Recent Advances in the Catalytic Synthesis of Î±-Ketoamides - ACS

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Review

Recent advances in catalytic synthesis of #-ketoamides Dinesh Kumar, Sandeep R. Vemula, and Gregory R Cook ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01116 • Publication Date (Web): 17 Jun 2016 Downloaded from http://pubs.acs.org on June 19, 2016

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ACS Catalysis

Recent advances in catalytic synthesis of αketoamides Dinesh Kumar, Sandeep R. Vemula and Gregory R. Cook* Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 581086050, USA. Tel: 701-231-7413; Fax: 701-231-8831; Email: [email protected]

ACS Paragon Plus Environment

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ABSTRACT: α-Ketoamides and their derivatives are key constituents of natural products, biologically relevant molecules, drug and drug candidates and functional materials. Further they are versatile and valuable intermediates and synthons in a number of functional group transformations and total synthesis. In recent years tremendous growth has been realized in the development of synthetic methods for α-ketoamide preparation and their applications in synthetic and medicinal chemistry. Among the various catalytic methods of α-ketoamide formation, the following two approaches, namely double aminocarbonylation and oxidative amidation, have received much more attention and have been greatly studied because of the readily available of the starting materials, use of carbon monoxide (CO) as direct source of carbonyl functionalities, and use of molecular oxygen (O2) or air as the green terminal oxidant and/or reactants. Catalyzed α-ketoamide formation can be roughly classified into metal and non-metal catalyzed process. In context of metal catalysis, the most metal-involved reactions are performed using palladium (Pd) and copper (Cu), however other metals such as gold (Au), silver (Ag), and iron (Fe) based catalysts have also been investigated to some extent. On the other hand, non-metalcatalyzed α-ketoamide syntheses are mainly restricted to iodine-based catalysts in the presence or absence of other promoters. Our objective in this review is to highlight the important research endeavors related to the catalytic α-ketoamides synthesis, which include the trends in the catalytic synthesis of α-ketoamides, new breakthroughs, and recent advances until March 2016.

KEYWORDS:

α-Ketoamides,

catalysis,

amino

dicarbonylation,

oxidative

amidation,

chemoselectivity

1. INTRODUCTION


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α-Ketoamides and their derivatives are key constituents in natural products,1 biologically relevant molecules (anti-viral including anti-HIV,2 anti-tumor,3 anti-inflammatory including antiIBD,4 anti-bacterial5), drugs and drug candidates (Figure 1).6 Further they are versatile and valuable intermediates and synthons in a variety of functional group transformations and total synthesis. In recent years, tremendous growth has been realized in the development of synthetic methods for α-ketoamide preparation and their applications in synthetic and medicinal chemistry. α-Ketoamides

undergo

a

variety

of

reactions

including

but

not

limited

to

N-

alkylation/arylation/acylation, nucleophilic addition at the carbonyl group, chemoselective reduction (hydrogenation), and oxidation.7 These species often display unique reactivity as compared to isolated carbonyl compounds, particularly with regards to the electrophilicity of the ketone moiety. The amide can function as a moderator for reactivity as well as a handle for asymmetric reactions and catalysis.8 Further, appropriately substituted α-ketoamides undergo different types of classical reactions such as Michael reactions, iso-Pictet-Spengler reactions, Mannich reactions, Stetter reactions etc. to form a variety of valuable synthetic intermediates and products.9 The diverse reactivity of α-ketoamides has been further explored for the synthesis of various other heterocyclic frameworks such as indoles, oxindoles, β-lactams, and quinolines etc.10 A detailed review of the scientific literature reveals many research articles devoted to αketoamides in the context of its synthesis. However, only one review articles was discovered related to the synthesis of α-ketoamides when we started this review.11 Very recently, a comprehensive review on synthesis of α-ketoamides has appeared.12 In addition, two reviews on a special cyclic α-ketoamide, isatin, have appeared that are very specific and focused.13 This review is focused on catalytic methods and complements these other reviews.


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O

O

MeO

O

CF3

H N

F

H N

O

O

Cl

Cytokine inhibitor

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CO 2H

H N O

F 3C

O

Ph

Epoxide hydrolase inhibitor

RARγ agonist

CH3 CH3 O

Ph

O

H N

N O

H 2N

NH 2 O Bestatin analoges

Cl

Oxerin receptor agonist

O

O

H N

O O

Bu PTH

OH

O

H N O

OH

Cl

Cl Cl

OH Cl

NH HN

N O

O O

HN

H N

R

O

H N

Cl

O HN

O

HO

O

O N H O NH

H N

O N H

Cl

O NH

Me N

O N H

CO 2H

O OH

N NH 2 H Cyclotheonamide A; R = CHO Cyclotheonamide B; R = C(O)CH3

Chloropeptin I

Figure 1. α-Ketoamide containing biologically active compounds

2. CATALYTIC SYNTHESIS OF α-KETOAMIDES Classical methods of α-ketoamide synthesis involve the condensation of α-ketoacid derivatives, obtained by the reaction of α-ketoacid with differed coupling reagents such as oxalyl chloride, thionyl chloride, N,N'-dicyclohexylcarbodiimide (DCC), and hydroxybenzotrizol (HOBt) with amines. Considerable effort has been given to the catalytic direct synthesis of α-ketoamides, in particular via direct coupling processes, to reduce energy consumption, waste emission (atom economy), operating and purification steps. Among various catalytic methods of α-ketoamide formation, the following two approaches, namely double aminocarbonylation and oxidative amidation, have received much more attention and have been extensively studied because of the ready availability of the starting materials, use of carbon monoxide as direct source of carbonyl functionalities, and use of molecular oxygen (O2) or air as the green terminal oxidant. Amino dicarbonylation of halides with amines provides a broad range of α-ketoamides via a diverse array of starting substrates (halides and amines). Nevertheless, the selectivity over monocarbonylation to form simple amides under mild conditions remains a major challenge. On


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the other hand, oxidative amidation of α-ketoacids, α-ketoaldehydes, arylmethyl ketones, alkynes etc. to form α-ketoamides offers the advantage over amino dicarbonylation in terms of selectivity, but requirement of long reaction times, high temperature, multiple additives etc. and limited substrate scope are the major limitations. Aiming at these challenges, a wide variety of catalysts have been explored and significant developments to α-ketoamide synthesis have emerged. Our objective in this review is to highlight the important research endeavors related strictly to the catalytic α-ketoamides synthesis, which include the conceptual evolution of catalytic procedures, new breakthroughs, recent advances, and trends in the catalytic synthesis of linear α-ketoamides. Particular emphasis will be given on the key factors that affect the catalytic activity, reaction selectivity and reaction mechanisms, which are beneficial for designing new catalysts. Catalyzed α-ketoamide formation can be roughly classified into metal and non-metal catalyzed process. In context of metal catalysis, the most metal-involved reactions are performed using Pd and Cu, however other metals such as Au, Ag, and Fe based catalysts are also investigated and explored to some extent. On the other hand, non-metal catalyzed α-ketoamide syntheses are mainly restricted to iodine-based catalysts in the presence or absence of other promoters. Therefore, in the present review, we divided the catalytic synthesis of α-ketoamides into four major classes as mentioned below.

2.1 α-Ketoamide syntheses under palladium catalysis 2.2 α-Ketoamide syntheses under copper catalysis 2.3 α-Ketoamide syntheses under other transition metal catalysis 2.4 α-Ketoamide syntheses under iodine based catalyst system

2.1 α-Ketoamides syntheses under palladium catalysis 2.1.1 Pd-catalyzed amino double carbonylation reaction: Palladium catalyzed double carbonylation is one of the most exploited catalytic routes for the synthesis of α-ketoamides. Although, the concept of Pd-catalyzed double carbonylation emerged in 1960-1970 with the observed formation of oxoamide,14 synthesis of dialkyl oxalates15 and arylpyruvic acids,16 the very first report of double carbonylative route to α-ketoamides synthesis was reported in 1982 by Fumiyuki Ozawa and Akio Yamamoto17 involving stoichiometric use of


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monoalkylpalladium complexes in the presence of secondary amines under carbon monoxide (CO) atmosphere with good yields and selectivity (Scheme 1).

Scheme 1. First report of double carbonylation route to α-ketoamides using stoichiometric alkyl palladium complexes

A catalytic version of previously reported stoichiometric reactions established the first catalytic amino dicarbonylative route to α-ketoamide synthesis using aryl, arylalkyl, hetero-aryl, and vinylic halides in the presence of catalytic Pd-salts (Scheme 2).18

Scheme 2. First catalytic amino double carbonylation route to α-ketoamides Kobayashi and Tanaka19 reported a similar catalytic double carbonylative route to the αketoamides. They also attempted double carbonylation reactions with primary amines, however formation of the imine of α-ketoamides was observed. Following these two catalytic amino dicarbonylation reports, various details in context of factors affecting selectivity of mono- and dicarbonylation and its mechanistic investigation has been put forward by Yamamoto and others20-23 which established the elementary steps of amino dicarbonylation process. A mechanism consisting of two connected catalytic cycles is shown in Scheme 3. Oxidative addition of Pd(0) into an aryl halide affords an organopalladium(II) species 1, which is a common intermediate in both cycles. Subsequent CO insertion into the Pd−C bond results in the formation of acylpalladium species 2 (cycle I) which on further coordination with another CO


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gives an acyl(carbonyl)palladium species 3. Depending on the nature of solvent and ligand used, it may be neutral or ionic in nature. Nucleophilic attack of the amine onto the CO ligand, provides complex 4 bearing two monocarbonylated ligands, which on reductive elimination gives α-ketoamide and reforms the active Pd(0) catalyst to complete the cycle. Under catalytic cycle II, CO coordinates with palladium to form arylcarbonylpalladium species 5. Subsequent attack by amine leads to an arylcarbamoyl species 6, which on reductive elimination forms the simple amide and generates Pd(0) species. The yields and selectivities of α-ketoamides are controlled by various factors including the substrate (organic halide), amine, CO pressure, nature of catalyst, solvent, and temperature, which are described below.

Scheme 3. Catalytic cycle of Pd-catalyzed amino carbonylative route to α-ketoamides/amides


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(i) Catalyst: Among various transition-metal based catalysts, palladium complexes having tertiary phosphine ligands found as the best catalysts for the double-carbonylation reaction. Nevertheless monodentate phosphines as well as bidentate phosphines were also found effective in some cases. The best yield of α-ketoamides was obtained with balanced (neither too strong or too weak) coordinating ability of the tertiary phosphine ligand. Strongly coordinating phosphines with high basicity and low steric demand tend to result in poor yields. Among the bidentate phosphine ligands, N,N′ bis-[(diphenylphosphino)phenyl]formamidinate (dpfam) was found highly effective in Pd-catalyzing amino-dicarbonylation of aryl iodides with amine nucleophiles (Scheme 4).24

Scheme 4. Pd2Me2(µ-Cl)(µ-dpfam)-Catalyzed amino dicarbonylation reaction On similar lines, phosphorus−nitrogen ligands L1−4 have been found effective for amino dicarbonylation of iodobenzene with diethylamine in DMF at 90 °C with high selectivity compared to classical Pd(II)/PPh3 catalyst system (Table 1).25 Table 1. Catalytic comparison of different phosphorus−nitrogen ligands under Pd(II)-catalysis for aminocarbonylation of iodobenzene.

Entry

Ligand

% Conversiona

% Selectivitya

1

PPh3

96

71/21

2

L1

100

60/40

3

L2

97

90/10

4

L3

99

71/29


8

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5

L4

99

89/11

6

L5

58

96/04

a

Based on GC-MS Nomura and coworkers26 examined the effect of copper (CuI) co-catalyst on the Pd-

catalyzed amino dicarbonylation reaction. The copper iodide assisted the amino dicarbonylation reaction by removing one phosphine ligand from the intermediary palladium complex to form a more reactive iodo-bridged heterobimetallic (palladium−copper) species (Figure 2) facilitating αketoamide formation.

Figure 2. Iodo-bridged heterobimetallic (Pd-Cu) species.

(ii) Effects of Substrates and CO Pressure: In general the reactivity of the arylhalide decreases in the order of ArI > ArBr >> ArCl. The reactivity order is a reflection of the relative ability of the Pd(0) species to undergo oxidative addition into the aryl halides in the catalytic double-carbonylation process. Attempts have been made to overcome the poor reactivity of chloroarenes via bi-metallic activation under Pd-catalysis using (choroarene)chromium complexes favoring oxidative addition of the C-Cl bond to the Pd(0)-complexes.27,28, 29 Introduction of substituents onto the phenyl ring vary the reactivity of phenyl halides. Electron-withdrawing substituents at the para position increased the reactivity but decreased the selectivity for α-ketoamide formation. On the other hand, introduction of para electron-donating


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substituents decreased the reactivity. Inclusion of methyl groups at the ortho positions of phenyl halides strongly retarded the reaction. Although the reaction could be carried out under atmospheric pressure of carbon monoxide (CO), significant benzamide formation resulted, thus 10 – 40 bar pressure of CO was optimal. In general, the higher CO pressure enhanced both the selectivity and reaction rate for αketoamides formation.

(iii) Effect of Amine: The type of amines employed in the double carbonylation have a considerable impact on the yield of α-ketoamides. More highly basic secondary amines are suitable for the reaction but the yield was influenced by the steric bulk. Although they gave αketoamides in higher selectivity. Primary amines also served competently for the double carbonylation to afford α-ketoamides, however the in-situ generated α-ketoamides could react further to afford Schiff bases of α-ketoamides.

(iv) Effect of Other Factors: In catalytic reactions with PhI, Et2NH, and CO, solvents of higher dielectric constant had favorable effect on reaction rate, but the effect of solvent on the selectivity was not significant. In cases where amines are used in excess compared, they also served as solvent in promoting the reactions. Typically amino dicarbonylation reactions took place under heating condition (60 – 100 °C), but in general, lower temperature favored higher selectivity of α-ketoamides formation. Extensive progress has been made in past decades in the area of amino dicarbonylation research. For the sake of convenience, we have classified the progress of amino dicarbonylation research into two categories: (i) conventional development, which mainly deals with improvement in substrate scope and selectivity, (ii) sustainable development which includes development of greener protocols such as amino dicarbonylation using green reaction media, ligand-free amino dicarbonylation, amino dicarbonylation using supported Pd-catalyst system, amino dicarbonylation using atmospheric pressure of CO, integration of novel technologies to the amino dicarbonylation process etc.

2.1.1.1 Pd-catalyzed double carbonylation reaction: Conventional development


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In 1994, Yamamoto30, 31 described the catalytic amino dicarbonylation of allylic chlorides to form β, γ-unsaturated α-ketoamides in the presence of (Ph3P)2PdCl2 at room temperature under high CO pressure (100 atm) with high selectivity and yields (Scheme 5).

Scheme 5. Yamamoto’s protocol for Pd-catalyzed amino dicarbonylation of allyl chlorides

Mechanistically, the reaction proceeds with the formation of “π-allylpalladium complexes” 732 followed by CO insertion to form acylpalladium species 8. Further CO coordination, subsequent amine attack on 9 followed by reductive elimination of 10 gives desired α-ketoamide (Scheme 6).


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Scheme 6. Proposed mechanism for Pd-catalyzed amino dicarbonylation of allyl chlorides Fuchikami and co-workers33 reported the amino dicarbonylation of perfluoroalkyl substituted 2-iodoalkanes with primary or secondary amines in the presence of palladium catalyst with good yields and selectivities (Scheme 7).

Scheme 7. Fuchikami’s protocol for the Pd-catalyzed amino dicarbonylation of alkyl iodides bearing perfluoroalkyl group Zhou and Chen34 reported the amino dicarbonylation of diaryliodonium salts with secondary amines to give α-ketoamides in the presence of a Pd/Cu-catalyst system with good yields and high selectivity under mild reaction conditions (Scheme 8). The use of CuI as a cocatalyst is essential as the lower yields resulted without it even with a longer reaction time.


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Scheme 8. Zhou’s protocol for the Pd-catalyzed amino dicarbonylation of diaryliodonium salts

The mechanism shown in Scheme 9 describes the palladium-catalyzed di- and monocarbonylation of diaryliodonium salts in the presence of secondary amines. When intermediate 11 undergoes CO insertion to afford the aroylpalladium species 12, an α-ketoamide is produced. Alternatively, coordination of CO to form 13 followed by reaction with amine gives the simple amide. Hence the selectivity for α-ketoamide formation is mostly determined by the reactivity of amine to 12. The faster the rate of reaction of amines with 12 is, the better the selectivity for αketoamide formation is. Primary amines are usually not suitable for this reaction; leading to the exclusive formation of amides under optimized conditions. The diaryliodonium salt also had an effect on the selectivity for α-ketoamide formation. The presence of electron-withdrawing substituents enhanced the eletrophilicity of CO-coordinated arylpalladium species and resulted in a decrease in the selectivity for α-ketoamide formation.

Scheme 9. Mechanistic pathway for the Pd-catalyzed amino dicarbonylation of diaryliodonium salts

Employing amino acid esters as N-nucleophiles in amino dicarbonylation was demonstrated by Kollár and co-workers35 using Pd(OAc)2/PPh3 as catalyst system in DMF under milder conditions. Thus, α-ketoacylated amino acid derivatives were produced with excellent selectivity (Scheme 10).


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Scheme 10. Kollár’s protocol for the Pd-catalyzed amino dicarbonylation of iodobenzene with amino acid esters In a significant improvement, Kollár and co-workers36, 37 reported the synthesis of novel ferrocene α-ketoamides via palladium-catalyzed amino dicarbonylation reaction. The selectivity ratio mainly depended on the catalyst and on the nature of amines used (Table 2).

Table 2. Amino dicarbonylation of iodoferrocene in the presence different secondary amines.

Entry Amines

Phosphines

Conversiona

Yieldsb

95

Ratioa (14 : 15) 79 : 21

1

Morpholine

PPh3

2

Morpholine

dppp

91

77 : 23

68

3

Morpholine

dppb

95

77 : 21

69

3

Morpholine

PBu3

95

41 : 59

--

4

Piperidine

PPh3

89

70 : 30

57

5

Et2NH

PPh3

97

69 : 31

63

6

nBu2NH

PPh3

97

73 : 27

67

7

cHex2NH

PPh3

91

06 : 94

--

a

70

Conversion and ratio was determined by GC. bIsolated yield of 14


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Kollár and co-workers38 further reported the preparation of α-ketoamides using structurally complex alkenyl iodides with t-butylamine in the presence of Pd(OAc)2/PPh3 catalyst system (Figure 3).

Figure 3. Complex alkenyl iodides as substrate in the Pd-catalyzed amino dicarbonylation. On a similar line, the same group39 further deomnstrated the amino dicarbonylation of 1iodocyclohexene in the presence of palladium-phosphite precatalysts. Systematic investigation has revealed that the chemoselectivity towards α-ketoamide formation was strongly influenced by the amine nucleophiles, temperature and CO pressure. However, the structure of the phosphite ligands had very little effect on catalytic activity or chemoselectivity (Scheme 11).

Scheme 11. Kollár’s protocol for the Pd-catalyzed amino dicarbonylation of iodocyclohexane. Castanet and co-workers40 tested the amino dicarbonylation of iodopyridines in the presence of different Pd-catalysts with and without external phosphine ligands. For simple 2iodopyridine, the best result was obtained with a combination of Pd(OAc)2 and PCy3 whereas for the 6-chloro-2-methoxy-3-(methoxymethyl)-4-iodopyridine, combination of Pd(dba)2 with PPh3 served best (Scheme 12).


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Scheme 12. Castanet’s protocol for the Pd-catalyzed amino dicarbonylation of iodopyridines Kollár and co-workers41 examined the amino-dicarbonylation reaction of a variety of primary and secondary amines, including amino acid derivatives with iodo-heteroarenes such as 2-iodopyridine, 3-iodopyridine and iodopyrazine under Pd(OAc)2/PPh3 catalyst system. Whereas a mixture of α-ketoamide and carboxamide was obtained in the case of 3-iodopyridine, an exclusive formation of N-alkyl/aryl-carboxamides were obtained by using 2-iodopyridine and iodopyrazine (Scheme 13).

Scheme 13. Kollár’s protocol for the Pd-catalyzed amino dicarbonylation of iodo-heteroarenes


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The exclusive amide formation in the case of 2-iodopyridine (and iodopyrazine) was probably due to (i) predominant stabilization of the Pd–arylglyoxyl derivative (aryl = 2-pyridyl or 2-pyrazyl) by complexation of the heteroaryl moieties and (ii) inhibition of reductive elimination from the acyl-aminocarbonyl–palladium species to respective α-ketoamide (Scheme 14).

Scheme 14. Potential intermediates in the aminocarbonylation of 2-iodopyridine

In a significant improvement over traditional amino dicarbonylation of aryl halides, Li and co-workers42 reported the first Pd-catalyzed direct inter-aminocarbonylation of indoles leading to corresponding amides and α-ketoamides that tolerated both secondary and primary amines by slight modification of reaction conditions (Scheme 15). As shown, the amino dicarbonylation of indoles with various N-protective groups preceded smoothly, providing moderate to good yields of indole-3-α-ketoamides. Further, indoles with electron-donating groups demonstrated better reactivity compared to those bearing halide moieties in general. The reactivity of different amines was examined using N-methyl indole, as expected, secondary amines gave better results. Further, primary amines such as allylamine and benzylamine performed well in the double carbonylation protocol, producing the desired products in moderate yields.


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Scheme 15. Pd-Catalyzed direct inter-amino dicarbonylation of indoles

2.1.1.2 Pd-catalyzed double carbonylation reaction: Sustainable development

Amino dicarbonylation using green reaction media: Palladium is an extraordinarily versatile catalyst for double carbonylation reactions, however the high cost of Pd-catalysts and poor recovery of traditional homogeneous Pd-catalysts indicted the use of easily separable solvents to ease the problems. The idea of greener solvents43 has emerged to limit the negative impact of volatile organic solvents on the environment, and the use of greener solvents such as water,44 supercritical fluids,45 and ionic liquids46 (ILs) have emerged as solvents of the future. These have added benefits easier separation of products and catalysts. Tanaka and co-workers47 reported the first examples of traditional palladium catalyzed single and double carbonylation of aryl halides with amines in ionic liquid such as 1-butyl-3methylimidazolium tetrafluoroborate ([bmim][BF4]) and hexafluorophosphate ([bmim][PF6])


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with excellent selectivity for α-ketoamides formation (Table 3). The method allowed the catalyst/ionic liquid mixture to be recycled after removal of the products by extraction with ether.

Table 3. Amino dicarbonylation of iodobenzene using ionic liquid as reaction medium.

Entry Solvent

Conversion (%)b

Yield (%)b 18

19

Selectivity to 15

1

Diethylamine 100

82

18

82

2

IL1

100

83

17

83

3

IL2

100

76

24

76

a

Reaction conditions: Ionic liquid (2 ml), Pd(OAc)2 (0.5 mol%), PPh3 (2 mol%), PhI (2.66 mmol), NEt2H (13.3 mmol), 80 °C, 3 h. bBased on iodobenzene and determined by GC using ndecane as internal standard. Sustainable amino dicarbonylation using ionic liquid as reaction media was further demonstrated by Ryu and co-workers.48 They reported a successful application of a microflow system to Pd-catalyzed amino dicarbonylation reactions in ionic liquids at low CO pressures with better selectivity and higher yields compared to the conventional batch system (Scheme 16). Additional studies indicated that at low pressure, the limiting factor for determining the selectivity ratio in a batch system was diffusion of CO into the ionic liquid.49

Scheme 16. Ryu’s protocol for the Pd-catalyzed amino dicarbonylation of iodobenzene in ionic liquid media.


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Further, Ryu and co-workers50 reported photo-induced amino dicarbonylation reactions with alkyl halides to produce amides and α-ketoamides using ionic liquids, such as [bmim][PF6] and [bmim][NTf2], with a catalytic amount of a Pd–carbene complex. However, poor yields and selectivity were observed for α-ketoamides formation. The Pd-catalyst and ionic liquid could also be reused using cyclohexane for extraction of the products (Scheme 17).

Scheme 17. Ryu’s protocol for the Pd-catalyzed amino dicarbonylation of cyclohexyl iodide in ionic liquid media under microflow system.

Amino dicarbonylation under atmospheric pressure of CO A significant problem associated with double carbonylations is the use of air-sensitive alkylphosphine ligands under high-pressure conditions to promote selective α-ketoamides formation. Uozumi and co-workers51 reported a practical protocol for double carbonylation of aryl halides with a palladium catalyzed reaction under atmospheric pressure of CO (1 atm) at ambient temperature (25 °C). The process used triphenylphosphine as a ligand in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in THF (Scheme 18). The use of a combination of PPh3, THF, and DABCO was crucial to allow an efficient catalyst system with much higher selectivity for the double carbonylation product (92%) as the use of other combination of ligands (2bis(diphenylphosphino)ethane, n-Bu3P), bases (Et3N, pyridine, DBU) and solvents (Et2O, DMF, DMSO) decreased the selectivity significantly.

Scheme 18. Uozumi’s protocol for the Pd-catalyzed amino dicarbonylation of iodobenzene under atmospheric pressure of CO


20

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In 2012 Skrydstrup and co-workers52 developed an innovative technology to perform amino dicarbonylation reaction using 9-methylfluorenecarbonyl chloride (COgen) as a solid source of CO in a specially designed sealed two-chamber glass reactor53 at ambient temperature (Scheme 19). This double carbonylation protocol has been exploited for the novel synthesis of 13

C and

2

H phenethylamine derivatives, such as β-amino alcohols, phenethylamines, 2-

oxazolidinones, etc specifically,

13

C-isotope labeling of norepinephrine, mescaline, and

clenbuterol has been studied.

Chamber 1

R1 Ar-I + HN

Chamber 2

Pd(dba) 2 (2 mol%) HBF 4P(t-Bu) 3 (4 mol%) DBU (2 equiv) THF

COgen (1.5 mmol) Pd(dba) 2 (5 mol%) P(t-Bu) 3 (10 mol%) Cy2NMe (2 equiv) DMF

R2

R1

O

N

Ar

R2

O

Scheme 19. Pd-catalyzed amino dicarbonylation of aryl iodide using 9-methylfluorenecarbonyl chloride (COgen) as a solid source of CO [Reprinted with permission from (J. Org. Chem.

2012, 77, 6155–6165). Copyright (2012) American Chemical Society.] Amino dicarbonylation under phosphine free conditions Sergio Castilló54 developed a phosphine-free Pd/DBU-catalyzed double aminocarbonylation of aryl iodides and amines as a practical and general method for the synthesis of α-ketoamides with excellent conversions and selectivities under atmospheric CO pressure (Scheme 20). The use of other bases such as DMAP, DABCO were found inferior.

Scheme 20. Castillo’s protocol for the Pd-catalyzed amino dicarbonylation of aryl iodide under phosphine free conditions


21

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High conversions (93–99%) were obtained for para-, ortho- and meta-iodo anisoles, however, stark differences in selectivity were seen. With p-iodo anisole, excellent selectivity for the double carbonylation product was obtained (98%), however, in the case of o-iodoanisole, selective monocarbonylation was observed (98%). The low selectivity obtained with the oiodoanisole could not be explained by the steric factor alone as o-tolyliodide led to the selective double carbonylation product. Further, the presence of electron withdrawing groups directed the reaction towards the amides. To examine the role of DBU, the preformed [PdCl2(DBU)2] complex 20 was subjected to optimized reaction conditions devoid of amine nucleophile. Two new products namely double carbonylated species containing a charged DBU unit 21, and the cis and trans isomers of the Pdacyl complex [Pd(DBU)2(CO-aryl)I] 22 were observed (Scheme 21).

Scheme 21. Species detected by NMR in the presence of all reagents used in catalysis except the amine nucleophile.

Mechanistically, following oxidative addition of aryl iodide to Pd(0) and, subsequently, coordination and migratory insertion of CO, a Pd-acyl species is formed which on further reaction with another molecule of CO forms a cationic species containing a terminal CO and an acyl moiety with the iodide as counter-ion (Scheme 22). Nucleophilic attack at the terminal CO from the amine forms a Pd-acyl-amide species. Alternatively, DBU (Nu = DBU) could attack to form a palladium intermediate that reacts with the amine to produce the Pd-acyl-amide species. Thus, this step is important achieve high selectivity for the double carbonylation product. Reductive elimination produces α-ketoamides and regenerates the initial Pd(0) catalyst. Thus the strong nucleophilic character of DBU allows for the selective attack at a terminal CO coordinated to Pd. The attack at the terminal CO rather than at the Pd-acyl moiety is presumably


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due to the steric hindrance contributed by the DBU bicycle. This would interfere with attack at the Pd-acyl.55 Therefore, the role of DBU in this process could be described as a ligand, a nucleophile (or acyl transfer agent) and a base.

Scheme 22. Proposed last steps of the catalytic cycle leading to product, α-ketoamide under phosphine free condition, in the presence of DBU. Recently Han and co-workers56 described a ligand and additive free Pd-catalyzed double carbonylation of aryl iodides with primary or secondary amines to produce α-ketoamides at atmospheric CO pressure at room temperature in PEG-400 (Scheme 23). Analysis of the reaction mixture indicated the palladium nanoparticles (3.0 ± 0.6 nm) formation57 was the real active catalyst as the addition of Hg (100 equiv to Pd) completely shutdown the reaction. A large scope of aryl iodides and amines could be utilized with excellent chemoselectivities. Importantly, the practical utility of current protocol has been demonstrated by the synthesis of bioactive molecules and chiral α-ketoamides. Under optimized conditions, a gram scale reaction was performed which provided the α-ketoamide in excellent yield. They further demonstrated the recycling uses of the catalytic system up to five times without significant reduction of catalytic activity.


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Scheme 23. Han’s protocol for the ligand and additive free Pd-catalyzed double carbonylation of aryl iodides

Amino dicarbonylation using heterogeneous Pd-catalysis: Although double carbonylation under one atmosphere of CO has been reported, the reaction only proceeded in the presence of a copper co-catalyst, nucleophilic amine bases, bulky trialkylphosphine ligands, and/or specific reaction media. Recently Sato and co-workers58 reported a two-step protocol for the amino dicarbonylation of aryl iodides with amines using palladium nanoparticles (PdNPs) under atmospheric pressure. The nanoparticles were presumably leached from a sulfur modified Au-supported palladium material (SAPd). Reaction ensued to produce α-ketoamides in good to excellent yields (Scheme 24).


24

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Scheme 24. Sato’s protocol for the amino dicarbonylation of aryl iodides in the presence of SAPd.

The double carbonylation reactions were compatible with aliphatic amines such as secondary cyclic and acyclic amines as well as acyclic primary amines. However with aniline, αketoamide formation was not observed. Variously substituted aryl/heteroaryl iodides were found suitable for this protocol with good yields and selectivities. A potent anti-HIV agent was prepared in a single step via double carbonylation of 2-iodonaphthalene with Nbenzoylpiperazine (Scheme 25). They further demonstrated the large-scale reaction using SAPd with excellent yields (85%).

Scheme 25. One step synthesis of anti-HIV molecule via double carbonylation in the presence of SAPd.

SAPd could be recycled at least five times without a significant loss of catalytic activity, and the desired carbonylation products were obtained in good yields and with good chemoselectivities throughout (Table 4). The amount of leached palladium in the reaction media was determined by inductively coupled plasma mass spectroscopy (ICP-MS) analysis, and the catalyst loading in each reaction was determined to be between 0.009 and 0.18 mol%. Table 4. Reusability of SAPd and catalyst loading.a


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Yields ± SDb,c Amount of leached Pd ± SDd (µg)

Cycle 1st

87 ± 3

56 ± 3

2nd

88 ± 3

50 ± 35

3rd

91 ± 1

28 ± 7

th

91 ± 2

30 ± 16

5th

90 ± 3

23 ± 16

Average of

89

38

4

5 cycles a

Conditions: 4-Iodoanisol (0.5 mmol), morpholine (1.5 mmol), K2CO3 (1.0 mmol), DMF (3 mL). Yield was determined by GC analysis using bibenzyl as an internal standard. cYields are average values of 3 reactions. dAmounts of leached Pd were measured by ICP-MS analysis and are average values of three experiments. b

Dufaudz and co-workers59 reported the synthesis of α-ketoamides with excellent conversion (up to 80%) and selectivities (up to 96%) during the reaction of aryl iodides with primary and secondary amines using 1 mol% covalently immobilized palladium complexes on SBA-15 silica [(Ph3P)2PdCl2@SBA-15, Figure 4] in the presence of K2CO3 as base in MEK or DMF. Finally, catalyst recycling of (Ph3P)2PdCl2@SBA-15 demonstrated that the catalyst could be recylced up to 3 times without impeding catalyst performance.

Figure 4. Immobilized palladium complexes on SBA-15 silica [(Ph3P)2PdCl2@SBA-15] Máté Papp and Rita Skoda-Földes60 reported the amino dicarbonylation of aryl iodides with secondary amines using phosphine-free silica supported Pd-catalyst with excellent selectivity. However, hindered amines interfered with double carbonylation and led to the formation of amides as the main products. Under optimal conditions, the catalyst could be recycled at least six times. The catalyst was prepared via simple impregnation of silica with a mixture of a palladium precursor and an ionic liquid (Scheme 26).


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Scheme 26. Dufaudz’s protocol for the preparation of silica supported Pd-catalyst (SILP-Pd-4) and their utilization for amino-dicarbonylation reaction Zhang and co-workers61 discovered a covalent triazine framework-supported palladium (Pd/CTFs) for the selective double carbonylation of aryl iodides under ambient pressure of CO. This ligand-free system resulted in high selectivity in the synthesis of α-ketoamides (Scheme 27). The enhanced catalytic activity and the high selectivity of Pd/CTFs at atmospheric pressure could be attributed to the synergetic effect of palladium nanoparticles (active catalytic center) and high porosity of CTFs (CO adsorption). Wide substrate scope, low catalyst loading and good recyclability of the catalyst were noticeable advantages.

Scheme 27. Zhang’s protocol for the amino-dicarbonylation of aryl iodides using covalent triazine framework-supported palladium (Pd/CTFs).

Amino dicarbonylation using microreactors The ability of microreactors to sense the rapid change of reactants and conditions was demonstrated by Buchwald and Jensen62 in their communication for the synthesis of α-


27

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ketoamides via amino dicarbonylation of bromobenzonitrile (Scheme 28). While carbonylation reactions of aryl bromides are more difficult than the corresponding aryl iodides, lower cost and larger selection of commercially available aryl bromides are attractive. Data indicates an expected decrease in selectivity for α-ketoamide formation with an increase in temperature (98 and 160 °C), along with enhanced selectivity for the formation of a α-ketoamide with increasing pressure (4.5, 7.9, and 14.8 bar), which corresponded to the amount of dissolved CO in the solvent (Figure 5).

Scheme 28. Buchwald’s protocol for aminocarbonylation of 4-bromobenzonitrile under microreactor

Figure 5. Product ratio of α-ketoamides to amides for the aminocarbonylation of 4bromobenzonitrile. On a similar line, Skoda-Földesa and co-workers63 reported the double carbonylation of iodobenzene with amines using microfluidics-based flow reactor (X-CubeTM) with immobilized Pd(PPh3)4 catalyst. Excellent selectivity of α-ketoamides formation (70–96%) was obtained by tuning the reaction conditions based on the choice of the nucleophile (amines). The highest yields were obtained at relatively low temperature (80 °C) employing DBU as the base with


28

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primary amines. Imine formation was observed at higher temperatures. Importantly, they observed the acylation of DBU 2364 mediated via the Pd(II)-acyl complex formed by the reaction of the Pd(0) precursor, iodobenzene and CO, producing the ring-opened 24 (Scheme 29).

Scheme 29. Formation of 24 via carbonylation of iodobenzene in the presence of DBU.

2.1.2 Pd-catalyzed aerobic oxidative cleavage of α-arylamino amides to form α-ketoamides: Laurent El Kaïm65 reported a novel palladium-catalyzed aerobic oxidative cleavage of αarylamino amides as a new route to α-ketoamides (Scheme 30).

Scheme 30. Kaïm’s protocol for the Pd-catalyzed aerobic oxidative cleavage of α- arylamnio amides to α-ketoamides

Under similar conditions, however the alkyl derivatives were non-reactive and failed to produce desired α-ketoamides. The need for an acidic proton in the substrate under these conditions was probably associated with the formation of the palladium enolate 25, which evolves into an iminium derivative 26, which produced α-ketoamides in the presence of water or peroxides present in the medium, accounts for the inability of alkyl derivatives to form α-ketoamides (Scheme 31).


29

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Scheme 31. Mechanistic pathway for the Pd-catalyzed aerobic oxidative cleavage of αarylamnio amides to α-ketoamides

2.1.3 Pd-catalyzed decarboxylative coupling of α-oxo carboxylic acids with cyanamides Patel and co-workers66 reported a novel decarboxylative protocol for the synthesis of Nmonosubstituted α-ketoamides from the reaction of α-oxo carboxylic acids with cyanamides under Pd(II)-catalysis via a unique 1,2-palladium migration from N to C involving chemoselective aroyl addition, generated from α-oxocarboxylic acids via decarboxylation, to cyanamides (Scheme 32). The protocol exhibited diverse tolerance to a varaitey of functional groups including reactive halides as well as nitrile under milder reaction conditions.

Scheme 32. Patel’s protocol for the Pd-catalyzed decarboxylative synthesis of α-ketoamides from α-oxo carboxylic acids

Mechanistically, the Pd(II) initially undergoes complexation with cyanamide to give intermediate 27. The acyl radical generated attaches to 27 to give a Pd(IV) species 28 in the presence of the oxidant (NH4)2S2O8. This is then followed by 1,2-palladium migration67 from N to C giving intermediates 29. The subsequent reductive elimination regenerates Pd(II) for another catalytic cycle with ketimine intermediate 30. The in-situ hydrolysis of this intermediate results in the formation of α-ketoamides. Thus, (NH4)2S2O8 plays the dual role as an oxidant and as a radical initiator in this reaction (Scheme 33).


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Scheme 33. Proposed mechanism for the formation of α-ketoamides via Pd-catalyzed decarboxylation of α-oxo carboxylic acids.

2.2 α-Ketoamides syntheses under copper catalysis Copper catalysis has been known as a powerful tool for its ubiquitous applications in organic synthesis. It is not only one of the least expensive and most abundant metals, but also has a range of oxidation states that can be exploited in catalytic cycles [Cu(0), Cu(I), Cu(II), and Cu(III)] allowing it to act through one-electron or two-electron processes. As a result, both radical pathways and powerful two-electron bond-forming pathways can occur. These features afford a remarkably broad range of applications allowing copper to catalyze the oxidation and oxidative coupling of many substrates. Copper-catalyzed aerobic oxidative coupling reactions allow for the direct C-H functionalization, and can be a powerful tool for constructing C-C bonds and C-X (X = N/O/S) bonds. Reactions can be conducted in air or under O2 atmosphere with oxygen playing the role of


31

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stoichiometric oxidant. In contrast to other oxidants, O2 is reduced to water or H2O2, both of which are relatively non-toxic.

2.2.1 Cu-Catalyzed oxidative amidation of aryl acetaldehydes or aryl methyl ketones: Jiao and co-workers68 reported the copper-catalyzed aerobic oxidative coupling of aryl acetaldehydes with anilines to give α-ketoamides involving C-H (sp2 & sp3) and N-H bonds cleavage (Scheme 34).

Scheme 34. Jiao’s protocol for the Cu-catalyzed oxidative amidation of aryl acetaldehydes

Under optimized conditions, both electron-rich and electron-deficient aryl acetaldehydes could be efficiently transformed into the desired products with excellent yields. Halogensubstituted aryl acetaldehydes and naphthyl-substituted acetaldehyde were tolerated well, leading to the desired products. Similarly anilines with both electron-donating and electron-withdrawing groups provided α-ketoamides with moderate to excellent yields. However anilines with electron-donating substitutents lower yields were obtained as compared to those than those bearing electron-withdrawing substitutents, probably due to the ability of electron-rich amines to form a radical cation, which could react to afford an azo compound.69 The alkyl aldehydes or alkyl amines could not be converted into the desired products under this protocol. Using the optimized conditions, they demonstrated the synthesis of an orexin receptor antagonist from the simple 2-phenylacetaldehyde in 40% yield (Scheme 35).

Scheme 35. Synthesis of orexin receptor antagonist via Cu-catalyzed oxidative amidation of


32

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ACS Catalysis

phenyl acetaldehyde

The most plausible mechanism for the copper-catalyzed aerobic oxidative coupling is shown below (Scheme 36). Aldehydes can react with anilines to form imines 31, which could be oxidized to superoxide radical 32 by a radical pathway under aerobic condition.70 In parallel, the Cu(I) is oxidized to more active Cu(II) which combines with 32 to form a Cu(III) complex 33.71 Further intramolecular addition to the imines and N-Cu bond homolysis could form the radical intermediates 34 which can be oxidized by Cu(II) or molecular oxygen, resulting the formation of intermediates 35.72 Subsequent fragmentation73 of 35 leads to the desired α-ketoamides. An 18

O2 labeling study indicated that both of the oxygen atoms incorporated into the α-ketoamides

stemmed from the molecular dioxygen.

Scheme 36. Proposed mechanism for the Cu-catalyzed oxidative amidation of aryl methyl ketones Ji and co-workers74 developed a copper-catalyzed direct oxidative synthesis of αketoamides from readily available aryl methyl ketones and amines employing molecular oxygen (O2) as the oxygen source under mild and neat conditions without any ligands or additives (Scheme 37).


33

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Scheme 37. Ji’s protocol for the Cu-catalyzed oxidative amidation of aryl methyl ketones under neat condition

In general, the reactions of aryl methyl ketones containing electron-withdrawing or electron-donating groups, long chain alkyl-substituted aryl methyl ketones, heteroaryl methyl ketones, and 2-acetylnaphthalene were transformed into the desired products in good yields. However, alkyl methyl ketones (e.g. benzylacetone, butanone etc.) were not effective substrates. On the other hand, both cyclic and acyclic secondary amines were found as suitable reactants. In contrast, anilines failed to produce desired products. Based on the detailed mechanistic investigations, a tentative reaction pathway has been proposed (Scheme 38). Firstly, Cu(II) and superoxide radical (O2˙−) are formed through the reaction of Cu(I) and O2 in the presence of amines.75 Subsequently, Cu(II) and superoxide radical reacted with enamines 36 generated in situ from aryl methyl ketones and amines to produce aminodioxetanes 37. The O–O bond cleavage of aminodioxetanes led to aryl glyoxals 38.76 Finally, the addition of amine to aryl glyoxals lead hemiaminal intermediates 39 that was readily oxidized by dioxygen to produce α-ketoamides in the presence of copper catalyst.77 18O labeling experiments revealed that both oxygen atoms of the α-ketoamides derived from molecular oxygen. Involvement of photosensitized singlet molecular oxygen was ruled out, as the excellent formation of α-ketoamides observed in the presence of singlet oxygen inhibitor, 1,4diazabicyclo[2,2,2]octane (DABCO). Further, the progress of reaction in the dark supports the non-involvement of photosensitized singlet molecular oxygen.


34

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Scheme 38. Proposed mechanism for the Cu-catalyzed oxidative amidation of aryl methyl ketones under neat condition In a significant improvement Liu and co-workers78 reported a room temperature coppercatalyzed aerobic oxidation for the synthesis of α-ketoamides from arylmethyl ketones in the presence of N-iodosuccinimide (NIS) as an additives with good yields and selectivity (Scheme 39).

Scheme 39. Liu’s protocol for the room temperature Cu-catalyzed oxidative amidation of aryl methyl ketones

Mechanistically, NIS mediated iodination of in-situ formed enamine generates intermediate 4079 which can undergo nucleophilic substitution to give α-amino substituted iminium 41, in which CuBr facilitates the C–I bond cleavage.80 Meanwhile, a superoxide radical (O2˙−) is generated from dioxygen during the oxidation of Cu(I) into Cu(II), which adds to the 41 immediately to afford radical intermediates 42. Intramolecular cyclization affords the key aminodioxetane 43. During this process, Cu(II) is reduced to Cu(I) by single electron transfer (SET) to accomplish the catalytic cycle.81 Ring-opening through O–O bond heterolysis leads to


35

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intermediates 44. C–N bond cleavage in 44 furnishes the final α-ketoamides. Alternatively, an amide by-product can be generated via C–C bond cleavage (Scheme 40).

Scheme 40. Proposed mechanism for the NIS mediated Cu-catalyzed oxidative amidation of aryl methyl ketones

On the same line, a copper-catalyzed aerobic oxidative coupling of aryl methyl ketones with N,N-dimethylformamide was reported by Zhou and Song82 to afford α-ketoamides by sequential dioxygen activation, C–H bond functionalization, and amide bond formation. In 2016, S. Dutta and co-workers83 reported the oxidative amidation of methyl ketones to αketoamides using hydrogen peroxide as the stoichiometric oxidant and iodine as an additive under mild reaction conditions in the presence of heterogeneous retrievable silica nanospheresupported copper catalytic system (SiO2@APTES@DAP–Cu). This catalyst was prepared via immobilization of diacetyl pyridine (DAP) onto amine-functionalized silica nanospheres (Figure 6).


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Figure 6. Silica nanospheres supported copper catalyst (SiO2@APTES@DAP-Cu) Sekar and co-workers84 reported first one-pot route for a copper-catalyzed synthesis of αketoamides from 1-arylethanols and amines involving tandem alcohol oxidation, sp3 C–H oxidation, and oxidative amidation under copper catalysis (Scheme 41).

Scheme 41. One-pot synthesis of α-ketoamides from 1-arylethanols

2.2.2 Cu-Catalyzed oxidative amidation-diketonization of terminal alkynes: The concept of using dioxygen (O2) as both the oxidant and reactant via dioxygen activation was smartly exploited by Jiao and co-workers85 for the synthesis of α-ketoamides via Cu-catalyzed oxidative amidation-diketonization of terminal alkynes (Scheme 42). Notably, both electron-rich and electron-deficient aryl alkynes, heteroaryl-substituted alkynes, and alkenyl-substituted alkynes could be converted into the desired products with good yields. In the case of aryl amines, anilines with electron-donating groups reacted more efficiently than anilines bearing electronwithdrawing groups.


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Scheme 42. Jiao’s protocol for the Cu-catalyzed oxidative amidation-diketonization of terminal alkynes

Investigation of the reaction under an

18

O2 atmosphere demonstrated the dioxygen

activation, showing that both oxygen atoms of the α-ketoamide originated from molecular dioxygen. Further, the reaction in the presence of H218O did not form the

18

O-labeled α-

ketoamides, providing more support for dioxygen activation. Mechanistically, alkyne insertion to an amine-Cu complex 45 generates Cu(II) intermediate 46. Next, Cu-assisted imine radical 47 is generated followed by the formation of superoxide radical 48. Intramolecular cycloaddition to the imine gives the corresponding aminyl radical 4986 that upon a second hydrogen abstraction by TEMPO or oxygen, forms the intermediate 50.72 This, on subsequent fragmentation87 produces the desired α-ketoamide (Scheme 43).

Scheme 43. Proposed mechanism for the Cu-catalyzed oxidative amidation-diketonization of alkynes


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On the similar line Shah and co-workers88 reported an improved protocol for synthesizing α-ketoamides using Cu(OTf)2-catalyzed oxidative amidation-diketonization of terminal alkynes with primary as well as secondary amines (Scheme 44).

Scheme 44. Shah’s protocol for the Cu(OTf)2-catalyzed oxidative amidation-diketonization of terminal alkynes

The reaction likely begins with the formation of adduct 51 by reacton of the Cu catalyst and amines, which can proceed through two different routes. In the case of primary amines, O2 insertion into intermediate 52 results in the formation of superoxide radical 53, which can undergo intramolecular cycloaddition to form aminyl radical 54.85 In the presence of TEMPO, intermediate 54 undergoes hydrogen abstraction and leads to the formation of intermediate 55, which, through O-O bond cleavage, results in formation of desired α-ketoamides. In the case of secondary amines, there is no possibility of radical formation, hence O2 insertion results in the formation of intermediate 58, which undergoes C-N and C-O bond cleavage to give 59.74 This facilitates the second attack of the amine, resulting in hemiaminal intermediates 60, which, in the presence of O2, oxidizes to give the α-ketoamides (Scheme 45).


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Scheme 45. Proposed mechanism for Cu-catalyzed oxidative amidation-diketonization of terminal alkynes with primary/secondary amines Hwang and co-workers89 developed a green process for the preparation of α-ketoamides via visible-light-induced Cu-catalyzed direct oxidative C-N coupling reactions using terminal alkynes and anilines at room temperature without the necessity of hazardous chemicals or reaction conditions with wide scope of substrates including electron deficient anilines (Scheme 46).

Scheme 46. Hwang’s protocol for the visible light induced Cu-catalyzed oxidative amidationdiketonization of terminal alkynes

Using this photochemical process; a one-step synthesis of epoxide hydrolase inhibitors 61 and 62 was achieved. Overall, this green process enabled the preparation of epoxide hydrolase


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inhibitor 62 on large scale with an E factor of 47.7, 95% atom economy, 81.7% atom efficiency, 100% carbon efficiency, and 76.6% reaction mass efficiency. This was much more efficient than previous reports90 (Scheme 47).

Scheme 47. Visible light induced Cu-catalyzed one-pot synthesis of epoxide hydrolase inhibitors. Mechanistically, the reaction is initiated with the formation of a weak Cu(I)–aniline complex 6391 followed by addition of phenylacetylene to form Cu(I)-phenylacetylide 64. In the next step, nucleophilic addition of aniline to complex 66 results in the formation of the complex 67 [Cu(III) species].92 Subsequent reductive elimination of Cu(III) leads to the formation of a Cu(I)-coordinated ynamine complex 6893 that readily reacts with O2 to form Cu(II) peroxocomplex 69.94 Isomerization of the resulting Cu(II) peroxo complex 69 to Cu(I) species 70 occurs with concurrent formation of a C-N bond.95 Finally, this complex can undergo transformation to regenerate CuCl and form intermediate 71 which on subsequent cleavage produced the desired α-ketoamide (Scheme 48).


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Scheme 48. Proposed mechanism for the visible light induced Cu-catalyzed oxidative amidation-diketonization of terminal alkynes

2.2.3 Cu-Catalyzed aerobic oxidative cross-dehydrogenative coupling (CDC) of amines with α-carbonyl aldehydes: Jiao and co-workers96 reported a novel copper-catalyzed aerobic oxidative crossdehydrogenative coupling (CDC) of amines with α-carbonyl aldehydes to form α-ketoamides (Scheme 49).


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Scheme 49. Jiao’s protocol for the Cu-catalyzed aerobic oxidative cross-dehydrogenative coupling (CDC) of amines with α-carbonyl aldehydes

The developed protocol exhibits good substrate scope in terms of amine precursors as well as α-carbonyl aldehydes. Both electron-rich and electron-deficient anilines reacted smoothly to produce the desired products. Interesting, N-substituted anilines such as N-methyl-, N-ethyl-, and N-phenylaniline also performed well. Furthermore, aliphatic secondary amines reacted to give the products in good to excellent yields. Notably, the scope of substituted amines could be expanded to aliphatic primary amines, which generally are not available through other aerobic oxidative approaches. Electron-donating and electron-withdrawing groups on the aryl α-carbonyl aldehydes both reacted efficiently and the transformation proceeded with high yields in both cases. Mechanistically, phenylglyoxal reacts with H2O to form phenylglyoxal monohydrate 72.

97

Facilitated by the carbonyl group of α-carbonyl aldehyde, the addition of amine to aryl

glyoxal gives hemiaminal intermediate 73.98 Concurrently, the Cu(I) salt chelates with the ligand and is oxidized by dioxygen to form the more active (µ-η2 : η2-peroxo)dicopper(II) complex 74. Subsequently, intermediate 73 is oxidized by copper complex to produce α-ketoamide (Scheme 50). Further study suggested that molecular oxygen acts not only as the oxidant, but also as an initiator to trigger the catalytic process. Furthermore, mechanistic studies demonstrated that the carbonyl of α-carbonyl aldehyde plays a role as the directing group to facilitate this chemical process.77


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Scheme 50. Proposed mechanism for Cu-catalyzed aerobic oxidative cross-dehydrogenative coupling (CDC) of amines with α-carbonyl aldehydes On the similar line Truong and Phan99 reported the oxidative cross-dehydrogenative coupling of amines and α-carbonyl aldehydes to form α-ketoamides using heterogeneous CuMOF-74 catalyst without added ligands or bases.

2.2.4 Cu-Catalyzed decarboxylative acylation of the acyl C–H of formamides In a novel approach Wang and co-workers100 developed the synthesis of α-ketoamides via Cucatalyzed decarboxylative acylation of formamides with α-oxocarboxylic acids. Examination of a model reaction involving 2-oxo-phenylacetic acid and DMF in the presence of Cu-salts led to the identification of CuBr2 as an effective catalyst in the presence of DTBP (di-tert-butylperoxide) and PivOH as an additive (Scheme 51).

Scheme 51. Wang’s protocol for the Cu-catalyzed decarboxylative acylation of formamides

Aside from DMF, other dialkylformamides, such as N,N-diethylformamide and N,Ndibutylformamide, were well tolerated. However, the product yields decreased chain length of


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the formamided increased owing to their steric hindrance. Further, cyclic formamides, such as 1formylpiperidine and 4-formylmorpholine, and N-monosubstituted formamides such as Nmethylformamide, N-ethylformamide, and N-tert-butylformamide were well tolerated, producing α-ketoamides in good yields. Although it is not clear, the transformation probably proceeds via a combination of C–H activation of formamide by a free radical101 and a transition metal-catalyzed decarboxylation of α-oxocarboxylic acid.102 Mechanistically, homolysis of DTBP produces a tertbutoxy radical, which abstracts a hydrogen atom from DMF to generate the radical intermediate 75. On the other hand, 2-oxo-2-arylacetic acid reacts with Cu(II) catalyst to form a salt of Cu(II)-carboxylate 76, followed by formation of the organometallic species 77 via extrusion of CO2. The intermediate 75 couples with organometallic species 77 to generate intermediate 78, which on reductive elimination forms the desired product. Finally, oxidation of Cu(I) by DTBP regenerates Cu(II) to complete this catalytic cycle (Scheme 52).

Scheme 52. Proposed mechanism for Cu-catalyzed decarboxylative acylation of the acyl C–H of formamides On a similar line Duan and co-workers103 reported the copper-catalyzed reaction of αoxocarboxylic acids with formamides toward the synthesis of α-ketoamides. To gain better insight into the mechanism, an intermolecular competition experiments gave a KIE value of 2.5 indicating the C–H bond cleavage of acyl C-H of formamide was the rate-determining step. A


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13

C-labeling experiment unambiguously demonstrated that the amide carbon in the α-ketoamides

arose from the α-oxocarboxylic acids, rather than the DMF. In a successful attempt Zhou and co-workers104 reported the one-pot synthesis of αketoamides directly from arylacetic acids and N,N-dialkylformamides under copper catalysis (Scheme 53). Mechanistically, arylacetic acid is oxidized to 2-oxo-2-phenylacetic acid, which subsequently reacts with N,N-dimethylamine radical, formed via decomposition of DMF under the reaction conditions, yielding the final product.103

Scheme 53. Zhou’s protocol for the Cu-catalyzed decarboxylative acylation of the acyl C–H of formamides with arylacetic acids

2.2.5 Copper catalyzed amino dicarbonylation reaction The traditional protocols for the double carbonylation reactions utilize palladium, a precious metal, and air-sensitive phosphine ligands as the catalyst. Thus, developing a novel catalytic system without the need for precious metals or phosphine ligands is of contemporary interest. In this context, Xia and co-workers105 in their groundbreaking discovery reported a [(NHC)-CuX]based (X = Cl, Br, I) catalytic system for the double carbonylation of aryl iodides with secondary amines facilitated by imidazolium salts (Scheme 54).


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Scheme 54. Xia’s protocol for the Cu-catalyzed amino dicarbonylation reaction

After extensive screening, the use of IPrCuI (1-2 mol%) and the NHC precursor IPr·HCl as ligand (2-4 mol%) in the presence of Cs2CO3 (2 equiv) in 1,4-dioxane was found to be optimal. The NHC precursor IMes·HCl also found effective with IPrCuI complex under identical conditions, however it was inferior to IPr·HCl. The influence of halogen anions on the (NHC)Cu-X (X = Cl, Br, I) complex showed that IPrCuCl and IPrCuBr were not optimal. Based on the literature report106 and quantitative transformation of iodobenzene to corresponding αketoamide in the presence of [Cu(IPr)2]BF4 and NaI under optimized amino dicarbonylation conditions, the bis-carbene copper complex was identified as an active catalytic species.

2.3 α-Ketoamides syntheses under other transition metal catalysis

2.3.1 Silver-catalyzed synthesis of α-ketoamides via selective carbon–nitrogen bond cleavage of tertiary amines In spite of the high efficiency of many catalytic methods, the source of nitrogen in the product is limited to primary and secondary amines. This narrows the substrate scope of amines that can be utlized in the process of α-ketoamide synthesis. The synthesis of α-ketoamides using tertiary amines as nitrogen sources has not been reported probably due to the stronger nature of C–N bond as compared to that of the C–H bond in tertiary amines. In a groundbreaking discovery, Wang and co-workers107 demonstrated a novel process for the direct preparation of α-ketoamides through an Ag-catalyzed amidation of α-keto acids with tertiary amines. Reaction proceeded via


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selective C–N bond cleavage (Scheme 55). Compared with other reported α-ketoamides methods, this approach shows that inactivated tertiary amines can be employed as available nitrogen sources, which make it more attractive for organic synthesis.

Scheme 55. Wang’s protocol for the Ag-catalyzed synthesis of α-ketoamides from tertiary amines via selective C-N bond cleavage

Success of this reaction came with the use of 20 mol% Ag2CO3 in the presence of oxone (2 equiv) at 120 °C in CCl4 -DMF (4:1). 2-Oxo-2-arylacetic acids with electron-rich, electrondeficient, and halogen groups on the benzene rings reacted smoothly with triethylamine (Et3N) to produce the corresponding α-ketoamides in good yield. The presence of sterically hindered groups at the ortho positions slightly lowered the yields compared with their corresponding parasubstituted ones. In addition, 2-(naphthalen-1-yl)-2-oxoacetic acid and 2-(furan-2-yl)-2oxoacetic acid underwent the reaction smoothly to generate the respective α-ketoamides in good yields. Tertiary amines such as tri-n-propylamine and tri-n-butylamine reacted well with 2-oxo2-phenylacetic acids to give the desired products in good yields, however the yields of αketoamides was decreased with increasing length of the carbon chain of tertiary amines. Aliphatic tertiary amines underwent selective C-N bond cleavage under these reaction conditions. Amines such as 1-benzylpiperidine and tetramethylethylendiamine performed well. Importantly, the α-H of the tertiary amine played a key role in C–N cleavage under these conditions. When N,N-diethylaniline reacted with 2-oxo-2-phenylacetic acid, the corresponding α-ketoamide was isolated in 41% yield. Thus demonstrating that C–N bond cleavage took place at the carbon containing α-H. Use of amines such as morpholine and piperidine resulted in very poor yield (18% and 12% respectively) indicating reduced reactivity of secondary amines in this reaction (Scheme 56).


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Scheme 56. Mechanistic investigation under optimized conditions

Mechanistically, a one electron oxidation of the nitrogen and subsequent deprotonation of the hydrogen adjacent to the nitrogen. initially produces the iminium ion 79. Hydrolysis of 79 produces the key intermediate 80 via elimination of aldehyde. Presumably, the oxygen of the aldehyde stemmed from water.108 Further reaction of 80 with α-keto acid affords the final αketoamide and regenerates the silver catalyst (Scheme 57).109

Scheme 57. Proposed mechanism for Ag-catalyzed synthesis of α-ketoamides via selective carbon–nitrogen bond cleavage


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2.3.2 Gold-catalyzed α-ketoamides synthesized via aerobic dehydrogenative coupling of amines and phenylglyoxal derivatives Gold catalysts have recently become attractive as useful tools in organic synthesis. This is in part due to its properties as a soft Lewis acid and excellent reactivity.110 Gold-catalyzed coupling reactions involving Au(I)/Au(III) catalytic cycles with external oxidants has been useful for new synthetic transformations.111 However, gold-catalyzed oxidative coupling using simple aerobic is remains a challenge.112 Recently, Liu and co-workers113 reported the gold-catalyzed (5 mol% AuBr3) coupling of secondary amine with phenylglyoxal derivatives as a practical synthetic strategy for the synthesis of α-ketoamides under mild conditions in dichloromethane (Scheme 58).

Scheme 58. Liu’s protocol for the Au-catalyzed aerobic dehydrogenative coupling of amines and phenylglyoxal derivatives

The aerobic gold-catalyzed coupling protocol exhibited good substrate scope in terms of phenylglyoxal derivatives as well as amines. Both electron-rich and electron-deficient phenylglyoxal derivatives reacted smoothly to form the desired products with good yields. A wide range of different functional groups (chloro, bromo, trifluoromethyl, and methoxy) at the aromatic moiety of phenylglyoxals was tolerated well. However, aliphatic glyoxal such as ethyl glyoxalate resulted in poor yield (26% GC).

Different secondary amines (piperidine,

morpholine, pyrrolidine and diethylamine) worked well in the reaction, and produced the corresponding products in moderate to good yields. The formation of iminium ion 81 and subsequent addition of water leads to the formation of a hemiaminal 82 followed by gold-catalyzed abstraction of the alpha-proton by dioxygen, presumable through a radical mechanism, to form the amide C-O bond. In the presence of O2, the resulting Au(I) species can be re-oxidized to the catalytically active Au(III) ion to complete the cycle (Scheme 59).114


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Scheme 59. Proposed mechanism for Au(III)-catalyzed synthesis of α-ketoamides

2.3.3 Iron-TEMPO-Catalyzed synthesis of α-ketoamides Among the various transition metal catalysts, iron derived catalyst systems is very attractive to the synthetic organic community because of its high abundance, low cost, and eco-friendly character. However, they are much less utilized as catalysts than other transition-metal salts.115 In a recent study, Kotha and co-workers116 developed an iron based catalyst system to synthesize αketoamides under aerobic conditions via a domino alcohol oxidation/oxidative crossdehydrogenative coupling strategy. Systematic examination of different combinations of iron salts, ligands, bases, and TEMPO

(2,2,6,6-tetramethyl-1-piperidinyloxy)

for

the

model

reaction

of

2-

hydroxyacetophenone and 4-aminobenzonitrile in different solvents under variable reaction conditions led to the identification of optimal reaction conditions (Scheme 60). Under the optimized conditions, both aliphatic and aromatic amines reacted to form the products in excellent yield. Aromatic amines with an electron-withdrawing group performed superior to those that contained an electron-donating group. Whereas, electron-withdrawing and electronwithdrawing substituents on the aromatic ring of the α-hydroxy ketones worked equally well.

Scheme 60. Kotha’s protocol for the Fe-TEMPO-catalyzed synthesis of α-ketoamides


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Mechanistically the reaction proceeds via Fe-TEMPO-catalyzed oxidation of α-hydroxy ketones to the corresponding α-ketoaldehyde intermediates 83117, 118 followed by nucleophilic addition of the amine to form hemiaminol 84. Finally, the hydroxy group is oxidized to afford a carbonyl group and yield α-ketoamide (Scheme 61). Isolation and characterization the αketoaldehyde 83 and hemiamino acetal intermediate 84 under the reaction conditions supports the proposed domino alcohol oxidation/oxidative CDC reaction sequence pathway. In this reaction sequence, the Fe-TEMPO complex may act as a catalytic oxidizing agent for the hydroxy group of the keto alcohol/hemiaminol intermediate. Molecular oxygen performs as the stoichiometric terminal oxidant.

Scheme 61. Proposed mechanism for domino alcohol oxidation/oxidative CDC reaction sequence for the synthesis of α-keto amides

2.4 α-Ketoamides syntheses under iodine (I2) based catalyst system 2.4.1 Oxidative amidation of methyl ketones Avoiding usage of toxic metals and eliminating heavy metal impurities, especially in pharmaceuticals, is an ever-growing demand and needed in developing environmentally benign, green synthetic methodologies. In this context, Wang and co-workers119 developed a very efficient protocol for the oxidative amidation of acetophenone derivatives with secondary amines in the presence of I2 (30 mol %) and tert-Butyl hydroperoxide (TBHP, 3.0 equiv) under solvent free conditions at room temperature, converting various aryl/heteoaryl methyl ketones to corresponding α-ketoamides in good to excellent yields (Scheme 62).


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Scheme 62. Wang’s protocol for the iodine catalyzed oxidative amidation of aryl methyl ketones

Mechanistically, it involves the formation of enamine derivatives 85 from aryl methyl ketones and amine in the first step. Iodonium ion generated in-situ by I2/TBHP system reacts with the enamines to form three membered iodonium intermediates 86, which on subsequent intramolecular ring opening and hydrolysis form the phenacyl iodide intermediate 88. Nucleophilic substitution of amine with phenacyl iodide produced 89, which upon free radical substitution with tert-butylperoxy radical, and oxidization by TBHP yielded the α-ketoamide (Scheme 63).

Scheme 63. Proposed mechanism for oxidative coupling using TBHP-I2 system.


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On similar lines, two other research groups120, 121 have published their findings on the use of N-iodosuccinimide (NIS) and molecular iodine as the iodine source respectively. Lamani and Prabhu120 reported a mild protocol for the oxidative amidation of aryl methyl ketones with secondary amines using NIS (30 mol%) as the iodine source and TBHP (3.0 equiv) as the oxidant in acetonitrile at room temperature. Use of NIS for the coupling led them to decrease the amount of amine used from 8 equiv reported in Wang’s protocol119 to 3 equiv. Their findings were similar to that of Wang’s,119 likely involving an intermediate phenacyl iodide and α-amino ketone. In a significant improvement, Wan and co-workers121 have published their findings on the use of I2 (50 mol%) – TBHP (6.0 equiv) for oxidative amidation of aromatic methyl ketones with both the secondary and primary amines to afford α-ketoamides in yields ranging from 40% to 96% (Scheme 64). It is noteworthy to mention that the protocol tolerates various sensitive functional groups such as ether, ester, boc-amines, easily oxidizable groups such as free hydroxyl, C_C multiple bonds. Various heteroaryl ketones such as thiophene, thiazole, pyridine, pyrazine, and benzofuran groups were transformed smoothly to yield corresponding products in good yields. Compared to the previous reports by Wang119 and Prabhu,120 Wan’s methodology was shown to be compatible with various primary amines and it can also be scaled up to 100 mmol scale without much erosion in the yields, illuminating the practical utility of the protocol.


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Scheme 64. Wan’s protocol for iodine catalyzed oxidative amidation of aryl methyl ketones containing sensitive functional groups Mechanistic investigations validated the previous hypothesis119,

120

and further

demonstrated the posibiliyt of new intermediates 92, 93 and 94. Iodination on α-aminoketones 91 provided α-amino iodoketone intermediates 92. Ionization of 92 generates iminium ion intermediate 93. Hydrolysis of the intermediate 93 produces α-hydroxy aminoketone 94,122 which on subsequent oxidation of the latter by TBHP produces corresponding α-ketoamides in good yield (Scheme 65).


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Scheme 65. Proposed mechanism for the oxidative amidation of aryl methyl ketones in the presence of iodine

To test the involvement of intermediate 94, rather than direct oxidation by α-amino ketone by TBHP,

18

O labeling experiments were carried out in the presence of H218O. Products

with and without incorporation of 18O were obtained (Scheme 66). The presence of 18O labeling in product supports the nucleophilic addition of a water molecule on iminium ion intermediate 93 to form hydroxy intermediate.

Scheme 66. 18O labeling studies for testing nucleophilic addition under Wan’s protocol


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Further advancement in the synthesis of α-ketoamides from methyl ketones was obtained when Mai and co-workers123 reported the use of formamide derivatives as amine partners in oxidative coupling (Scheme 67). Use of TBAI (20 mol%) in the presence of TBHP (5 equiv) in water was found to be optimal for the successful transformation. Absence of reaction with amines in the present protocol indicates that formyl group is essential for the transformation.

Scheme 67. Mai’s protocol for the TBAI-catalyzed decarbonylative amidation of aryl methyl ketones

The mechanism for the decarbonylative coupling involves the in-situ generation of tertbutoxyl with the assistance of iodide anion oxidation. Homolytic C-H cleavage of methyl ketones and N,N-dialkylformamide in the presence of tert-butoxyl radical generates 95 and 96 respectively. 96 then undergoes decarbonylation to form aminyl radical, which reacts with 95 to form α-aminoketone 97.124 Hydroxy intermediate 100 was then formed upon hydrolysis of iminium ion intermediates 99 that then undergoes TBHP oxidation to form the desired product (Scheme 68).


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Scheme 68. Proposed mechanism for oxidative amidation of methyl ketones catalyzed by TBAI/TBHP system Wang and co-workers125 reported a rather similar approach for the decarbonylative oxidative amidation of methyl ketones with N-mono and disubstituted formamide derivatives (Scheme 69). Addition of benzoic acid in toluene at 80 oC led them to use I2/TBHP system, which otherwise was found inactive in Mai’s protocol.123


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Scheme 69. Wang’s protocol for the benzoic acid assisted iodine catalyzed decarbonylative oxidative amidation of aryl methyl ketones

Experimental results indicated the influence of electronic factors on the reaction, as electron-withdrawing substituent bearing aryl methyl ketones were more effective partners than electron donating substituents. Methyl formamides were found to be good amine coupling partners compared to the ethyl counterparts, as the deacetylation is rather unfavorable compared to decarbonylation. It is noteworthy to mention that the present protocol is also compatible with N-monoalkyl substituted formamides yielding secondary α-ketoamides in moderate yields (5560%). Mechanistically, the first step involves the acid catalyzed decarbonylation to deliver amines facilitated by benzoic acid. These amines then react with methyl ketones to provide enamine intermediates 101 (Scheme 70). Intermediate 101 then rearranges to iminium ion intermediate 102 by the assistance of iodonium ion generated via TBHP oxidation of I2. The iminium ion upon hydrolysis, nucleophilic substitution with amines and subsequent oxidation of α-aminoketones 97 follows the similar lines of mechanism proposed by same authors to produce α-ketoamides.119


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Scheme 70. Mechanistic hypothesis for benzoic acid assisted decarbonylative oxidative amidation More recently Wu and co-workers reported an extension of their strategy126 for the synthesis of ketoamides using formamidine hydrochloride as amine surrogate to yield primary αketoamides (Scheme 71).127 This method is particularly useful as it induces free amine group on ketoamides, which is a useful intermediate for the synthesis of various N-substituted ketoamides that are otherwise difficult to synthesize in I2 promoted synthesis.

Scheme 71. Wu’s protocol for the oxidative amidation of aryl methyl ketones using formamidine hydrochloride as amine surrogate

Mechanistically, it follows similar lines wherein methyl ketones form α-iodoketones 88 upon iodination, the latter then undergoes Kornblum oxidation to


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phenylglyoxals 103 in the presence of DMSO. Iodine activates the glyoxal intermediates 103 and reacts with formamidine hydrochloride to afford hydroxy intermediate 104128 that upon oxidation form imide intermediates 105 which on hydrolysis and acid catalyzed decarbonylation forms corresponding primary α-ketoamides (Scheme 72).126

Scheme 72. Plausible mechanism for oxidative amidation using formamidine as amine source.

Control reactions with ammonium acetate or ammonium hydroxide, as partners didn’t yield corresponding α-ketoamides indicating the absence of ammonia direct release by the hydrolysis of formamidine hydrochloride. They have also shown that N-formyl-2-hydorxy arylacetamide 106 yielded product in 18% yield whereas N-formyl-2-oxo arylacetamide 107 gave product in 85% yield under standard conditions indicating latter as a key intermediate for α-ketoamide synthesis (Scheme 73).


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Scheme 73. Control experiments to show involvement of intermediate 103

Although not a catalytic process, reports by Ahmed and co-workers and more recent work by Guo and co-workers for the oxidative amidation of 2-oxoaldehydes128 and methyl ketones promoted by stoichiometric amounts of I2-DMSO,129 or I2 in dioxane using O2 as sole oxidant are worth mentioning.130

2.4.2. Oxidative amidation of alkenes and alkynes: Inspired by the findings of Ahmed and co-workers128 on the usage of I2-DMSO system for oxidative amidation of aromatic methyl ketones, Bhahwal and co-workers reported131 a new methodology for the synthesis of secondary and tertiary α-ketoamides using readily available terminal alkynes as starting materials. By envisioning that the addition of Lewis acids will affect stabilization of the iminium ion intermediate, they reported the first non-metal mediated oxidative coupling of alkynes with both primary and secondary amines in good yields (Scheme 74).

Scheme 74. Ahmed’s protocol for iodine-catalyzed oxidative amidation of alkynes

Upon screening different Lewis acids, they found that metal Lewis acids, Yb(OTf)3, Sc(OTf)3, In(OTf)3, were inactive in yielding the product where as TMSOTf (2.5 equiv) was


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found effective in the successful transformation of terminal alkynes to ketoamides in good yields. Initially, enol triflates 108 formed by the addition of TMSOTf to terminal alkynes in the presence of I2. 108 upon oxidation with I2 forms iodoketones 88, releasing HI that gets recycled upon oxidation with DMSO. Iodo ketones then undergo kornblum oxidation affording glyoxal intermediates 103. I2 activated glyoxal 103 couples with amine partners yielding iminium ion 93. DMSO promoted oxidation of iminium ion yields corresponding ketoamides (Scheme 75).

Scheme 75. Proposed mechanism for the iodine catalyzed oxidative amidation of alkynes

Following up with oxidative amidation of terminal alkynes, the same group led by Shah advanced the strategy by employing readily available terminal olefins for the facile synthesis of α-ketoamides using stoichiometric amounts of iodine.132 They have developed three different oxidant systems, (i) I2-DMSO catalytic system at 80 oC; (ii) I2-TBHP system under solvent free conditions at room temperature; (iii) I2-SeO2 system for the synthesis of secondary α-ketoamides. By employing I2-DMSO, I2-TBHP systems terminal olefins were successfully coupled with secondary amines to yield tertiary α-ketoamides in good yields. I2-SeO2 system was found


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effective when aromatic primary amines were used as coupling partners yielding secondary αketoamides in moderate yields (Scheme 76).

Scheme 76. Shah’s protocols for the iodine catalyzed oxidative amidation of terminal alkenes

Hypervalent iodine compounds have attracted the scientific community because of their ready availability, environmentally benign nature and they act as good electrophiles in activating double bonds of alkenes.133, 134 Recently, Sekar and co-workers used 2-iodoxybenzoic acid (IBX) as an oxidizing agent with I2 in stoichiometric amounts (2.0 equiv each) for the transformation of styrene derivatives to tertiary α-ketoamides (Scheme 77),135 While secondary amines such as piperidine, morpholine, and pyrrolidine gave the desired products, primary amines and aromatic amines were found inactive.

Scheme 77. Sekar’s protocol for the oxidative amidation of terminal alkenes using I2/IBX system Mechanistic details were found to be on the similar lines of the previous reports.132 The first step is the formation of halohydrin 109 by the addition of IOH released in situ by I2/IBX to


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styrenes. Phenylglyoxals 103 formed by kornblum oxidation of phenacyl iodide 88 reacts with amines forms α-amino hydroxy intermediates 110, which then oxidizes to α-ketoamides in the latter step (Scheme 78).

Scheme 78. Mechanism proposed for the oxidative amidation of terminal alkenes by I2/IBX system. 2.4.3. Oxidative amidation by sp3 C-H activation: In recent years, vinylic and aliphatic C-H activation has become an attractive strategy for various organic transformations.136 In this context, Sun and co-workers137 reported an oxidative amidic coupling of ethylarenes with formamide as amine partners. TBAI (20 mol%) in the presence of TBHP (12 equiv) was effective in transforming rather inert sp3 C-H bonds of ethylarenes to corresponding ketoamides in moderate yields irrespective of the position of the substitutions on phenyl ring (Scheme 79). Excessive use of oxidant can be accounted for through the involvement of TBHP in both oxidizing ethylarene to respective methyl ketones, decarbonylation of formamide and also in the sequential cross dehydrogenative amidation to yield products.

Scheme 79. Sun’s protocol for the TBAI-catalyzed decarbonylative oxidative amidation of ethyl arenes.


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Dimethylformamide as well as various N-formyl cyclic amines were suitable coupling partners for the synthesis of tertiary α-ketoamides, while when N,N-diisopropylformamide is used as coupling partner, it unexpectedly yielded secondary ketoamides, presumably by the cleavage of C-N bond. Following this work, Feng and co-workers138 recently reported a similar approach for the oxidative cross coupling of methylarenes with formamide derivatives as coupling amines using TBAI (10 mol%)/di-tert-butyl peroxide (8.0 equiv)/Cs2CO3 (2 equiv) combinations (Scheme 80). They have shown a considerable effect of base on the reaction, as addition of Cs2CO3 led to increased yields. Various substituted phenyl derivatives were successfully converted to tertiary ketoamides in good yields. While ortho substitution generally reacted with moderate yields, bulky t-Butyl group at ortho position shut the reaction completely. Methyl heterocycles were also found to be suitable for the reaction, but methyl cyclohexane derivatives were found to be inactive for the reaction conditions.

Scheme 80. Feng’s protocol for the oxidative amidation of methyl arenes.


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3. CONCLUSIONS AND SUMMARY

We have been experiencing a “fabulous growth” of catalytic protocols that give us convenient and potent methods for synthesizing α-ketoamide-based target molecules of high synthetic and medicinal significance in a step-economical mode. Among different metal-based catalyst systems, Pd-catalysis is the most explored for double aminocarbonylation processes with good to excellent control of selectivity. Sustainable development of double aminocarbonylation has been demonstrated which includes the use of green reaction media, ligand-free approaches, use of recyclable heterogeneous Pd-catalyst system etc. Pd-catalyzed direct inter-aminocarbonylation of indoles, decarboxylative coupling of α-oxo carboxylic acids with cyanamides, and aerobic oxidative cleavage of α-arylamino amides to form α-ketoamides are notable progress under Pdcatalysis. Copper catalysis is mainly explored for oxidative amidation process, which includes but is not limited to the α-ketoacids, α-ketoaldehydes, and arylmethyl ketones. Cu-Catalyzed oxidative amidation-diketonization of terminal alkynes to form α-ketoamides using molecular oxygen (O2) as both the oxidant and reactant via dioxygen activation is remarkable discovery. Further, use of Cu-catalyst for amino dicarbonylation of organic halides is a significant development as it avoids the use of costly Pd-catalysts for identical process. Apart from Pd and Cu, other metals such as Au, Ag, and Fe based catalysts are also investigated and explored to some extent. Non-metal catalyzed α-ketoamide syntheses are mainly restricted to iodine-based catalysts in the presence or absence of other promoters with substrate scope and synthetic utility similar to Cu-catalyzed process. Considering the sustainable nature of catalytic procedures along with the cost-effective earth’s abundant metal catalysis, further exciting developments are expected in this research area. Future development of metal-free protocols is expected in context of environmental friendly development under mild conditions using easily available starting materials and green reaction media.


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5. AUTHOR INFORMATION Corresponding Author Gregory R. Cook, Department of Chemistry and Biochemistry, PO Box 6050, North Dakota State University, Fargo, North Dakota 58108-6050, USA. [email protected] 6. NOTES The authors declare no competing financial interest. 7. ACKNOWLEDGMENT We acknowledge the generous financial support of this work from North Dakota State University. Authors sincerely acknowledge the reviewers for their critical evaluation and suggestions. The authors dedicate this review to Prof. Asit K. Chakraborti on the occasion of his 63rd birthday.

8. ABBREVIATIONS anti-HIV, anti-human immunodeficiency virus; anti-IBD, anti-inflammatory bowel disease; ILs, ionic liquids; PdNPs, palladium nanoparticles; SAPd, sulfur modified Au-supported palladium; DABCO,

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