriozole in good yields (Scheme 46). The cyclization reaction is controlled by both steric and electronic factors on the aryl rings, as substrates with para-COMe, para-CO2Et, and para-OMe


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

substitutents did not cyclize to the desired product. Substrates containing the bromine group provided exclusively the de-brominated products. Unsymmetrical substrates give regioisomeric cyclized products, with the cyclization favoring the non-substituted aryl ring as the major regioisomer. The authors have proposed the six-membered palladacycle 34 as a key intermediate to afford the desired product (Scheme 46). The palladacycle undergoes reductive elimination forming the C-N bond along with formation of Pd(0), which is subsequently re-oxidized to Pd(II) by molecular O2. The same group also extended C-H aerobic oxidative amination of bis(aryl)amidines to synthesize N-aryl benzimidazoles by using Pd(PPh3)2Cl2 (10 mol %) and Cs2CO3 (2 equiv) in DMSO at 120 oC (Scheme 47).126 N,N’-Bis(phenyl)formamide having methyl substituents at the ortho-position of both the phenyl rings do not cyclize probably due to steric hindrance. Symmetrical substrates with substituents like methyl, ethyl, fluoro and 2-propyl at meta- or para- positions of both the phenyl rings cyclized to give the respective N-aryl benzimidazoles as a single regioisomer. The common palladium precursor Pd(OAc)2 do not work in this reaction; treatment with that catalyst resulted in decomposition of the bis(aryl)amidines.

Scheme 46. Pd-Catalyzed C-H Activation/C-N Bond Formation to Synthesize 1-Aryl-1HBenzotriazoles

Scheme 47. Palladium-Catalyzed Aerobic Oxidative C–H Amination to Synthesize 2Unsubstituted and 2-Substituted N-Aryl Benzimidazoles

Koenig, Stahl and coworkers utilized an aryl C-H amination for the synthesis of indole-2carboxylates employing 2-acetamido-3-arylacrylates in the presence of O2 as the stoichiometric


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ACS Catalysis

oxidant.127 Pd(OAc)2 (10 mol %) in O2 (1 atm) as the terminal oxidant in 24 h at 100-120 oC affords the aminated products moderate to high yields. Unprotected and benzoyl-protected amine were not effective, but a tosyl protected substrate gave a maximum 83% yield at 120 oC. Substrates possessing electron withdrawing and donating groups required higher temperature to access higher yields. The authors proposed a Pd(II)-amidate species that can activate aryl C-H bond to make Pd(II) six-membered palladacycle 35 (Scheme 48) which reductively eliminates to give indole product and ligated Pd(0) which subsequently oxidizes to Pd(II) by O2. Scheme 48. Intramolecular Aryl C–H Amination of Ethyl-2-Acetamido-3-Arylacrylates O Pd(OAc)2 (10 mol %) 3Å MS

O R1

OEt NHAc

O 2 (1 atm) DMSO/toluene or p-xylene (1:1), 80-120 oC, 24 h

O R1

N Ac

II NAc Pd L L 35

OEt

17 examples 36-95%

OEt

Pd(II) six-membered palladacycle

Recently, Yoo and Lee reported the efficient synthesis of C-N coupled heterobiaryls by sequential N-H functionalization reactions.128 The N-H insertion between 1-sulfonyl-1,2,3triazoles and 9H-carbazole in presence of Rh2(oct)4 (0.5 mol %) affords N-carbazolated enamide in good to excellent yields. The C-H amination of (Z)-ene-1,2-diamine is challenging regioselectively because the cyclization requires an anti-orientation between carbazoles and Nsulfonyl amino group. Intramolecular C-H amination affords the synthesis of indoles containing carbazoles employing Pd(OAc)2 (10 mol %) as catalyst and Ag2CO3/CuOAc as oxidants (Scheme 49). The ethyl group on carbazole as well as electronically diverse substituents on the phenyl and sulfonyl groups are tolerable to afford various carbazole-indole products in good yields. Scheme 49. Palladium catalyzed Synthesis of Heterobiaryls by Regioselective C–H amination N N SO2R 2 + N R1

H N

R3

R3

Rh 2(oct) 4 (0.5 mol %) N 1,2-DCE, 80 12 h

oC

R1

H N SO R 2 2

81-98%

R3 Pd(OAc) 2 (10 mol %) N CuOAc (3 equiv) or Ag2CO 3+CuOAc (0.5+1.2 equiv) toluene, 120 oC 17 h

R1

N SO2R 2 11 examples 60-90%

N II N Ts Pd

Shi and coworkers reported the direct intramolecular amidation of dipeptides by direct aryl C-H activation of the phenylalanine residue to afford cyclic unnatural amino residue (Scheme 50).129 Many N-triflated short peptides react efficiently with Pd(OAc)2 (10 mol %) in presence of


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Ce(SO4)2 as an oxidant giving cyclized products in good yields. At least, 6 equiv DMF and 0.2 equiv MsOH are required for the reproducible yields of the products (Scheme 50). This C-N bond cyclization reaction showed broader scope with many amino acids at the C-terminus. Other protecting groups like Ts, TFA, Boc or Ac initiated less than 5 % yields of the cyclized products.

Scheme 50. Palladium-Catalyzed C-H Activation/C-N Bond Formation by Direct Amidation of the Phenylalanine Moiety in Short Peptides O R1

NHTf

N H

R2

Pd(OAc) 2 (10 mol %) Ce(SO 4)2 (6 equiv)

O

R1

DMF (6 equiv), MsOH (0.2 equiv), DCM, 120 oC, 2 d

N HN R 2 Tf 15 examples 30-73%

Gaunt and coworkers developed a catalytic C-H bond amination forβ-arylethylamine motif through Pd(II)/(0) catalytic cycle (Scheme 51).130 This reaction requires Pd(OAc)2 (10 mol %) in the presence of Na2CO3/PivOH buffer and Cu(OAc)2 at elevated temperature (110 oC) to afford products in the range of 61 to 86 % yields. The use of pivalic acid is crucial for this transformation as its replacement with acetic acid does not initiate the reaction. Fagnou and coworkers have reported the significance of pivalic acid as a proton shuttle in Pd-catalyzed C-H bond arylation process.131 Scheme 51. Amine Directed Pd(II)-Catalyzed C-H Bond Amination Pd(OAc) 2 (10 mol %) Cu(OAc) 2

H H R1

NH

H

R2 Na 2CO 3-PivOH DCE, 110 oC

H N

R2


Wu, Chen and coworkers utilized oxygen as a terminal oxidant as a greener approach for the synthesis of indazolo[3,2-b]quinazolinones employing 2-aryl-3-(arylamino)quinazolinones and Pd(OAc)2 (5 mol %) in DMF (Scheme 52).132 This reaction does not work under N2 atmosphere. The authors proposed that the sp2-nitrogen atom of the quinazolinone ring coordinates with the Pd-center rather than sp3-nitrogen atom in the arylamino group to give 36 (Scheme 52). This intermediate then undergoes rollover cyclometalation followed by subsequent intramolecular CN bond formation to afford indazolo[3,2-b]quinazolinones. Scheme 52. Palladium-Catalyzed Intramolecular Aerobic Oxidative C−H Amination of 2‐ Aryl3-(arylamino)quinazolinones


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ACS Catalysis

3.2.2. Pd(0)/Pd(II) Cycle In 2010, Hartwig and coworkers developed a direct amination of aromatic C-H bonds using oxime esters as the nitrogen source to form indole compounds under redox-neutral conditions.133 Varieties of indole derivatives have been synthesized with Pd(dba)2 (1 mol %) as a catalyst in presence of Cs2CO3 base (1 equiv) (Scheme 53). Substrates containing meta-substituents on an aryl ring in the R2 position showed a strong dependence on the substituents. Similarly, substituents on para-position possessing electron donating capacity give lower yield than with electron withdrawing capacity. Interestingly, aryl chlorides and bromides are inert under these reaction conditions indicating that Pd(0) prefers insertion into the N-O bond of the oxime acetate over the carbon-halogen bonds. Mechanistically, the authors proposed that the N-O bond of the oxime undergoes oxidative addition and followed by tautomerization to give 37 (Scheme 54). They have isolated and characterized (by X-ray diffraction) a complex ligated with PCy3 generated from N-O bond oxidative addition to probe the mechanism. Complex 37 undergoes CH activation and forms Pd(II) palladacyclic complex 38 which reductively eliminates to give indole product, regenerating Pd(0) catalyst. Scheme 53. Palladium-Catalyzed C-H Amination of Aromatic C-H bonds with Oxime Esters R2 R1

N

R2

Pd(dba) 3 (1 mol %) Cs 2CO3 ( 1 equiv)

R3 OAc

R3

R1 N H

Toluene, 150 oC, 24 h

13 examples 40-69% Selected substrate scope

OMe

Ph Me N H

69%

OMe

Br

Me N H 63%

N H

71%

43%

Cl

Cl

Me

Me

N H

Me Br

N H 60%

N H 41%


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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ACS Catalysis

Scheme 54. Proposed Mechanism of Palladium-Catalyzed C-H Amination of Aromatic C-H bonds with Oxime Esters Ph Ph

Me

N

Me N H

OAc

LnPd(0) oxidative addition to N-O bond


Ph Me

Ph

NH Pd Ln

palladacyclic complex

Me

N PdL n

38

OAc AcOH Ph Me

Tautomerization

HN PdL n 37

OAc

3.2.3. Oxidative High Valent Pd(II)/Pd(IV) Cycle The selectivity issue in Pd(II)/Pd(IV) catalysis for C-H bond amination is challenging. The final product-forming reductive elimination step prefers to create other bonds such as C-C or C-halide instead of C-N bond. Gaunt and coworker reported the synthesis of cabazoles employing a Pd(II)-catalyzed intramolecular C-H bond amination.134 The reaction of N-Bn biphenyl with Pd(OAc)2 (5 mol %) as a catalyst in presence of PhI(OAc)2 as oxidant (1.2 equiv) gave 96 % carbazole product (Scheme 55). Unlike Buchwald’s procedure, 114,117 these amination reactions proceed efficiently in 1 h at room temperature. Many electron deficient molecules need 1 equiv of AcOH and longer reaction time for better yields. Various alkyl substituents including iPr, tBu, Bn and allyl groups on nitrogen are tolerated and provide the good yields of carbazoles. The authors have isolated trinuclear palladium complex 39 (by X-ray crystallography) and proposed multinuclear Pd(IV) intermediate species 40 during the catalytic cycle (Scheme 56). The Pd(IV) species accelerates reductive elimination to form the carbazole product.


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 55. Oxidative Pd(II)-Catalyzed C-H Bond Amination to Carbazole at Room Temperature Pd(OAc) 2 (5-10 mol %) PhI(OAc) 2 ( 1.2 equiv)

R1 H N R3 R2

R1 N R3 R2

toluene, rt, 1-24 h

25 examples 56-96% Selected substrate scope

N Bn

N Bn

N tBu MeO 2C

96%

60%

80% CO 2Me

MeO N Bn

85%

N

N Bn

94%

79%

Scheme 56. Proposed Mechanism of Oxidative Pd(II)-Catalyzed C-H Bond Amination to Carbazole

H N Bn N Bn Pd(OAc) 2 reductive elimination IV OAc Pd N

OAc H N Pd OAc Bn

Bn

40 Multinuclear Pd(IV)

oxidation PhI(OAc) 2

II Pd N H Bn 39 As trinuclear Pd complex

Youn and coworkers reported the use of the inexpensive oxidant oxone under mild conditions in intramolecular oxidative C-H amination of N-Ts-2-arylanilines.135 A reaction of Pd(OAc)2 (5


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ACS Catalysis

mol %), oxone (1 equiv), and p-TsOH (0.5 equiv) in PivOH:DMF(1:3) at room temperature afforded N-Ts-Cabazole product in 98 % yield (Scheme 57). Authors proposed the oxidation of the 6-membered palladacycle to Pd(IV) species followed by reductive elimination with concomitant C-N bond formation as reported by Gaunt and coworkers.134 There is a delicate balance of acidity in the NH group through the nitrogen protecting group and the aryl substituents of the protected aniline. This balance is essential for the maximum efficiency in the reaction. Stahl and coworkers utilized molecular oxygen as the oxidant in an aerobic aryl C-H amination to convert N-benzenesulfonyl-2-aminobiphenyl to N-benzenesulfonylcarbazole employing in-situ generated peroxide-based oxidant from O2 and 1,4-dioxane solvent (Scheme 58).136 Glycolic acid and dioxane are required for the success of this reaction as oxidative decomposition of dioxane leads successful formation of carbazole product. Authors have proposed a mechanism where in-situ generated peroxide as an oxidant is responsible for formation of the Pd(IV) intermediate species, which eventually leads to product after reductive elimination. Scheme 57. Oxone Oxidative Palladium-Catalyzed C-H Bond Amination to Carbazole Pd(OAc) 2 (5-10 mol %) R1 oxone ( 1 equiv)

R1 H N Ts

N Ts

R2

R2

p-TsOH (0.5 equiv) PivOH:DMF(1:3) 25-80 oC, 6-24 h

61-98%

Scheme 58. Palladium Catalyzed Aryl C–H Amination with O2 via in situ Formation of Peroxide-based Oxidant from Dioxane Pd(OAc) 2 (1 mol %) DAF (1 mol %) NSO 2Ph

NHSO 2Ph GA (2 equiv) Dioxane, 80 oC, O2 (1 atm), 20 h

80%

O O DAF =

OH

GA = N

N

OH

Recently, Cho, You and coworkers reported the combination of Pd-catalysis and photocatalysis to avoid the stoichiometric amounts of chemical additives required for the synthesis of Nsubstituted carbazoles using intramolecular C-H bond amination (Scheme 59).137 The authors used catalytic amounts of Pd(OAc)2 and [Ir(dFppy)2Phen]PF6 (dFppy = 2-(2,4difluorophenyl)pyridine) 41 ; phen = 1,10-phenanthroline) in presence of visible light in aerobic atmosphere. Various N-substituted 2-amidobiaryls provide good to excellent yields of carbazoles in DMSO including N-benzenesulfonyl amidobiaryls, 2-acetamidobiaryls and thiophen containing benzenesulfonamide. Authors proposed a photoinduced electron transfer from a sixmembered palladacycle to the photoexcited Ir catalyst as observed in electrochemical and transient photoluminescence spectrospcopy.


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 59. Combined Visible Light Photoredox and Palladium-Catalyzed C-H Bond Amination to Carbazole Pd(OAc) 2 (10-15 mol %) [Ir(dFppy) 2phen]PF 6 ( 1 mol %)

R1

R1

H N R3

N R3

R2

R2

DMSO (0.2 M), blue LEDs (7 W), O2, 80 oC, 8-16 h

R 3 = SO2Ph, SO2PhMe SO2Me COMe Ac

75-94% + PF 6

F N

[Ir(dFppy) 2phen]PF 6 =

N

F Ir

F

N N F 41

Yu and coworkers exploited Pd(II)/Pd(IV) chemistry in C-H amination reaction for the preparation of β-, γ-, and δ- lactams in excellent yields (Scheme 60).138 The electronic variation of the arene due to electron withdrawing or electron donating substituents has no major impact on the yield of the aminated products. The combination of CuCl2 and AgOAc as stoichiometric oxidants is required for this C-H lactamization reaction. The authors proposed that CuCl2 provides chloronium ion (Cl+) that oxidizes Pd(II) to Pd(IV) through the Shilov mechanism.139140 It is not clear whether CuCl2 acts as a 2-electron or 1-electron oxidant. One of the posibilities is C-N reductive elimination step produces PdCl2 and changes to Pd(OAc)2 through ligand exchange with AgOAc to complete the catalytic cycle.

Scheme 60. Lactamization of Aryl C-H bond via Pd-Catalyzed C-H Activation

R1

R 2 R 3H N

Pd(OAc) 2 (10 mol %) CuCl 2 ( 1.5 equiv)

R2R3 C O

R1

OMe

N

AgOAc (2 equiv) DCM, N 2, 100 oC, 6-10 h

O

OMe 16 examples 58-96%


C O N OMe 94%

N

MeO

N

OMe

OMe 90%

86%

C O

C O N

N

OMe

OMe

78%

C O

C O F

58%

C O N OMe 72%


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ACS Catalysis

The Yu group also extended the study of triflamide protected alkylamines by using both a one electron oxidant [Ce(SO4)2] and a two electron oxidant [N-fluoro-2,4,6-trimethylpyridinium triflate] (Scheme 61).141 One electron oxidant acts as a bystanding, as it does not add an additional nucleophile to the palladium centers during oxidation process.57 The use of N-fluoro2,4,6-trimethylpyridinium triflate showed better performance than Ce(SO4)2, as SO42- anions are harmful to the reaction by forming unreactive PdSO4. It is also possible that the one electron oxidant forms a Pd(III) intermediate that does not undergo reductive elimination to form the C-N bond as readily as the Pd(IV) intermediate, which is formed by the 2-electron F+ oxidant. It is not clear whether the C-N bond forming reductive elimination occurs from a Pd(III) or a Pd(IV) intermediate species. At least 1.2-6 equivalent of DMF as a labile ligand is required for the success of this reaction. Various functional groups including electron withdrawing and donating groups gave moderate to good yields. In many meta-substituted arene substrates, C-N bond is formed exclusively at the sterically less hindered site. The authors proposed the Pd(IV) intermediate from oxidation that subsequently leads to selective reductive elimination to form the aminated product. It is believed that bystanding F+ oxidant is not only capable of oxidizing Pd(II) to Pd(IV) but also capable of promoting selective reductive elimination to form C-N bond with the suitable nucleophilicity of hetero nitrogen atom. This reaction is less efficient in phenylpropylamine in comparison to phenylethylamine as the former gave low yield of cyclized quinoline products in comparison to indolines from later.

Scheme 61. Palladium-Catalyzed C-H Amination Using N-Fluoro-2,4,6-Trimethylpyridinium Triflate Pd(OAc) 2 (10-15 mol %) Oxidant ( 2 equiv) R1

R1 NHTf

N Tf

DMF (1.2 equiv) DCE, 120 oC, 72 h

22 examples 40-91%

Me Oxidant = Me

N F

Me OTf


Me N Tf

N Tf 80%

94%

Me

N Tf 82%

CF3 N Tf 65%

Cl CO 2Me N Tf 62%

N Tf 91% (98%ee)

3.3. Directing Groups in Intramolecular C-N Bond via Five or Six-Membered Palladacycles Directed C-H functionalization by forming five- or six-membered palladacycle is a welldeveloped strategy. If an existing functional group within a substrate molecule is ineffective for intramolecular chelation to palladium, the specific introduction of a well-designed, removable


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Page 46 of 97

auxiliary-directing group remains an alternative.142 In 2005, Daugulis first introduced the picolinamide group as an excellent directing group for a number of C-H functionalization reactions.116 Since this first example, Daugulis 116,143, Chen 144-146, Yu 149, Shi 153, Zhao 157, and Ma158 have introduced various directing groups for C-N bond formation under mild reaction conditions (Figure 2). O HN

O

N

Chen, 2012 Daugulis, 2012

O

HN

HN

N

N

Chen, 2013

Chen, 2013

HN

N N N

O S

HN

O

N

Yu, 2013

Bn

O

Shi, 2013

CO2Me O N H

O N

HN

O

N

Me

OMe Zhao & Yao, 2014

Ma, 2015

Figure 2. Directing Groups Forming Five and Six-Membered Palladacycle in C-N Bond Formation 3.3.1. Oxidative High Valent Pd(II)/Pd(III) or Pd(IV) Cycle In 2012, Daugulis and coworkers reported a picolinamide directed Pd-catalyzed C(sp2)-H bond activation to synthesize 5-member heterocycle through C-H and N-H coupling (Scheme 62).143 Chlorine as well as methoxy group on the aromatic ring and ester group on indoline are tolerated during C(sp2)-H bond activation. More interestingly, the 3-phenylindoline product is obtained in good yield by the cyclization of 2,2-diphenylethylamine. Simultaneously, Chen and coworkers reported the Pd-catalyzed intramolecular amination of ortho-C(sp2)-H bonds for the synthesis of indoline compounds using picolinamide(PA)-protected β-arylethylamines (Scheme 63A).144-145 The use of Pd(OAc)2 (5 mol %) at 60 oC for 24 h or Pd(OAc)2 (0.5 mol %) at 80 oC for 24 h are equally good reaction conditions for the excellent yields (>95 % and 94 %) respectively of indolines. Electron deficient β-arylethylamine substrates are more selective and give better yields of desired indolines (with a small amount of undesired acetoxylated products) than electron rich β-arylethylamines. The picolinamide protecting group can be easily removed under mild condition using 1.5 equiv of NaOH in MeOH/THF/H2O at 50 oC in 24 h. It is proposed that picolinamide-directed intramolecular amination undergoes by Pd(II)/(IV) catalytic cycle even though they are not able to isolate the palladacycle intermediate 42. The ortho-C-H palladation is assisted by the anchoring of the Pd(II) to the picolinamide. The palladacycle intermediate 42 is then oxidized to Pd(IV) by oxidant PhI(OAc)2 and subsequent selective C-N reductive elimination leads to the indoline product. As proof that palladacycle 42 is being generated, the Chen group perfomed a deuteration experiment (with AcOD and Pd(OAc)2) and isolated the ortho-deuterated product. The Chen group also reported the intramolecular amination of the ortho-C(sp2)-H bonds of aryl acetamides using bidentate directing groups 8aminoquinoline and 2-pyridylmethylamine groups to provide indolinone products (Scheme


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ACS Catalysis

63B).146 These directing groups alleviated the need for the benzylic geminal dialkyl substitution condition required for lactam synthesis developed by Yu138 in C-H amination. Scheme 62. Daugulis’s Picolinamide Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination Pd(OAc) 2 (5 mol%) PhI(OAc) 2 (2 equiv)

R2 R3 R1

HN

R2 R1

O

N

R3 N

Toluene, 80-120 oC 24 h

O

N

O

N

IV N Pd

42 8 examples 16-86%

Scheme 63. Chen’s Picolinamide Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination 63A Pd(OAc)2 (2 mol%) PhI(OAc)2 (2 equiv) Toluene, Ar, 60 oC, 24 h

R2 R3 R1

HN

O

N

R2 1

R

N

Or Pd(OAc)2 (0.5 mol%) PhI(OAc)2 (2 equiv) Toluene, 80 oC, 24 h

N

R3

IV N Pd

O

N

O

42 16 examples 32-95% 63B Pd(OAc)2 (5 mol%) PhI(OAc)2 (1.3 equiv)

O R1

HN

DG

Toluene, 60 oC, 24 h

R1

O N DG

DG = N

N

The Chen group recently reported a very efficient strategy for the synthesis of highly strained four-membered benzazetidines employing N-benzyl picolinamides (Scheme 64).147 The newly synthesized phenyliodonium dimethylmalonate oxidant is selective as it oxidizes the Pd(II) palladacycle in favoring a kinetically controlled C-N reductive elimination to give the strained ring products. PhI(DMM) is synthesized by mixing PhI(OAc)2 and dimethylmalonic acid in chloroform at 45 oC and then removing the HOAc under reduced pressure. Benzylamine substrates with bulky substituents on the ortho position can give up to a 20% yield of benzazetidine product with PhI(OAc)2 but with PhI(DMM) up to 86% yield. Unsubstituted benzylamines are unreactive under this reaction conditions and give only maximum 5% acetooxylated product. The authors proposed that this new dicarboxylate-based phenyliodonium(III) oxidant kinetically suppresses the C-O bond forming reductive elimination from Pd(III) intermediates. A bimetallic Pd(III)/Pd(III) complex with a bridging dicarboxylate ligand 43 is much more stable than the monometallic Pd(IV) complex (Scheme 64). This favors


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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C-N reductive elimination from the bimetallic complex with DMM over competing C-O reductive elimination by 5.7 kcal mol-1 reversing the selectivity by forming thermodynamically less favorable benzazetidine products. Scheme 64. Chen’s Picolinamide Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination for Benzazetidine Synthesis AcOH O

N H

R1

O

Pd(OAc) 2 (10-15 mol %) PhI(DMM) (2-3 equiv)

O

R1 N

Pd III

N

PhCl, Ar, 100-110 oC, 12 h

O

Cl

CF3

N

O

N N Pd III HOAc 43

F 3C

O

O

R 13 examples 53-86%


CF3

N

N

R

N

O

bimetallic Pd(III)/Pd(III) complex with a bridging dicarboxylate ligand

CO 2Me N

N N

O

O

72%

N

N

N

N

O

86%

O

N

53%

67%

Liu and coworkers utilized the picolinamide directing group to synthesize heterocyclic compounds including quinolinones and pyridones. The authors extended this coupling reaction to synthesize fused heterocycles via C-N bond formation employing pyridone with Pd(OAc)2 (10 mol %) and cyclic hypervalent iodine oxidant (Scheme 65).148 Scheme 65. Application of Picolinamide Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination O

N

NH

N

O

Xylene, 80 oC, 24 h

NH

N

O

O

N

PdBr 2 (5 mol %) Oxidant (2 equiv)

O

Pd(OAc) 2 (10 mol %) Oxidant (2 equiv) ArmylOH/HOAc (4:1) 110 oC, 24 h

N

N

O

53%

45%

Oxidant =

N

OAc I O O

Yu and coworkers reported 2-pyridinesulfonyl as a directing group in a protected phenethylamine compounds to a variety of substituted indoline derivatives using PhI(OAc)2 as


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ACS Catalysis

an oxidant (Scheme 66).149 Carretero and coworkers first introduced the use of 2pyridinesulfonyl group as a powerful directing group for various C-H functionalization reactions.150-151 In the same reaction condition, when the trifluorosulfonyl protecting group is used, acetoxylation of the aromatic ring is produced. This clearly indicates how these protecting groups control the competitive reductive elimination pathways from Pd(IV) complexes.152 Various substrates containing electron donating as well as electron withdrawing groups including Br and Cl at the ortho- and meta- positions gave indolines in good yields. The removal of 2pyridinesulfonyl-protecting group was achieved by the treatment with magnesium metal in methanol at 0 oC. Yu’s proposed mechanism is same as Chen’s mechanism,144-145 where Pd is coordinated by two N-atoms of 2-pyridinesulfonyl protecting group to cleave the ortho-C-H bond (Scheme 67). This produces an organopalladium (II) intermediate 44, which on subsequent oxidation by PhI(OAc)2 provides an Pd(IV) species 45. This critical species undergoes selective reductive elimination forming C-N bond in desired indoline product regenerating the active palladium (II) catalyst (Scheme 67). Shi and coworkers reported a similar reaction with the 1,2,3-triazole-directed C-H activation using Pd(OAc)2 (5 mol %), and PhI(OAc)2 (2 equiv) in DCE at 80 oC (Scheme 68).153 The triazoleamide directing group effectively activates sp2 C-H bonds in a large group of substrates giving cyclized products in good to excellent yields. Other hetero aromatic compounds which are more electron rich than triazole like imidazole, furan and pyrazole did not initiate C-H activation. The authors were able to demonstrate the power of directing group in selective C-H functionalization in forming cyclization products or acetoxylation products. Picolinamide (PA), oxalylamide (OA), and triazoleamide (TAA) directing groups give cyclization product over acetoxylation product due to a favored in-plane reductive elimination. Out-of-the-plane reductive eliminations in Pd(IV) intermediates from the use of tridentate directing groups lead to acetoxylation products.154-156 The out-of-the-plane reductive elimination favors the acetoxylation product because the Pd-C bond is forced into the axial position when a tridentate directing group is bound. Scheme 66. 2-Pyridinesulfonyl Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination

Pd(OAc) 2 (10 mol%) PhI(OAc) 2 (2 equiv)

R2 R3 R1

HN N

R1

O S

O

R2

Toluene, 130

oC,

4h

R3 N O N S O 15 examples 51-82%


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 67. Proposed Mechanism of 2-Pyridinesulfonyl Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination

N

O HN S H O N

N S O

Pd(OAc) 2

O

reductive elimination L oxidation IV N Pd S O N O

II N Pd S O N O 44

organopalladium (II) intermediate

PhI(OAc) 2

45

Scheme 68. 1,2,3-Triazoleamide Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination R2 R3 R1

HN O

N N N Bn

R2

Pd(OAc) 2 (5 mol%) PhI(OAc) 2 (2 equiv)

R1

R3 N

DCE, Ar, 80-100 oC, 24 h

O

N Bn N N

13 examples 53-85%

Zhao, Yao, and coworkers developed oxalyl amide derivatives as an effective directing group to cyclize through C(sp2)-H bonds of amine compounds.157 Oxalyl amide as the auxiliary provided the desired cyclized product in excellent yield with low catalyst loading in the presence of hexafluoroisopropanol as a solvent. The oxalyl amide protected β-arylethylamine derivatives are cyclized efficiently under milder reaction conditions through six-membered palladacycle intermediate to generate indoline products (Scheme 69). Substrates having both electrondonating and electron-withdrawing groups were tolerated and gave cyclized products in good to excellent yields. Interestingly, the challenging 2,5-disubstituted product was also observed in good yield with a slight increase in the loading of the catalyst. The authors preliminary mechanistic study suggested that oxalyl-amide-directed intramolecular C(sp2)-H amination follows a Pd(II)/(IV) catalytic cycle, as they were able to isolate an N,O-bidentate palladacycle intermediate 46 (Scheme 69). The rate determining C-H palladation step is followed by PhI(OAc)2 oxidation to Pd(IV) species, which undergoes selective C-N reductive elimination to furnish the product.


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ACS Catalysis

Scheme 69. Oxalylamide Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination for Indoline Synthesis Pd(OAc) 2 (1-3 mol%) PhI(OAc) 2 (1.5 equiv)

R2 R3 R1

HN

R1

O

R3 N(i-Pr) 2

N

Hexafluoroisopropanol or PhCl, 60-80 oC, Ar, 12 h

O

(i-Pr) 2N

R2

O

O

O

F N O

O

76%

N

N(i-Pr) 2

O 2 46

O

O

92%

Me

Me N

N(i-Pr) 2

O

N(i-Pr) 2

O

94%

N

N(i-Pr) 2

Br

N(i-Pr) 2

O

O

N, O- bidentate palladacycle


N

O

Me

16 examples 61-94%

OMe

N Pd

O

O

83%

CO 2Me N(i-Pr) 2

N Me

O

N(i-Pr) 2

O

O

61%

63%

Ma and coworkers recently reported that the 2-methoxyiminoacyl (MIA) group is a powerful amine auxiliary for C(sp2)-H amination to afford the substituted indoline 2-carboxylates, which could be transformed to dipeptides under hydrogenation conditions (Scheme 70).158 The catalyst loading of Pd(OAc)2 (5 mol %) with 1-fluoro-2,4,6-trimethyl-pyridinium tetrafluoroborate (1.5 equiv) as oxidant and DMF (1.25 equiv) as an extra ligand gave the best result of C-H aminated products. Variations of substituents in the directing groups as well as in the aromatic ring of phenylalanine substrates are tolerable for the reaction. The authors have proposed a double palladium chelate structure 47, which undergoes to Pd(IV) complex upon oxidation and subsequently undergoes reductive elimination to furnish the amine product (Scheme 70). Scheme 70. Synthesis of Substituted Indoline-2-carboxylate via Pd-Catalyzed Direct C-H Amination

R1

CO 2Me HN

Pd(OAc) 2 (5 mol %) F + (1.5 equiv)

N

O

N

R2

DMF (1.25 equiv), DCE, 110 oC, 8 h

OMe

N MeO

O R2

17 examples 54-90% F+ =

CO 2Me

CO 2Me

R1

II N Pd N

O

OMe 47 Pd(II) double chelate

N F BF 4


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3.4. Directing Groups in Intramolecular C-N Bond via Seven-Membered Palladacycle Directed C-H functionalization by forming five- or six-membered palladacycle is well developed. Expanding on this known work, Zhao and coworkers developed seven membered palladacycles for the construction of intramolecular C-N bonds (Figure 3). X

O O

N H

H N

X

N

O NMe2

O X = NPhth

X = CH2 or O

Zhao & Zhang, 2016

Zhao & Yao, 2014

Figure 3. Directing Groups Forming Seven-Membered Palladacycle in C-N Bond Formation Pharmaceutically important tetrahydroquinolines (THQs), and benzomorpholines (BMPs) are the resultant products through intramolecular C-N amination via 7-membered palladacycle species developed by Zhao, Yao and co-workers.157 The substrate scope for the intramolecular amination of phenylpropylamine is broad, including Ac, NO2, Br, and I substituents. Under standard reaction conditions, various substituted 2-phenoxyethylamine oxalyl amides were converted into the corresponding benzomorpholines in good yields (Scheme 71). The authors proposed a mechanism which follows a Pd(II)/(IV) catalytic cycle. Scheme 71. Oxalylamide Directed Palladium-Catalyzed Intramolecular C(sp2)-H Amination Pd(OAc) 2 (3-10 mol%) PhI(OAc) 2 (2 equiv)

X

X R1

O

R1 N H

O N(i-Pr) 2

N Hexafluoroisopropanol 60-80 oC, Ar, 24 h

N(i-Pr) 2

O O

X = CH 2 or O

16 examples 52-83% Selected Substrate Scope MeO 2C

MeO 2C

N

N

N N(i-Pr) 2

O

N(i-Pr) 2

O

O

O

O

82%

56%

O

OMe O

N O 80%

O 58%

F

Cl

N N(i-Pr) 2

O O 74%

N(i-Pr) 2

O

52%

N N(i-Pr) 2

O

OAc

N N(i-Pr) 2

O

N N(i-Pr) 2

O O 76%

N(i-Pr) 2

O O 79%

Yu and coworkers reported a PdCl2 catalyzed, 2,5-lutidine promoted sequential arylation of the β-C(sp3)-H bonds of propionamide followed by C(sp2)-H amination in one pot to afford varieties of 4-aryl-2-quinolinones. The final intramolecular C(sp2)-H amidation product is


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ACS Catalysis

initiated by a 7-membered palladacycle.159 Zhao, Zhang and coworkers reported a sequential βC(sp3)-H arylation and selective intramolecular amination using a N,O-bidentate directing (glycine dimethylamide) group for the synthesis of 2-quinolinone derivatives (Scheme 72).160 Glycine dimethylamide (GDMA) protected 2-phthalimidopropionic acid was first treated with Pd(OAc)2 (5 mol%), ArI (1.2 equiv.), AgOAc (2 equiv.) in hexafluoroisopropanol (HFIP) at 80 o C for 12 h to provide β-arylated product. The direct addition of oxidant PhI(OAc)2 (2.5 eq), additive pivalic acid (0.3 equiv.) and solvent HFIP (4 mL) in the arylated product at 70 oC for another 18 h afforded the cyclized C(sp2)-H aminated prodcuts. GDMA-directed intramolecular amination is equally effective for simple carboxylic acid derivatives as well as for the synthesis of 3,4-dihydro-2(1H)-quinolinone derivatives. Scheme 72. Glycine Dimethylamide (GDMA) Directed Palladium-Catalyzed Sequential C-H Arylation and Amination

O PhthN

I N H

H

NMe 2

+

R

O (1.05-1.5 equiv.)

1. Pd(OAc) 2 (5 mol %) AgOAc (2 equiv), HFIP (1 mL), air, 80-120 oC, 12 h 2. PhI(OAc) 2 (2.5 equiv.), PivOH (0.3 equiv.), HFIP (4 mL), Ar, 70-120 oC, 18 h

NPhth R N

O

O NMe 2 42-85%

NPhth R O

HN O NMe 2

3.5. Intramolecular C-N Bond via Reductive C-H Amination Nitro groups are important as N-atom precursors in intramolecular C-H bond amination. Watanabe and coworkers reported a palladium-catalyzed reductive N-heterocyclization of nitroarenes for the synthesis of indole and 2H-indazole derivatives.161 Söderberg and coworkers reported a palladium-phosphine catalyzed reductive N-heteroannulation of 2-nitrostyrenes employing carbon monoxide to synthesize indoles in good yields.162 The combination of Pd(OAc)2 (6 mol %) with triphenylphosphine (24 mol %) under 4 atm of carbon monoxide in acetonitrile at 70 °C provides the best results (Scheme 73). Scheme 73. Palladium-Catalyzed Synthesis of Indoles by Reductive N-Heteroannulation of 2Nitrostyrenes R2 R3

Pd(OAc) 2 (6 mol %) PPh 3 ( 24 mol %) R1

R1 NO 2

R2

CO (4 atm), CH 3CN 70 oC, 15 h

R3 N H 40-100%

The Smitrovich group reported a regioselective amination of an unactivated sp2 C-H bond by using CO as the stoichiometric terminal reductant to generate carbazoles from nitroarenes in good to excellent yields (Scheme 74).163 Dong and coworkers reported an indole synthesis


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

demonstrating C-H bond amination employing carbon monoxide (CO) as a terminal reductant in reaction with nitroalkenes (Scheme 75).164 The mild reaction condition of Pd(OAc)2 (2 mol %), 1,10-phenanthroline (4 mol %) and 1 atmosphere of CO in DMF at 110 oC afforded an indole product in 99 % yield. Mechanistically, reductive cyclization of nitroalkene gives a five membered palladacycle 48 which on subsequent decarboxylation generates η2-bound nitrosoalkene complex 49 (Scheme 76). This complex undergoes intramolecular 4π+2ω, five atom electrocyclization to form nitronate 50. On subsequent hydrogen shift and re-aromatization gives N-hydroxyindole which then reduces to the desired indole by a second equivalent of CO. The author’s approach of utilization of nitrosoalkene for amination is an alternative to the traditional reagents like iminoiodinanes, haloamines, azides which react with Pd-metal to provide electrophilic nitrogen species. Scheme 74. Palladium-Catalyzed Reductive C-H Amination of Nitroarenes with Carbon monoxide R2

R2

Pd(OAc) 2 (0.5 mol %) 1,10phenanthroline ( 3.5 mol %) R1

R1 NO 2

NH

CO (70 psi), DMF 140 oC, 16 h

8 examples 22-97%

Scheme 75. Palladium-Catalyzed C-H Amination via Reduction of Nitroalkenes with Carbon monoxide

Pd(OAc)2 (2 mol %) 1,10-phenanthroline ( 4 mol %)

R1

R1

R2 R2

NO2

CO (1 atm), DMF 110 oC, 3-16 h

N H 9 examples 58-99%


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ACS Catalysis

Scheme 76. Proposed Mechanism of Palladium-Catalyzed C-H Amination via Reduction of Nitroalkenes with Carbon monoxide

CO2

+

+

CO

NO2

N H [PdLn] CO

Cyclopalladation H-shift

Ph

Ph

N O [LnPd]

N

50

O

O [PdLn]

48 O electrocyclization

Ph

decarboxylation

CO2

N 49

O

[PdLn]

3.6. Intramolecular C-N Bond via Amines with Leaving Group on Nitrogen In many cases, C-N bond formation is initiated by the activation of the nitrogen atom that generally lead to either nitrene or other Pd-nitrogen reagent. In 1977, Taniguchi and coworkers reported Pd-catalyzed thermal synthesis of substituted indoles in good yields using 2Hazirines.165 The authors were able to crystallize the palladium diazine complex and the cleavage of C-N bond initiated the formation of palladium vinyl nitrene that reacts the proximal arene to form the indole product. Chiba and coworkers reported that α-aryl-α-aminocarbonyloxime Opentafluorobenzoates are good substrates for the synthesis of 2,3-disubstituted indole derivatives via aromatic C-H amination (Scheme 77).166 High catalyst loading PdCl2(MeCN)2 (25 mol %) is required for the satisfactory yield as other palladium precursors like Pd(OAc)2, Pd(OTf)2 and PdBr2 are ineffective for this transformation. O-benzoate or acetate oxime gave poor yields over O-pentafluorobenzoates. The authors proposed an electrophilic aromatic substitution mechanism via N-Pd species 51 rather than sigma-bond metathesis as the mechanism, which they demonstrated by conducting deuterium labeled experiment.


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Scheme 77. Palladium-Catalyzed C-H Amination of α-aryloxime-O-pentafluorobenzoates O

O O

R2 R1

1,2-DCE, 80

N

CH3

N H

3.5-12 h

OCOC6F5

O N

O

R2

R1 oC,

O

N

PdCl2(MeCN)2 (25 mol %) MgO ( 5 equiv)

N

N [Pd(II)]

16 examples 33-91%

51 Selected substrate scope O

N

O

O

N

O

O

N

O

N

O

CH3

CH3 Br

O

N H

N H

N H

N H

75%

91%

87%

49%

Br

Doi, Inamoto and coworkers reported a catalytic method for the synthesis of pharmaceutically important 2-quinolinone compounds by C(sp2)-H activation. This sequence of activation and cyclization proceeds in an efficient way in presence of PdCl2 (10-15 mol %) and co-catalytic Cu(OAc)2 (50 mol %) under an air atmosphere (Scheme 78).167 The nitrogen atom of the amide moiety protected by the tosyl group or acetyl group works the best for this cyclization and gives high yields of the deprotected 2-quinolinone derivatives. This methodology is useful for the cyclization of a range of substrates possessing various functional groups on the benzene ring along with unsymmetrical substrates having different substituents in two benzene rings. Halogen atoms along with bromine as well as methoxy groups at all positions ortho-, meta-, or para-, are tolerated in this reaction. Roy and coworkers reported the use of a Pd-Cu bimetallic system to develop the intramolecular C-N bond formation which employs the indole C2-H bond activation to afford indoloisoquinoline and aza-indoloisoquinoline derivatives (Scheme 79).168 Scheme 78. Synthesis of 2-Quinolinones by Palladium-Catalyzed Intramolecular Amidation of C(sp2)-H Bonds PdCl 2 (10-15 mol %) Cu(OAc) 2 (50 mol %)

R1

R2

CONHTs

DMSO, 120-140 oC O 2, 18-38 h

R1

R2 N H

O

17 examples 18-98%


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ACS Catalysis

Scheme 79. Palladium-Copper Catalyzed Synthesis of Substituted Indoloisoquinolines and Azaindoloisoquinolines

Pd(OAc) 2 (10 mol %) Cu(OTf) 2 (20 mol %) N X

N

N OMe

R

o-xylene, 110 oC 2-6 h

X

N R

X = C, N R = Et, Me, iPr

12 examples 62-78%

3.7. Intramolecular C-N Bond via Sequential Coupling and Amination Peng and coworkers reported Pd(II) catalyzed sequential C-H arylation followed by aerobic oxidative C-H amination to synthesize benzimidazole-fused phenanthridines (Scheme 80).169 The Pd(II/IV) cycle for C-C bond formation is followed by Pd(0/II) cycle for C-N bond formation through five membered and seven membered palladacycle respectively. The final product is released along with Pd(0) species which is re-oxidized by O2 to regenerate Pd(II) species for the next round of catalytic cycle. Scheme 80. Palladium-Catalyzed Sequential C-H Arylation and Aerobic Oxidative C-H Amination R2 N R1

+

N H

PdCl 2 or Pd(OAc) 2 (10 mol %) Xphos (20 mol %),

H

R2 N R1

N

I R3 (3 equiv)

N N H

K 2CO3 (3 equiv) DMF, 160 oC, air, 72 h R3

via C-H arylation intermediate

32-90%

Doi and coworkers reported a tandem-type oxidative Heck reaction between cinnamamides and arylboronic acid followed by intramolecular C-H amidation for the synthesis of 4-aryl-2quinolinone derivatives (Scheme 81).170 Many substituted cinnamamides and arylboronic acids react in the presence of Pd(OAc)2 (10 mol %), and 1,10-phenanthroline (10 mol %) in addition to copper and silver re-oxidant. Scheme 81. Tandem Palladium-Catalyzed Oxidative Heck and Intramolecular C-H Amidation Reaction

NHOMe +

R1 H

R2

Pd(OAc) 2 (10 mol %) 1,10-phen (10 mol %)

O (HO)2B R2 (4.5 equiv)

Cu(TFA)2-H 2O (1 equiv) Ag2O (8 equiv) AcOH, 100-120 oC 1-43 h

R1 N

O

OMe 12-81%


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Chen and coworkers reported a synthesis of phenanthridines via palladium-catalyzed picolinamide-directed sequential arylation with an aryl iodide followed by intramolecular dehydrogenative C-H amination (Scheme 82).171 Scheme 82. Sequential Palladium-Catalyzed Arylation and Intramolecular C-H Amination Reaction Pd(OAc)2 (5 mol %) PivOH (0.3 equiv) NHPA

R1 H

+

Pd(OAc)2 (10 mol %) PhI(OAc)2 (2 equiv)

R1

I R2 (2 equiv)

KHCO3 (2 equiv) toluene, N2, 120 oC 24 h

NHPA

R2

Cu(OAc)2 (2 equiv) toluene, N2, 120 oC 24 h

31-92%

R1 N

R2 38-58%

4. PALLADIUM CATALYZED C-N BOND FORMATION EMPLOYING C(sp3)-H BOND Conceptually, unactivated or inert C(sp3)-H bonds can be aminated similar to C(sp2)-H bond, but this activation carries significantly higher challenge. This includes high bond dissociation energy (BDE) and lack of empty low energy orbitals or filled high energy orbitals which could readily interact with orbitals with the metal center, as is the case with unsaturated hydrocarbons.36 The control of selectivity in C(sp3)-H activation is more difficult than C(sp2)-H activation due to absence of π-groups. Hartwig and coworkers have studied C(sp3)-N reductive elimination in presence of phosphine 172 and N-heterocyclic carbene (NHC) bulky ligands.173 But, unlike C(sp2)-H reductive elimination, the corresponding elimination process is challenging for alkyl metal amido complexes because they are more prone towards β-hydride elimination rather than productive C(sp3)-N reductive elimination. 4.1. Intermolecular C(sp3)-H Bonds Amination The intermolecular C-H amination of unactivated C(sp3)-H bonds is challenging for various reasons. Most of the reports to date are based on highly reactive nitrene intermediates. In 2006, Che and coworkers pioneered an effective Pd-catalyzed, regioselective β-amidation of 1o C(sp3)-H bonds in aliphatic O-methyl oximes employing sulfonamides as nitrogen source (Scheme 83).73 The reaction is clearly selective for monoamidation at 1o C(sp3)-H bond over 2o C(sp3)-H bond. The authors proposed the formation of a chelation-directed palladacycle employing palladium acetate and β-hydrogen activation in the O-methyl oximes, which is followed by nitrene insertion to the Pd-C bond to furnish the amidation product.


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ACS Catalysis

Scheme 83. Palladium catalyzed Direct Intermolecular C(sp3)-H Amidation of Aliphatic Oximes Pd(OAc) 2 (5 mol %) Amides (1.2 equiv) N

H OCH 3

NHR

K 2S2O8 (5 equiv) DCE, 80 oC, 14-20 h

N

OCH 3

R = SO 2(p-Cl-C 6H 4) = COCF 3

Selected substrate scope Cl

HN

N

O C

O CF 3

HN

N S

Cl

O N

OCH 3

OMe

OCH3

N

HN O S O

O S N O H

Cl 88%

76%

93%

79%

Zhang and coworkers reported a remote amide directed intermolecular C-H amination using nonnitrene nitrogen source N-fluorobenzenesulfonimide (NFSI).174 This amination reaction works only with p-tolylamide in presence of Pd(OAc)2 (10 mol %) and 2.5 equiv NFSI (Scheme 84). This is an exclusively para-benzylic C-H amination, as ortho-tolylpivalamide and metatolylpivalamide do not form product under the reported conditions. The mechanism of this reaction is unclear; however, the authors suggested that the amination proceeds through Pd(IV) species. Scheme 84. Amide Directed Palladium-Catalyzed Benzylic C-H Amination with NFSI NH

R1

2 C R O

Pd(OAc) 2 (10 mol %) NaHCO 3 or KF (4 equiv)

F + PhO 2S

N

SO2Ph

(2.5 equiv)

DCE, 90 oC, 0.3 - 19 h

(PhO 2S)2N

R1

NH 2 C R O

14 examples 51-94%

Muñiz and coworkers reported an oxidative amidation of C(sp3)-H bonds of 8-methylquinoline and 2-tert-butylpyridine.175 Palladium hexafluoroacetylacetonate along with Nfluorobis(phenylsulfonyl)imide are effective sources as catalyst and nitrogen precursor, respectively, in dioxane (Scheme 85A). In exploration of substrates, 2-methylphenyl ethers having a more labile coordinating group react with the preformed bathocuproine palladium complex and NFSI to give amine product in 81% yield (Scheme 85B). Various 2-methylanisoles having para, meta and ortho substituents on the ring works well in the reaction. The C-H functionalization is very selective for the methyl group over ortho-tert-butyl or ortho-phenoxy groups (Scheme 85B). NFSI plays a critical role for the success of the reaction. The authors proposed a monomeric palladacycle 52 with the help of N-chelated C-H activation (Scheme 86). This complex oxidizes with NFSI to a cationic fluorinated high oxidation state Pd(IV) species 53 followed by direct nucleophilic substitution at the electrophilic carbon in the α-position to form 54 with new C-N bond. Following the C-N bond formation, the resulting Pd(II) intermediate cleaves by free H-hfacac releasing amidated product and original catalyst (Scheme 86).


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Scheme 85. Palladium-Catalyzed Direct C-H Amidation of 8-Methylquinoline and 2Methylanisoles Scheme 85A

Pd(hfacac) (10 mol%) FN(SO2Ph)2 (2 equiv) N N

Dioxane, 100 oC 24 h

N(SO2Ph)2 95%

Scheme 85B

Pd(hfacac) (10 mol%) BC (10 mol %)

OMe R1

Ph OMe R1

N Pd(OAc)2

N(SO2Ph)2

FN(SO2Ph)2 (2 equiv) dioxane/DMF(4:1) or dioxane/DMF(3:1) 90 oC, 15 h

N Ph

9 examples 49-81%

[(bc)Pd(OAc)2]

Selected Substrate Scope O

tBu OMe

OMe

N(SO2Ph)2

OMe

N(SO2Ph)2

F

81%

OMe

N(SO2Ph)2

53%

N(SO2Ph)2

49%

54%

Scheme 86. Proposed Catalytic Cycle of Palladium-Catalyzed Direct C-H Amidation of 2Methylquinoline HF +

N

N [Pd(hfacac)2]

N(SO2Ph)2

H-hfacac H-hfacac

CF3 O F O

N

CF3

Pd O

CF3 palladacycle

N Pd O CF3 N(SO2Ph)2

52

F-N(SO2Ph)2

54 CF3 nucleophilic substitution

F O N Pd O

oxidation CF3

53 N(SO2Ph)2

Buchwald and coworkers reported a C-H amination of unactivated C(sp3)-H bonds employing aryl amines as the nitrogen source (Scheme 87).176 Various anilines possessing electron


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ACS Catalysis

withdrawing and donating groups as well as heteroaryl amines give good to excellent yields (Scheme 87). This transformation utilizes 1-bromo-2,4,6-tri-tert-butylbenzene and similar derivatives for tandem C(sp3)-H activation followed by C-N coupling in presence of Nheterocyclic carbene ligand for the best result. Amination is very selective for only the methyl groups of tert-butyl group as isopropyl, cyclopentyl or cyclohexyl group resulted no C-H amination products. The authors reported that sterically less hindered bromide substrate, especially in ortho-position, produced C-N cross-coupled diaryl amine product instead of C-H activation product. As proposed by the authors, the aryl bromide oxidatively adds to the Pd(0) to give Pd(II) intermediate species 55 (Scheme 88). This species undergoes C-H activation of one of the C(sp3)-H bonds forming 5-membered palladacycle 56 followed by the protonation of the C(sp2)-Pd bond. The resultant alkyl Pd(II) species 57 undergoes ligand exchange with aniline forming amine co-ordinated Pd(II) species 58, which finally undergoes reductive elimination to generate C-H activated product with concomitant release of Pd(0) (Scheme 88). Scheme 87. Palladium-Catalyzed Intermolecular C-H Amination of Unactivated C(sp3)-H Bonds Br

NH 2

tBu

tBu

+

Pd 2(dba) 3 (5 mol %) SIPr.HBF 4 (11 mol %) NaOtBu (1.5 equiv)

H N

tBu

R

R

tBu (1.2 equiv)

Toluene (0.1 M), 110 oC, 4 h

tBu 16 examples 37-86%

iPr

iPr N

N + iPr iPr

SIPr.HBF4 =

BF 4-

Selected Substrate Scope H N

tBu

tBu 83%

H N

tBu

tBu 75%

H N

tBu

tBu

tBu

73%

75%

H N

iPr

CF 3

H N

O

N

H N

O

tBu

tBu

81%

70%


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 88. Proposed Mechanism of Palladium-Catalyzed Intermolecular C-H Amination of Unactivated C(sp3)-H Bonds H N

tBu

tBu

Br tBu

Reductive elimination

LPd(0) tBu

L Pd NHPh tBu 58

H

tBu

HX

tBu

Ligand exchange

55

L PhNH2

Pd L Br tBu

Pd

C-H activation X

tBu 57

tBu

tBu

HBr Pd

Protonation 56 HX

tBu

L

Palladacycle

Yu and coworkers reported a palladium-triarylphosphine catalyzed intermolecular amination of C(sp3)-H bonds in aliphatic amides at the β-position.177 O-benzoyl hydroxylamine as a nitrogen source and electron deficient phosphine ligand, tris[3,5-bis(trifluoromethyl)phenyl] are crucial components of the reaction (Scheme 89). A wide range of amides synthesized from different aliphatic acids containing CF3 as well as electronically different β- andγ-aryl groups are compatible with reaction conditions. This reaction not only shows exclusive mono-amination in the presence of two or three α -methyl groups but also in a single α-methyl group. Amides with α-protons are not compatible in this reaction conditions. In addition to O-benzoyl hydroxylamine, piperidine as well as many functionalized piperidines and Boc-protected piperazine provide good yields of the amination products. While no detailed experimental studies were conducted, the authors proposed a mechanism invoking the Pd(0)/(II) catalytic cycle (over the Pd(II)/(IV) cycle) because of (a) good yields produced by Pd(0) sources as catalyst precursors, (b) an external oxidant was not required and (c) previous X-ray crystal structure of related compound obtained from oxidative addition of an oxime ester to Pd(0) (Scheme 90). Obenzoyl hydroxylamine undergoes oxidative addition to the Pd(0)Ln to provide 59 which coordinates to amide substrate in basic condition to give 60. Complex 60 cleaves β-C(sp3)-H bond (the rate limiting step by KIE) to generate five-membered palladacycle 61 which subsequently undergoes reductive elimination to release product along with regeneration of Pd(0)Ln (Scheme 90). It is possible that electron deficient triarylphosphine ligand assists in stablilizing Pd-amido bond as well as in C-N bond forming reductive elimination step.


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ACS Catalysis

Scheme 89. Palladium-Catalyzed Intermolecular C-H Amination of C(sp3)-H Bonds for the Synthesis of β-Amino Acids

O H R1

R

F

CF3

N 2H

N OBz

F

N

(4 equiv)

N H

2 R4 R1 R

Cs2CO3 (4 equiv), 4Å MS, DCM, 120 oC, N 2 16 h

CF3

F

O

R3

R3

R4

+

F

F

[{Pd(allyl)Cl}2] (5 mol %) PAr3 (20 mol %)

F

F F

23 examples 52-78%

Selected Substrate Scope F

F O N O

F

CF3

N Me Me H

F

O O

F

N Me

N H CF3

N

O

F

N

F

F

CF3

N Me Me H

F

F MeO

F

O

CF3

N H Me Me

O

O N

F

CF3

O

F F

N Boc

N

F

N H Me Me

78%

F F

F CF3

O N

F F NPhth

66%

CF3

68% F

F

N N Me Me H

F N H

O

F

66% F

F O

CF3

52%

77%

F

F

F

52%

Me Me 67%

F N H

CF3 F F

Scheme 90. Proposed Pd(0)/(II) Mechanism of Palladium-Catalyzed Intermolecular C-H Amination of C(sp3)-H Bonds for the Synthesis of β-Amino Acids F R1

O N

R 2 Me Me

CF3

F N H

F

R2

R1

F

N Pd(0)Ln

CsHCO 3

OBz


oxidative addition

F CsO Me Me

F

CF3 Ln

N

F

PdII F NR 1R 2 Ar3P C(sp 3)-H bond 61 cleavage CsOBz + CsHCO 3 CsO Me Cs 2CO3

F

NR 1R 2 PdII OBz 59

F O H Me

Me

F N H

CF 3 F F + Cs 2CO3

F CF 3 CsHCO 3

N F Me PdII F H 1 2 Ar3P OBzNR R 60 Pd-amido complex

Qin and coworkers extended Yu’s intermolecular amination of unactivated C(sp3)-H bonds using the strategy of a bidentate directing group, a 2-aminothioether, instead of a monodentate fluorinated aniline.178 Direct amination of β-C(sp3)-H bonds of α -mono-substituted propionic


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Page 64 of 97

acid derivatives provide various unnatural and functional β-2-amino carboxylic acid analogues employing O-benzoyl hydroxylmorpholine as a nitrogen source (Scheme 91). PdCl2 (10 mol %) with Cs2CO3 as the base in benzene proved to be the best combination to provide the good yields. A large range of substrates including linear or cyclic aliphatic chains, electronically diverse benzyl analogues, δ-aryl substituents, and TBS-ether, benzyl ether or Boc-protected amines in the α-position are widely tolerated. In addition to O-benzoyl hydroxylmorpholine, numerous other amine sources including piperazine and both simple and functional piperidines provide good yields of products. The authors proposed a Pd(II)/(IV) catalytic cycle as the mechanism based on the fact that Pd(0) reagents or in situ-generated Pd(0) catalyst were ineffective for the reaction. With the assistance of a bidentate directing group (2-aminothioether) and Cs2CO3, PdCl2 gives a N,S-anchored five-membered palladacycle intermediate 62, which activates β-C(sp3)-H bond (Rate limiting step, KIE = 2.9) to generate a Pd(II) bicyclic intermediate. This undergoes oxidative addition with O-benzoyl hydroxylmorpholine to generate a Pd(IV) intermediate, which reductively eliminates to afford a product. A ligand exchange regenerates Pd(II) for the next catalytic cycle. Scheme 91. Palladium-Catalyzed Intermolecular C-H Amination of Unactivated C(sp3)-H Bonds

O H

PdCl2 (10 mol %) Cs2CO3 (2 equiv)

S + R2 R3 N OBz

N H

R1

O R3

Benzene, 110 oC 24-34 h

N R1

R2

(2.5 equiv)

S

O N II Pd S

N H

62 29 examples 35-91%

Pd(II) bicyclic intermediate

Selected Substrate Scope O N

S O N H

O

N

O N

S O N Boc

88%

N

61%

O N O

81%

S N H

N

S N H

O

88%

N H

O

O

N H

O 86%

S

N

N 2H TBSO 86%

F

O

S O N H

N

S N H

MeO2C 81%

S

35%

Recently, Liu and coworkers reported an intermolecular amination of unactivated C(sp3)-H bonds employing NFSI as both the amino source and the oxidant (Scheme 92).179 This protocol activates C(sp3)-H bond by exploiting a bidentate directing group that includes an oxime functional group. Interestingly, only β-methyl group undergoes this C-N bond formation, as activated methylene C-H bonds like benzylic or α-heteroatomic hydrogens do not participate in C-N bond formation. Authors proposed a five membered palladacycle 63 through the activation of the C(sp3)-H bond (Scheme 92). NFSI oxidatively adds to the palladacycle to form Pd(IV) species followed by reductive elimination to generate the amine product.


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ACS Catalysis


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Scheme 92. Palladium-Catalyzed Intermolecular Amination of Unactivated C(sp3)-H Bonds Pd(OAc) 2 (10 mol %) AcOH (4 equiv)

F + N

SO2Ph CH3CN, 80

(2 equiv)

N R1

N

PhO 2S

oC,

N 2, 12 h

(PhO2S)2N

N

N

O

R1 R2

O

R2

O

15 examples 8-95%

H

N N Pd II OAc 63

5-membered palladacycle through β-methyl hydrogen of imine compound

4.2. Intramolecular C(sp3)-H Bonds Amination Traditionally, cyclic amines and their derivatives were synthesized mainly either by nucleophilic displacement of amine nitrogen or reductive elimination. Hydroamination of alkenes and alkynes, cycloadditions and radical cyclizations are other common methods to construct C-N bonds in polysubstituted N-heterocycles. Direct and straight-forward intramolecular C(sp3)-H amination provides quick access to various amine compounds. This is a challenging task because of the thermodynamic and kinetic stablility of the C-H bond. Numerous reaction methods and strategies have been developed for the direct intramolecular amination of activated C(sp3)-H bonds like benzylic, allylic and C(sp3)-H bonds located αto the electron withdrawing groups.180182 Here we will discuss very limited and relevant examples of activated C(sp3)-H bonds amination and focus mostly on unactivated alkyl C(sp3)-H bond amination. A large number of intramolecular C(sp3)-H amination reactions utilize a heteroatom-directed activation mechanism. A chelating group in the substrate facilitates C-H activation to proceed regioselective functionalization by coordinating it to the catalyst183-184 (Scheme 93). Scheme 93. Heteroatom-Directed C-H Activation R

R H

n

DG

FG

Pd

R

[Pd] n

n DG

FG DG

Pd DG = directing group; FG = functional group

In 1880, Hofmann pioneered the discovery of intramolecular amination of unactivated C(sp3)-H bonds and synthesized octahydroindolizine by treating N-bromo-2-propylpiperidine with hot H2SO4 and base (Scheme 94).185-186 Today, this reaction is known as the Hofmann-LöfflerFreytag (HLF) reaction and is extremely important for the synthesis of five membered tertiary amines using N-halogenated amine precursors. As an alternative to the acidic reaction conditions, the HLF reaction is equally effective under neutral and basic conditions to afford polycyclic amide and amine products. Scheme 94. Hofmann’s Pioneering Synthesis of Octahydroindolizine 1. H 2SO 4, 140 oC N

Br

2. strong base

N


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ACS Catalysis

Less reactive aliphatic C(sp3)-H bonds in amines are crucial for IDCA (intramolecular dehydrogenative C-H amination) reactions, as the lack of reactivity enhances the chemical selectivity of the transformations. Directed cyclopalladation due to favorable five or six membered rings are highly useful complementary transformations to radical or nitrene based amination of secondary or tertiary C-H bonds.187 In many IDCA reactions, initially formed palladacycle oxidizes to higher oxidation state Pd(IV) to enhance C(sp3)-N reductive elimination. Glorius and coworkers developed an IDCA of C(sp3)-H bond activation into C-N bond formation cascade by using a tert-butylphenyl acetamide derivative and AgOAc as an oxidant via oxidative cyclization (Scheme 95A).188 The acetyl group proved to be the best as a N-substituent, as other acyl groups like pivaloyl, benzoyl, or trifluoroacetyl are unreactive. A delicate balance between electronic and steric properties of the nitrogen substituent is crucial for the success of reaction. Diverse substituents in different positions of benzene ring are widely tolerable. However, in ortho-aryl substituted benzene substrates, reactivity at the C(sp2)-H bond is favored over reaction at the C(sp3)-H bond (Scheme 95B). The authors proposed a Pd(II) palladacycle 64 as an intermediate that leads the final indoline product via two possible routes: (a) Pd(II) palladacycle 64 oxidizes to Pd(IV) species 65 by AgOAc and reductively eliminates the product (Scheme 96 route a) or (b) Pd(II) palladacyle 64 reductively eliminates giving indoline product and regenerating Pd(0) which subsequently reoxidizes to Pd(II) by AgOAc (Scheme 96 route b).


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 95. Palladium-Catalyzed Amidation of Unactivated C(sp3)-H Bonds to Synthesize Indolines Scheme 95A

R3

Pd(OAc)2 (10 mol %) AgOAc (3 equiv)

N H

Na2CO3 (3 equiv), Mesitylene, 140 oC, 12-36 h

R3

R1 R2

R1

N R2

26 examples 24-81%

Selected Substrate Scope O

EtO2C

O N

N

O

O

O

O 81%

78%

24%

80%

Me3Si

Ph N O 44%

N Cl

N

N

O 47%

N

N

O

O 73%

60%

Scheme 95B

Pd(OAc)2 (10 mol %) AgOAc (3 equiv) NHAc H

N Ac +

NAc

Na2CO3 (3 equiv), Mesitylene, 160 oC, 19 h 0%

39%


Page 68 of 97

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ACS Catalysis

Scheme 96. Proposed Mechanism of Palladium-Catalyzed Amidation of Unactivated C(sp3)-H Bonds to Synthesize Indolines H NHAc N Ac Pd(OAc)2 reductive elimination OAc IV Pd N Ac OAc

route b

H II OAc

Pd

N Ac

65 route a C-H activation Pd N Ac 64

2AgOAc

II

Pd(II) palladacycle HOAc

-Pd0

OAc NHAc -HOAc

nucleophilic substitution

N Ac

After Daugulis’s discovery of picolinic acid auxiliary for γ-arylation116, their group reported picolinamide directed Pd-catalyzed (IDCA) aliphatic and benzylic C(sp3)-H bond activation to synthesize five-member heterocycle through C-H and N-H coupling (Scheme 97).143 About 2 equivalent of oxidant PhI(OAc)2 in toluene is essential to convert Pd(II) to higher oxidation state Pd(IV) that leads to product in fair to good yields regenerating Pd(II) catalyst through reductive elimination. This methodology is equally effective for direct C(sp2)-H and N-H coupling to synthesize indolines in good yields. If the six membered chelate intermediate 66 is not formed, acetoxylation product is expected to be dominant.


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Scheme 97. Palladium-Catalyzed Direct C-Hand N-H Coupling of Aliphatic and Benzylic C(sp3)-H Bonds Pd(OAc) 2 (5 mol%) PhI(OAc) 2 (2 equiv)

O N

H N

N

O N

N

Pd N L

Toluene, 80-120 oC 24 h

O

66

6 examples 36-88%

6-membered chelate intermediate

Selected Substrate Scope O N

O N

N

O N

N

Me

O N

N Me

88%

40%

59%

Me N

Me

Br 42%

Simultaneously with Daugulis,143 Chen and coworkers reported an efficient picolinamidedirected intramolecular amination (IDCA) of the C(sp3)-H bonds at the γandδ positions of amine substrates providing 4-membered azetidines and 5-membered pyrrolidines, respectively.144 For azetidine formation as a major product, presence of β-substituent in the substrate is required (Scheme 98). Substrates without β-substituent give the acetoxylated product as a major product. The authors proposed that the clear choice of γ–selectivity is due to the formation of a kinetically favored five-membered palladacycle 67 that leads to C-N bond under oxidation through a Pd(II/IV) catalytic cycle. The competitive reductive elimination to form C-N and C-O is crucial in the Pd(IV) palladacycle as some substrates give acetoxylated products. The authors proposed that the rate of subsequent C-N and C-O reductive elimination is affected by the associated OAc ligand and the steric effect of the substrate. This reaction protocol is also efficient to form a five-membered pyrrolidine product from a six-membered palladacycle intermediate 68, as it is more favorable than forming four-membered azetidine from a five membered palladacycle (Scheme 99). Substrates having both primary C(sp3)-H bonds in γandδ positions also provide moderate yields of pyrrolidine cyclized products. Like azetidine formation, for the pyrrolidine formation as a major product, presence of γsubstituent in the substrate is required.


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ACS Catalysis

Scheme 98. Palladium-Catalyzed Synthesis of Azetidine via C(sp3)-H Activation at γ-Position Pd(OAc) 2 (5 mol%) PhI(OAc) 2 (2.5 equiv)

R2 R1 H HN

O

N

R2 IV Pd N

R1 N

AcOH (2 equiv) Toluene, Ar, 110 oC 24 h

67 five-membered palladacycle putative Pd(IV) intermediate

6 examples 25-91%


O

N

O

N

Me CO 2Me

OAc

N O

N

82% dr > 20:1

91%

N

O

N

O

N

CO 2Me

OAc

N

N

O

N

25%

70%

Scheme 99. Palladium-Catalyzed Synthesis of Pyrrolidines via C(sp3)-H Activation at δPosition R2 R3 H

R1 HN

O

N

Pd(OAc) 2 (5 mol%) PhI(OAc) 2 (2.5 equiv)

N

72% dr > 20:1

R2 R1 N

AcOH (10 equiv) Toluene, Ar, 110 oC 24 h

O

N

4 examples 17-86%

Substrate Scope

OAc

N

R3

N

O N

17%

CO 2Me O

N N

82% dr ~ 7:1

IV Pd N

68 six-membered palladacycle putative Pd(IV) intermediate

CO 2Me O

O

N

N N

CO2Me O

86%

In addition to picolinamide-directing group, Chen and coworkers extended the IDCA cyclization to carboxamides coupled to 8-aminoquinoline (AQ) and 2-pyridylmethyl amine (PM) as bidentate direction groups (Scheme 100).146 Reactions of these substrates afford excellent yields ofγlactams with high selectivity accompanied by small amount of acetoxylated product ( 20:1

CO 2Me N O

Bn

N N N

56% dr > 20:1

Me

Me N

O

Bn N N N

88% dr = 5:1

Zhao and coworkers reported that the oxalyl amide directing group is effective not only for C(sp2)-H bond activation but also for C(sp3)-H bond to synthesize pyrrolidines (Scheme 102).157 Substrates having two or three primary δ- C(sp3)-H bonds smoothly give cyclized products in good to excellent yields by employing Pd(OAc)2 (5 mol %) with 2.5 equiv of the oxidant


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ACS Catalysis

PhI(OAc)2. Many of these substrates afford better yields at temperatures ranging from 80 – 120 o C in mesitylene solvent. Many substrates with α- substituents give the better yield of pyrrolidines product. Scheme 102. Palladium-Catalyzed Intramolecular Amination of Unactivated C(sp3)-H Bonds Pd(OAc) 2 (5 mol%) PhI(OAc) 2 (2.5 equiv)

R2 R1

R3

O

(i-Pr) 2N

O

Mesitylene, 80-140 oC Ar, 12 h

O

N

25%

N(i-Pr) 2 O

N O 91%

R1 N(i-Pr) 2 O

7 examples 25-91%


O

R2 N

HN

H

R3

N(i-Pr) 2 O

N O 64%

N(i-Pr) 2 O

N O

N(i-Pr) 2 O

60%

The free amino group has high affinity for tight coordination to transition metals, diminishing the catalytic activity of the metal center. Matsubara and coworkers reported the use of unprotected aromatic primary amines in palladium catalyzed C-H aminations using water as the reoxidizing reagent with maximum 7% yield of aminated product.189 Gaunt and coworkers reported a similar directed C-H activation reaction with unprotected aliphatic secondary amines via a four membered palladacycle, which for the first time transformed an adjacent methyl group into the useful aziridine nitrogen heterocycle (Scheme 103).190 This IDCA reaction utilizes Pd(OAc)2 (5 mol %) in presence of PhI(OAc)2 oxidant. When ethyl substituted morpholinone undergoes C-H activation reaction, there is still high preference of aziridine product formed through the fourmembered cyclopalladation pathway, disfavoring a classical kinetically favored five-membered cyclopalladation (Scheme 104). The authors reported a detailed kinetic and computational study providing the role of acetic acid in reaction as well as mechanistic explanation of selective cyclopalladation.191 The amine first coordinates to Pd(OAc)2 to give monocoordinated Pdcomplex 71, which either coordinates to another amine to give either isolable off-cycle bis-amine Pd(II) complex 72 or four-membered palladacyle 73. Forming palladacycle 73 is considered the turnover limiting step (putative C-H activation complex). The concentration of amine is regulated by acid mediated equilibrium that controls the formation of the off-cycle bis-amine Pdcomplex. This complex, on treatment with phosphine, was isolated and characterized (by X-ray crystallography) as a mononuclear palladacycle species. The putative four-membered C-H activation complex 73 is presumably oxidized with PhI(OAc)2 to a Pd(IV) species 74. Interestingly, the reaction is very selective between the two different types of methyl groups on each side of N-atom, showing an important stereoelectronic differentiation created by the nearby carbonyl group forming the aziridine on that side. Amine compounds without the lactone fragment did not initiate C-N bond formation, indicating that Pd(IV) intermediate is controlled by the carbonyl group to initiate C-N bond forming reductive elimination.


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Scheme 103. Palladium-Catalyzed C-H Activation of Aliphatic Amines to Synthesize Aziridines Pd(OAc) 2 (5 mol %) PhI(OAc) 2 ( 1.5-2.5 equiv)

R3 R 2 N

H

CH 3 R1

O O

O

N

Ac2O (2 equiv), toluene or chlorobenzene (0.1-0.05 M) 70-80 oC, 12 h

amino-lactone

R1

O

CH 2

2 R3 R

13 examples 36-81%


O

O

Me

O

CH 2

N

O

Me

O N

O

O

CH 2

CH 2

N

Me Me

Me Me

Me Me

74%

77%

52%

Me

O N

CH 2

N Ts 73%

Scheme 104. Mechanism of Palladium-Catalyzed C-H Activation of Aliphatic Amines to Synthesize Aziridines Me Me Me Me N CH 2 O

N O O

H+

H

Me Me NH 2 CH 3 Me

O

CH 3 Me

O

O Me Pd(OAc) 2

Me Me N

Me

C-N reductive elimination (fast)

O Me O

O

O

O Me Me Pd N O O

Me Me Pd N

O

Me

O Me

OAc CH 3 O Me 71

O

O

H

O

Me H 3C

CH 3 Me

O N

AcO Me Me Pd Me Me N O

OAc

CH 3 O Me 72

74 1. oxidative addition fast {+ PhI(OAc) 2} 2. deprotonation fast (-AcOH)

C-H activation (turnover limiting step)

Me O Me Me Pd N O O Me

O

AcOH

73

4-membered palladacycle putative intermediate

Wu and coworkers reported the synthesis of the various substituted β-lactams with high regioselectivity utilizing C6F5I-promoted intramolecular dehydrogenative amination of unactivated β-C-(sp3)-H bonds of 8-aminoquinoline carboxamides (Scheme 105).192 Pentafluoroiodobenzene is considered a key for electronic and steric tuning of a catalytic intermediate species that favors the C-N bond forming step. The reaction combination of Pd(OAc)2 (5 mol %), oxidant AgOAc (1.2 equiv) and pentafluoroiodobenzene (5.5 equiv) under


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ACS Catalysis

microwave for 1.5 h at 160 oC gave 71-96 % yields of the desired β-lactam products. Numerous alkyl-substituted carboxamides also give the corresponding β-lactam products in good to excellent yields. The authors proposed a plausible reaction mechanism where carboxamide forms the five-membered palladacyle with Pd(OAc)2 and undergoes C-H activation to form bi-nitrogen coordinated palladium complex 75 (Scheme 106). Complex 75 undergoes oxidative addition to pentafluoroiodobenzene to give Pd(IV) species 76, which is followed by ligand exchange with AgOAc to afford one of two possible complexes – 77 and 78. Either one of these complexes can undergo C-N bond forming reductive elimination, releasing the β-lactam product and Pd-bound pentafluorobenzene 79. Intermediate Pd-species 79 on combination with carboxamide gives pentafluorobenzene as the side product and the palladacycle, continuing the catalytic cycle. Scheme 105. Palladium-Catalyzed Unactivated C(sp3)-H Bond Activation and Intramolecular Amination of Carboxamide

R1

Pd(OAc) 2 (5 mol %) AgOAc ( 1.2 equiv)

I

O

F NH N

+

F

F

F

R1

N

N

Solvent free, Microwave, 160 oC, 1.5 h

F

O

(5.5 equiv)

71-96%

Selected Substrate Scope MeO N

O N N

93%

O

O

N

N

N

87%

N

80%

O

Br

7 N

N

N

83%

O

94%


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Scheme 106. Proposed Mechanism of Palladium-Catalyzed Unactivated C(sp3)-H Bond Activation and Intramolecular Amination of Carboxamide H F

F

F

O Ph

F

NH N

F AcO Ph

N

Pd(OAc)2

O

Ln Pd F

F

N

F

F

protonation

HOAc

F 79

F

F

Pd

N

O Ph

F

F

F F Ph

F


F OAc

F Or

F Ph

Pd

O H P N d N

N

O

N

N O

O

78

77

C-H activation ligand exchange F

AgOAc

HOAc F F I N

F F Ph

Ln Ph

Pd

N N

Pd IV N

O 75

5-membered palladacycle

O 76

oxidative addition

I F

F

F

F F

Shi and coworkers reported a sequential C(sp3)-H monoarylation followed by amidation to develop a stereoselective synthesis ofα-amino-β-lactams (Scheme 107).193 The N,N-bidentate PIP amide directing group (PIP = 2-(pyridine-2-yl)isopropylamine) proved to be very effective and directed the metalation for both the arylation and amination. The use of NaIO3 or NaIO4 with Ac2O in MeCN was effective for the oxidation of Pd(II) palladacycle to Pd(IV) complex in the amination reaction and gave the highest yield and selectivity of lactam products. The intramolecular dehydrogenative methylene C(sp3)-H amidation of phenylalanine derivatives mainly provide the β-lactam as a single distereomer with a small quantity of the corresponding β-acetoxylated by-product due to the involvement of a trans-palladacyle intermediate, which reductively eliminates to the C-N bond formation product.


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ACS Catalysis

Scheme 107. Synthesis of β-Lactams via Pd-Catalyzed Sequential Monoarylation and Intramolecular C(sp3)-H Amination O PhthN H

I N H

+

Pd(OAc) 2 (10 mol %) CuF 2 (1.5 equiv), DMPU (5 equiv)

R

N (1.5 equiv.)

acetone, N 2, 100 oC, 24 h

Pd(OAc) 2 (10 mol %) NaIO 3 (2 equiv)

O PhthN

N H

PhthN N

N

R 35-89%

O

Ac2O (10 equiv), MeCN N 2, 70 oC, 48 h

R

N 46-86%

4.3. Intramolecular Allylic Amination via C-H Activation Generally, Pd-catalyzed allylic amination requires a nitrogen substituted with an electron withdrawing group that will act as a directing group. Larock and coworkers were the first to report a palladium catalyzed intramolecular allylic C-H amination where cyclization of tosylamides containing an alkene substituent afforded indoline products in good yields. (Scheme 108) 194 The authors proposed the involvement of π-allylpalladium intermediate as a key during C-N bond formation process. Scheme 108. Palladium(II)-Catalyzed Intramolecular Allylic Amination Pd(OAc) 2 (5 mol %) NaOAc (2 equiv) NHTs

O 2 (1 atm) DMSO, 25 oC, 72 h

N Ts 86%

Using this concept, Broggini and coworkers extended this work for the synthesis of six- and sevenmembered heterocycles employing intramolecular amination of N-allyl anthranilamides (Scheme 109).195 The product distribution is strongly dependent on the reaction conditions. The presence of pyridine (20 mol %) accelerates the preferential formation of 7-membered ring, but when pyridine is replaced by NaOAc (1 equiv) as an additive, six-membered compound is formed as a major product. The authors hypothesized the intermediacy ofε-3-allyl-palladium complex formed by direct C-H activation, which was later supported by Liu’s mechanistic study showing a rate determining allylic C-H activation and irreversible reductive elimination pathway on Pd-catalyzed oxidative allylic amination.196 Liu and coworkers reported an intramolecular aerobic oxidative allylic C−H amination ofδ,ε-unsaturated tosyl amides where altering the reaction conditions can modulate the regioselectivity of either 5- or 7-membered rings. The seven membered ring is obtained as the major product in the presence of base additive (NaOBz, 1 equivalent), maleic anhydride (40 mol %) and 4Å molecular sieves. The five membered ring is obtained as a major product by adding (salen)CrIIICl additive, discovered by White and coworkers.105 It has been proposed that ߨ-allyl palladium intermediate normally exists as an equilibrium mixture of syn and anti forms. The subsequent nucleophilic attack provides five or seven membered rings depending on exo or endo attack (Scheme 110). Zhang and coworkers also reported ligand-dependent Pd-catalyzed oxidative amino-cyclization to synthesize isoindolinones and iso-quinolin-1(2H)-ones using same allylic precursors.197


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Scheme 109. Base-dependent Palladium(II)-Catalyzed Intramolecular Oxidative Aminocyclization Ts

N O

Ts

Pd(OAc) 2 (10 mol %) Pyridine (20 mol %)

N

N

Xylene, O 2, 100 oC, 24 h

R

Ts

Pd(OAc) 2 (10 mol %) NaOAc (1 equiv)

NH

N N

DMSO, O2, 100 oC, 24 h

R

R

O

O

Scheme 110. Palladium(II)-Catalyzed Intramolecular Oxidative Allylic C-H Amination

PdX

PdX R

R

NH

O

O

N R

O

N R

NH

O

O PdII/L

exo

syn

anti base

HX

NHR H

Pd R

N endo

O anti

White and coworkers reported an intramolecular amination of allylic C-H bonds utilizing chiral homoallylic N-tosyl carbamates to diastereoselectively form vinyl oxazolidinones, precursors of syn-1,2-amino alcohols (Scheme 111).198 A phenyl bis-sulfoxide ligand and phenylbenzoquinone as the oxidant are required to access the high yields for this transformation. Yields and selectivities mainly depend on the substitution adjacent to the carbamoyl, with a tertiary group such as an isopropyl giving the best reactivity and selectivity. Similar to the work by Larock,194 the authors proposed the formation of π-allylpalladium intermediate 80, which is attacked by the nitrogen nucleophile via intramolecular substitution. The White group extended this amination to substrates possessing the more electron-deficient N-nosyl carbamate to produce six-membered vinyl oxazinanones.199 White group utilized a common terminal olefin in palladium- controlled C-O versus C-N allylic functionalization by manipulating the the role of bis-sulfoxide ligand200 and Lewis acid cocatalyst.201 The combination of ligand with palladium has shown a sequential C-H amination/vinylic C-H arylation in α-olefins.202 Poli and coworkers used acetic acid as the solvent in an intramolecular allylic amination and reduced the reaction time from 72 h to 24 h while maintaining the high yield and distereoselectivity.203 The authors proposed that acetic acid assists the re-oxidation of Pd(0) to Pd(II) and the ionization of intermediate palladium complexes. Detailed DFT analysis supports the structural and energetic features of key catalytic steps.


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ACS Catalysis

Scheme 111. Pd-Sulfoxide Catalyzed Intramolecular Allylic Amination

O

O

Pd(OAc) 2 (10 mol %) Ligand (10 mol %)

O

O

NHTs

R

PhBQ (1-2 equiv), THF, 45 oC, 72 h

O NTs

O

NHTs

R

R

PdLn 80

R = n-Pr, i-Pr, t-Bu Ligand =

O

S

Ph

S

O R = n-Pr (86 %, 23 % de) i-Pr (86 %, 71 % de) t-Bu (8 %, 89 % de)

Ph

5. PALLADIUM CATALYST IN NORBORNENE-MEDIATED C-H AMINATION The Catellani reaction can functionalize both the ortho and ipso positions of aryl halides in a single step mediated by norbornene. Norbornene-assisted Catellani-type aminations avoid a directing group on the substrate and generate a unique palladacycle that cannot undergoβhydride elimination.204-205 Ritter and coworkers reported the ortho-amination and ipsofunctionalization reaction of aryl iodides to provide 2,3-disubstituted anilines (Scheme 112).206 Reaction is norbornene-mediated but does not involve a coordinating directing group and represents the first example of intermolecular incorporation of a C-heteroatom bond at the ipso position in the Catellani reaction. Aryl iodides with ortho-substitution react with Nbenzoyloxyamines and bis(Pinacolato)diboron in presence of Pd(OAc)2, tris-p-MeO phenyl phosphine, norbornene, and cesium carbonate in toluene at 100 oC to give ortho-aminated phenyl pinacol boronate esters. Various BzO-amines incorporating six-membered rings are excellent Nsources but amines having five-membered rings or linear chains are not reactive under these conditions. Scheme 112. Palladium-Catalyzed ortho-Amination/ipso-Borylation and Azidation I R1

Pd(OAc)2 (5 mol %) (MeOC6H4)3P (10.5 mol %) Norbornene (1 equiv)

O R1

FG

B2Pin2 (1 equiv) BzO-amine (1.05 equiv) Cs2CO3 (2.5 equiv) Toluene, 100 oC, N2, 12 h

B

NaN3 (1.5 equiv) Cu(OAc)2 (10 mol %)

O NR2

Air, MeOH, 50 oC

N3 R1

NR2

FG 51-73% (2 steps)

FG

Exploring the extensive study by Catellani204 and Lautens205 of C-C bond formation, Dong and coworkers reported a palladium and norbornene co-catalyzed ortho-site selective arene C-H amination using aryl-halides (Scheme 113).207 N-benzoyloxyamines and isopropanol are employed as the amine source/oxidant and reductant, respectively, with Pd(OAc)2 (10 mol %) as a catalyst. Tris(4-methoxyphenyl) phosphine ligand and Cs2CO3 base are required for the amination (Scheme 113). In contrast to Buchwald-Hartwig reaction, this amination occurs at the ortho-position instead of ipso position and involves Catellani-type C-H activation with high functional group tolerance. The authors proposed an intermediate Pd(IV) species or direct electrophilic substitution of N-benzoyloxyamine by a special palladacycle for ortho C-N bond formation. This reaction also proceeds with broader amine sources like piperidine, azepane, diethylamine, pyrrolidine, and BOC protected piperazine.


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Scheme 113. Site-Selective Palladium and Norbornene-Catalyzed Arene C-H Amination R1 I

+

H

FG

Pd(OAc)2 (10 mol %) P(pOMe-C6H4)3 (25 mol %) Norbornene (25 mol %)

OBz N O

H N

FG

iPrOH (1.2 equiv) Cs2CO3 (2.5 equiv) Toluene, 100 oC, 24 h

(1.1 equiv)

R1

O 69-94%

Selected Substrate Scope OTBS

Me

O2N

94%

86%

N

N

O

O

H

H

N

N

F

Me

H

H

O

O 85%

87%

Wu and coworkers reported a norbornene-mediated ortho-amination and alkynylation as three component reactions (haloarene, alkoxyamine, and alkyne) (Scheme 114).208 In absence of norbornene, this double coupling reaction of C-I and C-H bonds (consecutive amination and Sonogashira) does not occur. Gu and coworkers reported a similar reaction for the synthesis of substituted alpha-alkynyl anilines where the reaction is terminated by decarboxylative alkynylation (Scheme 115).209 The alkynyl carboxylic acid is equally compatible with other N,Ndisubstituted O-benzoylhydroxylamines. Scheme 114. Palladium-Catalyzed One-Pot Consecutive Amination and Sonogashira Coupling

OH R1 I

+

H

FG

OBz N

Pd(OAc)2 (10 mol %) PPh3 (20 mol %) Norbornene (3 equiv)

R1

+

O

Cs2CO3 (3 equiv) Dioxane, 100 oC, 18 h

(1.1 equiv)

N

FG

O 56-96%

(1.2 equiv)

Scheme 115. Palladium-Catalyzed Catellani Reaction for Synthesis of Alpha-Alkynyl Anilines via Ortho C-H Amination and Alkynylation R1 I FG

H

+

OBz N

COOH

Pd(OAc)2 (5-10 mol %) PPh3 (12.5 mol %) Norbornene (6 equiv)

R1

+ Cs2CO3 (3 equiv) Toluene, 100 oC, 4 h

O (1.2 equiv) (1.5 equiv)

FG

N O 57-93%

Liang and coworkers reported a palladium catalyzed, norbornene-mediated ortho-amination and N-tosylhydrazone insertion reaction which generates ortho-aminated vinylarenes as a three component, one-pot reaction (Scheme 116A).210 The reaction constructs a C-N bond and a C-C bond employing an electron deficient N-benzoyloxyamine as an efficient electrophilic nitrogen


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Page 82 of 97

source and an N-tosylhydrazone as a nucleophilic coupling partner. A variety of substituted aryl iodides, electrophilic amine partners and substituted N-tosylhydrazones afford the corresponding ortho-aminated vinylarenes in moderate to good yields. Chen and team reported a similar palladium-catalyzed norbornene-mediated domino reaction of aryl halides, amines and activated terminal olefins to afford ortho-alkenyl aromatic amines in good yields (Scheme 116B).211 The Chen group also utilized aromatic pinacol boronate along with an aryl halide and O-acyl hydroxylamine in the similar reaction to afford biaryl tertiary amines in good yield (Scheme 116C).212 Aryl iodides with no ortho-substituent reacts with morpholino benzoate and phenyl pinacol boronate to provide the corresponding biaryl tertiary diamines in good yields. Scheme 116. Palladium-Catalyzed Norbornene Mediated Reactions 116A

R1 I

OBz N

+

H

FG

NNHTs

+

Ph

O (1.1 equiv)

(2.5 equiv)

Pd(OAc)2 (10 mol %) PPh3 (20 mol %) Norbornene (1 equiv) Cs2CO3 (5 equiv) Toluene, 100 oC, 20 h

R1

Ph

N

FG

O

36-73% 116B R1 I

OBz N

+

H

R2

+

O (1.5 equiv)

(1.2 equiv)

Pd(OAc)2 (10 mol %), (4MeOC6H4)3P (20 mol %) Norbornene (2 equiv) Cs2CO3 (3 equiv) CH3CN, 100 oC, 3-5 h

R1 R2 N O 14-81% E>Z

116C

I R1

H

+

OBz N

(1.5 equiv)

+

Ar Bpin (1.5 equiv)

Pd(OAc)2 (5 mol %) (2furyl)3P (20 mol %) Norbornene (0.5 equiv)

Ar R1

N

Cs2CO3 (3 equiv) Toluene, 80 oC, N2, 5 h 20-94%

Shi and coworkers reported Pd(0)-catalyzed C-N bond formation process using di-tertbutyldiaziridine as a nitrogen source with the formation of four C-N bonds and one spiro quaternary carbon in a single operation (Scheme 117).213 A sequence of Heck reaction, C-H activation and amination affords a variety of polycyclic indolines in good yields. Shi group also extended this reaction using iodobenzenes, norbornene and di-tert-butyldiaziridone giving a variety of polycyclic indolines in good yields (Scheme 118).214 The authors proposed a palladacycle 81 in association with norbornene which is followed by oxidative addition to the diaziridinone 82. This finally leads to two subsequent C-N bond formations (Scheme 119).


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Scheme 117. Palladium(0)-Catalyzed C-N Bond Formation using α-Methylstyrenes and Diaziridinone Pd(PPh 3)4 (10 mol %) PPh 3 (20 mol %)

O N N

+

R1

N R1

neat, 85 oC, 24 h

O

N

N

(4 equiv) 16 examples 56-83%

Scheme 118. Palladium(0)-Catalyzed C-N Bond Formation using Iodobenzene, Norbornene and Diaziridinone O I R1

N N

+

+

Pd(PPh 3)4 (5 mol %) CsCO 3 (2 equiv)

(2 equiv)

Toluene, 80 48-72 h

(1.05 equiv)

oC,

H R1

N

H

19 examples 67-97%

Scheme 119. Proposed Mechanism of Palladium(0)-Catalyzed C-N Bond Formation using Iodobenzene, Norbornene and Diaziridinone I H H N Pd(0) +

PdI

tBuNCO


Pd N N

PdI

O 82

Base

O Pd PPh 3

N N

Ph 3P 81

palladacyclic complex

6. CONCLUSION AND OUTLOOK In conclusion, we have summarized the extensive reactions and their mechanistic pathways for palladium complexes in C-H amination reactions. Despite significant progress in Pd-catalyzed amination reactions, many require stoichiometric external oxidants under sometimes harsh conditions. Future scenario should focus on the use of environmentally benign nitrogen sources in mild reaction conditions with no stoichiometric waste products. Minimum catalyst loadings and expansion of nitrogen sources through palladium complexes to make efficient C-N bonds


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also need further investigations. In order to accomplish these goals, a thorough understanding of reaction mechanisms is required along with the creativity and skills of the organic chemist. Site selectivity is another difficult challenge in Pd-catalyzed C-H amination, therefore, tuning selectivity as a function of palladium catalyst and nitrogen source would be a great future synthetic aspiration. In addition, many methods provide five membered N-heterocycle rings intramolecularly but the synthesis of six and seven membered rings still remains a challenge. Even though there are challenges to reconcile – including thermodynamic, kinetic, economic, and environmental requirements – progress to date inspires hope that future research in the area will eventually exploit the full range of C-H bonds more directly, efficiently and cleanly. Conflicts of interest There are no conflicts to declare. Acknowledgements We acknowledge financial support for this work by the National Science Foundation (CeRCaS NSF I/UCRC), the Virginia Center for Innovation Technology (MF16-013-LS), and the Virginia Commonwealth University Quest for Innovation fund. References 1. Kim, J.; Movassaghi, M. Biogenetically-Inspired Total Synthesis of Epidithiodiketopiperazines and Related Alkaloids. Acc. Chem. Res. 2015, 48, 1159−1171. 2. Li, L.-L.; Diau, E. W.-G. Porphyrin-sensitized solar cells. Chem. Soc. Rev. 2013, 42, 291−304. 3. Lee, M. M.; Teuscher, J.; Miyasaka, T.; Murakami, T. N.; Snaith, H. J. Efficient Hybrid Solar Cells Based on Meso-Superstructured Organometal Halide Perovskites. Science 2012, 338, 643−647. 4. Surry, D. S.; Buchwald, S. L. Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide. Chem. Sci. 2011, 2, 27−50. 5. Olah, G. A.; Ripudaman, M.; Narang, S. C. Nitration: Methods and Mechanisms; VCH Publishers, Inc.: New York, 1989. 6. Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382−2384. 7. Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691−1692. 8. Chan, D. M. T.; Monaco, K. L.; Wang, R.; Winteres, M. P. New N- and O-arylations with phenylboronic acids and cupric acetate. Tetrahedron Lett. 1998, 39, 29332936. 9. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winteres, M. P.; Chan, D. M. T.; Combs, A. New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation. Tetrahedron Lett. 1998, 39, 2941-2944. 10. Masanori, K.; Masayuki, K.; Toshihiko, M. Palladium-Catalyzed Aromatic Amination of Aryl Bromides with N,N-Di-Ethylamino-Tributyltin. Chem. Lett. 1983, 12, 927-928.


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Palladium-Catalyzed C-H Amination of C(sp ) and C(sp )-H Bonds

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