cross-coupling of amides by n–c bond activation...scheme 2 cross-coupling of amides by n–c bond...

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G. Meng et al. AccountSyn lett

SYNLETT0 9 3 6 - 5 2 1 4 1 4 3 7 - 2 0 9 6© Georg Thieme Verlag Stuttgart · New York2016, 27, 2530–2540account

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Cross-Coupling of Amides by N–C Bond ActivationGuangrong Meng‡ Shicheng Shi‡ Michal Szostak*

Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, [email protected]

‡ These authors contributed equally.

[M]O

R

N

Lm

R''

R'

n+2

twist±electronic activation

amide

destabilization

N−C activation

GENERAL AMIDE BOND ACTIVATION MANIFOLD

R'

NR'

O

R

cross-coupling

R

O

R

acyl aryl

R R

[M]n R X

• RCONR2 = RCOδ+/Rδ+

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Received: 10.08.2016Accepted after revision: 09.09.2016Published online: 04.10.2016DOI: 10.1055/s-0036-1588080; Art ID: st-2016-a0521-a

Abstract In recent years, significant conceptual advances have takenplace in the field of amide bond cross-coupling. Mild and selective func-tionalization of amides by transition-metal catalysis has an enormouspotential for widespread applications in both industry and academiadue to the unparalleled prevalence of amide-containing molecules.However, direct metal insertion into the N–C(O) amide bond is ex-tremely difficult as a consequence of amidic resonance. In this account,we summarize our work on the development of new cross-coupling re-actions of amides by N–C bond activation, and briefly discuss othermodern developments in this area.1 Introduction2 Amide Bond Ground-State Distortion3 Acyl Amide N–C Cross-Coupling3.1 Suzuki Cross-Coupling3.2 Negishi Cross-Coupling3.3 Esterification and Amidation via N–C Cross-Coupling4 Decarbonylative Amide N–C Cross-Coupling4.1 Heck Cross-Coupling4.2 Suzuki Cross-Coupling4.3 C–H Activation4.4 Decarbonylative Borylation5 Transition-Metal-Free Activation of Amide Bonds6 Mechanistic Studies7 Conclusions and Outlook

Key words amides, cross-coupling, N–C bond activation, Suzuki cou-pling, decarbonylative coupling, C–H activation, palladium, nickel

1 Introduction

The amide bond is one the most important functionalmotifs in chemistry and biology.1,2 Amide bonds are uniquefrom all other functional groups in that they form the es-sential links in peptides and proteins. Amides feature asprevalent pharmacophores in small-molecule pharmaceu-ticals.3 It is estimated that the amide functional group is

present in 55% of potential drugs, while approximately 25%of all registered pharmaceuticals contain amides.4,5 A recentsurvey estimates that reactions involving amide bonds areamong the most commonly performed processes by indus-trial organic chemists.6 Amides are present as key motifs insynthetic polymers, agrochemicals and functional materi-als.7,8 Moreover, amides serve as versatile, cheap and bench-stable intermediates in organic synthesis that are often de-rived from a different pool of precursors than carboxylic ac-ids and halides.9,10 However, despite the central role of am-ides as extremely common pharmacophores in medicinalchemistry, and equally importantly as bench-stable inter-mediates in organic synthesis and basic monomer units inpeptides and proteins, transition-metal-catalyzed transfor-mations of amides by N–C bond activation remain vastlyunderutilized (Schemes 1–3).11,12

Scheme 1 (A) Amide bond resonance. (B) Activation of N–C amide bonds toward transition-metal catalysis

The major challenge in transition-metal-catalyzedtransformations of amides by N–C cleavage is the high acti-vation energy required for the N–C(O) bond scission due to

NR

O

R'

R''

NR

O

R'

R''

NR

O

R'

R''I II III

A. Amide bond resonance: 15–20 kcal/mol (Pauling, 1935)

• planar amides are unreactive towards C−N metal insertion

N

ON O

twist

±electronic activation

[M] ON

Lm

[M]n

insertion

n+2

amide destabilization N–C activation

B. Amide bond activation by destabilization (steric or electronic)

© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 2530–2540

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nN to π*C=O conjugation.13 Classic studies by Pauling demon-strated that planar amide bonds contain approximately 40%double-bond character as a consequence of resonance,which led to the breakthrough prediction of the α-helix.14

Amide delocalization is critical for the structure of proteins,but it also makes direct metal insertion into the N–C amidebond extremely difficult (Scheme 1).11,12

Over the past four decades, transition-metal-catalyzedreactions have had a tremendous impact on the progress insynthetic organic chemistry, with the indisputable signifi-cance of these methods recognized by the 2010 Nobel Prizein Chemistry.15 The transition-metal-catalyzed activation ofamide N–C bonds holds an enormous potential for wide-spread practical applications in organic synthesis due to:(1) the inherent benefits of amides as acyl or aryl electro-philic precursors in general metal-catalyzed reaction mani-folds;11,12 (2) myriad potential metal-catalyzed transforma-tions that could be discovered after the fundamental stepsfor N–C activation have been demonstrated and the ratio-

nale for the development of new reactions has been out-lined;15 (3) the potential to employ the amide bond activa-tion platform for late-stage drug modification and in molec-ular biology for site-selective peptide cleavage, which is notfeasible with other acyl electrophiles.2–6

Recently, significant conceptual advances have takenplace in the field of amide bond cross-coupling (Scheme2).16,17 In this account, we summarize our work on the de-velopment of new cross-coupling reactions of amides viaN–C bond activation, and briefly discuss other modern de-velopments in the area. We focus both on the mechanisticaspects of the amide bond distortion and the reactions me-diated by different reaction manifolds by the N–C bondcleavage (i.e., acyl-type vs decarbonylative cross-couplings).We provide the reader with an overview of the area and itsemerging, but crucial role to other methods of transition-metal-catalyzed cross-coupling to forge carbon–carbonbonds (Scheme 3).18 Moreover, we review the recent out-standing developments in the formation of carbon–oxygen,

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Biographical Sketches

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Un
Guangrong Meng was born in
Shandong Province, P. R. of Chi-na, and received his B.Sc. de-gree from Dalian MedicalUniversity in 2011. He received

his M.Sc. from Fudan Universityin 2014. Currently, he is a Ph.D.student in the research group ofProfessor Michal Szostak at Rut-gers University in Newark. His

research interests are focusedon transition-metal-catalyzedreactions.

Shicheng Shi was born in Xu-ancheng, P. R. of China. In 2010,he received his B.Sc. degreefrom Nanjing Agriculture Uni-versity. In 2013, he received hisM.Sc. degree from the Shanghai

Institute of Organic Chemistry.After a short experience in in-dustry, he joined the group ofProfessor Michal Szostak at Rut-gers University, Newark in2014, and is currently working

toward his Ph.D. His research fo-cuses on developing new reac-tions based on transition-metalcatalysis.

Michal Szostak received hisPh.D. from the University ofKansas with Professor JeffreyAubé in 2009. After postdoctor-al stints at Princeton Universitywith Professor David MacMillan

and at the University of Man-chester with Professor DavidProcter, in 2014, he joined thefaculty at Rutgers University.His research group is focused onthe development of new syn-

thetic methodology based ontransition-metal catalysis, tran-sition-metal-mediated free-rad-ical chemistry, and applicationto the synthesis of biologicallyactive molecules.


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carbon–nitrogen and carbon–boron bonds by the amide N–C bond activation reported by Garg and Shi. The amidebond activation area is experiencing rapid growth; thesetransformations collectively demonstrate more than 10previously undocumented reaction types of the amidebond published since the first reports in 2015.

Scheme 2 Cross-coupling of amides by N–C bond cleavage

2 Amide Bond Ground-State Distortion

In 2015, our laboratory introduced a new generic modeof activation of amide bonds by geometric distortion,whereby metal insertion into an inert amide bond (amidebond resonance of 15–20 kcal/mol in planar amides, ca. 40%double bond character) can proceed only if the classic Paul-ing amide bond resonance has been disrupted (Scheme1B).19,20

In consideration of the amide bond planarity13 and ourown expertise in the area,21 we recognized that low-valentmetal insertion into the effectively ‘double bonds’ in planaramides to afford versatile acyl-metal intermediates rep-resents an unlikely scenario.22 Furthermore, we recognizedthat for the amide bond activation mode to be generallyuseful, the method must be mild, selective, and employbench-stable, readily accessible reagents. In addition, itwould be highly desirable if the rate of metal insertioncould be controlled by both the substrate and catalyst sys-tem, which could potentially lead to a powerful cross-cou-pling selectivity by the judicious choice of reaction parame-ters and coupling partners.23

Scheme 4 Selected examples of bridged lactams

The work of Kirby, Stoltz, Aubé and others on twistedamides was significant in realizing the concept (Scheme4).24 These researchers showed that amide distortion inconformationally restricted cyclic lactams can be applied asa controlling feature to alter amidic resonance. Accordingly,we hypothesized that in amides in which amidic resonanceis disfavored by steric or electronic reasons,25 metal inser-tion into the N–CO bond should be feasible. On the basis ofliterature precedents26 and our own studies on the N-/O-protonation aptitude of bridgehead bicyclic lactams,27 weconsidered that in amides in which the additive Winkler–Dunitz distortion parameter (Στ + χN)27,28 is close to 50°,metal insertion should be thermodynamically favorable un-der mild, synthetically useful reaction conditions. A strongcaveat of this model is that it seemingly contradicts theclassic Pauling’s amide bond resonance, which assumes co-planarity of typical acyclic amides.

However, the emergence of bridged twisted lactams andthe increased understanding of the structure–reactivity re-lationship of non-planar amide bonds realized in the lastdecade21,24 brought the possibility of effecting syntheticallyuseful distortion in simple acyclic amides. Indeed, literaturereports describe various examples of specific electronicallyand sterically distorted amides.21 However, most crucial tothe success of the amide bond N–C cross-coupling is the mas-sively underestimated fact that steric and electronic activa-tion of the amide bond in simple generally accessible acyclicamides is relatively straightforward to achieve. All examplesof amides reported to date undergoing the N–C bond cross-coupling feature markedly destabilized amide bonds. Itshould be noted that all these amides are bench-stable andreadily available from carboxylic acid precursors by stan-dard methods.9 The ability to promote previously elusive

Cross-coupling of amides via N−C bond activation (all since 2015)

R N

O

R1

R2

MLn

R R

O

R δ+

RC(O) δ+• acyl cross-coupling

R Y+

SuzukiNegishiEsterificationAmidation

M = Pd, NiY = B(OR')2, ZnX, HR = Ar, alkyl, OR', NHR'

R B(OH)2

R ZnX

RO H

RNH H

R N

O

R1

R2

MLn

• aryl cross-coupling

R Y+

HeckSuzukiC−H ActivationBorylation

M = Pd, Ni, RhY = H, B(OR')2R = vinyl, Ar, B(OR')2

– COR R

R B(OH)2

R H

RH

B2(OR')4

in total >10 distinct previously unknown reactions of amidesvia catalytic transformations

via

via

Scheme 3 Advantages of amides as cross-coupling partners

Amides as potential substrates in catalytic cross-coupling

until 2015: completely unexplored in transition metal catalysis• challenge: low reactivity due to nN → π*CO conjugation

• abundant feedstock

• biomolecules

• bench-stable intermediates

• pharmaceuticals

N

O

R

RN N

O

R

R

N

N

O

NMe2

Me

Me AA1AA2

AA3AA4

AA5

N

O O

N

RR

R

R

R

Zolpidem

Bridged lactams as models for disrupting amidic resonance

StoltzKirby Aubé

NH

OBF4

N O

N

ON

O

amino-ketoneamide reactivity


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transformations of amides via generic transition-metal-cat-alyzed activation modes represents a new powerful amidebond disconnection in organic synthesis with great rele-vance to biology, medicinal chemistry, polymers and mate-rials science.

3 Acyl Amide N–C Cross-Coupling

The generic cycle for the cross-coupling of amides byacyl-metal intermediates is shown in Scheme 5. The keystep involves a controlled metal insertion into the N–C am-ide bond. In this mechanism, bench-stable, readily accessi-ble amides serve as acyl precursor equivalents to other acylelectrophiles, such as aroyl halides, anhydrides, thioesters,and esters.29 The advantages of using amides as cross-cou-pling electrophilic partners include: (i) low price; (ii) stabil-ity; (iii) low toxicity; (iv) orthogonal cross-coupling condi-tions; (v) the potential to functionalize biologically activeamide-containing molecules.

Scheme 5 Cross-coupling of amides via acyl-metal intermediates

3. 1 Suzuki Cross-Coupling

We reported the first Suzuki cross-coupling of twistedamides with boronic acids using N-glutarimide amides assubstrates (Scheme 6).19,20 These reactions proceededsmoothly in the presence of Pd(OAc)2, PCy3HBF4 as a practi-cal bench-stable trialkyl phosphonium salt, H3BO3 andK2CO3 in THF at 65 °C. Cross-coupling with a broad range ofelectrophilic substituents at both the amide and the boron-ic acid component occurred with high selectivity. The oxi-dative addition into the amide N–C bond over the aryl chlo-ride was preferred under these conditions. Moreover, thecross-coupling of heterocycles and 1° and 2° alkyl amideswas possible, affording ketone products in good to excellentyields.

Interestingly, we found that the use of acid was criticalto obtain high reactivity. We propose that the switchable N-/O-amide bond coordination30 might be responsible for thiseffect. In support of this mechanism, a good correlation be-

tween the reaction efficiency and the pKa of acidic additivesused in the cross-coupling at room temperature was ob-served. 2-Nitrobenzoic acid (pKa = 2.16) afforded the bestresults. To our knowledge, this reaction represents the firstexample of the Suzuki cross-coupling of amides by N–C ac-tivation at room temperature, thus setting the stage for fur-ther developments of this synthetically valuable process.

Scheme 6 Pd-catalyzed Suzuki cross-coupling of amides by N–C cleav-age reported by our group

In the reaction development we screened the couplingof approximately >20 derivatives, including various sterical-ly and electronically activated amides. We consistentlyfound that the best results were obtained with N-glutarim-ide amides, while the related N-succinimide amides werefound to be less reactive. A distinct advantage of these am-ide precursors relies on the exquisite steric distortion,which in combination with the electronic activation en-ables the high reactivity that cannot be easily achieved withother non-planar amides.

Independently, the Suzuki cross-coupling by amide N–Ccleavage was reported by Zou31 (Scheme 7) and Garg32

(Scheme 8). The conditions reported by Zou employ N-Ts/Aramides in the presence of Pd(PCy3)2Cl2, K2CO3 and boronicacids in dioxane at 110 °C, while Garg reported the use ofN-Boc/alkyl amides, Ni(cod)2, SIPr [1,3-bis(2,6-di-i-propyl-phenyl)-4,5-dihydroimidazol-2-ylidine], K3PO4 and boro-nate esters in aqueous PhMe at 50 °C. In general, broad

MnLmNR

O

R1

R2

Y R

R M

ON R2

R1

L L

R M

OR

L

RM

R

L L

– YXX = halide, NR1R2

L±L

RR

O

n+2

n+2n+2

Mechanism: amide acyl N−C cross-coupling

selective N−CO activation

transmetalation

reductive elimination

Me

Me

75%

R

O

N

O

O

Ar

O

R

Pd(OAc)2 (3 mol%)PCy3HBF4 (12 mol%)

K2CO3, H3BO3THF, 65 °C, 15 h

+

X = H, 95%X = OMe, 98%X = CF3, 93%

Ph

O

XX = F, 95%X = Cl, 78%

Ph

O

X

Ph

OX

X = F, 65%X = Me, 84%

Ph

O

Ph

X = OMe, 81%X = CF3, 61%

O

Ph

O

98%

Ph

69%

O

Ph

O

Me(O)C

ClPh

O

NH

72%81%

O

F3C

Ph

O CHO

OMeMeO

91%80%

Ar B(OH)2

X

Me

>60 examples


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scope and good functional group tolerance was demon-strated. The Garg group showcased the utility of the amidebond N–C disconnection in sequential alternating C–C/C–Ocross-couplings in high yields. It should be noted that all

three types of amides are prepared from the same syntheticprecursors, while the reactions should be considered ascomplementary in terms of substrate scope, reaction condi-tions, catalyst system and operational simplicity.33

3.2 Negishi Cross-Coupling

Expanding the theme of ketone synthesis from amides,we developed the first Negishi diaryl ketone synthesis byN–C cleavage with good functional group tolerance(Scheme 9).34 Notably, using bench-stable Ni(PPh3)2Cl2 asthe catalyst, the cross-coupling was accomplished within15 minutes at room temperature. To our knowledge, this re-action represents the mildest conditions for the N–C amidebond cross-coupling reported thus far. The high functionalgroup tolerance, low cost, and operational simplicity are at-tractive features of this protocol. The bench stability of am-ides and ready access to functionalized arylzinc reagents,also on an industrial scale, should make this method easilyaccessible to the synthetic community. It is worth notingthat acyl-aryl Negishi-type and Fukuyama-type cross-cou-plings are less precedented due to different reactivity in ox-idative addition/transmetalation steps.

Scheme 9 Ni-catalyzed acyl-aryl Negishi cross-coupling of amides by N–C cleavage reported by our group

The Garg group reported an acyl-alkyl Negishi cross-coupling of aromatic amides using N-Ts/alkyl amides,Ni(cod)2 and SIPr at room temperature (Scheme 10).35 Thecoupling of benzyl, 1° and 2° alkyl organozinc reagents pro-ceeded in high yields. This reaction represents the first useof alkyl nucleophiles in the transition-metal-catalyzed N–Camide cross-coupling. As in the Suzuki cross-coupling ofamides, the two simultaneous reports on the acyl-aryl andacyl-alkyl Negishi cross-couplings convincingly demon-strate the potential of this reactivity platform in catalysis.36

Scheme 7 Zou’s Pd-catalyzed Suzuki cross-coupling of amides by N–C cleavage

78%

R

O

N

Ts

PhAr

O

R

Pd(PCy3)2Cl2 (5 mol%)PCy3 (3 mol%)

K2CO3, dioxane110 °C, 6–12 h

+

X = H, 93%X = OMe, 79%X = CF3, 95%

Ph

O

XX = CN, 98%X = NO2, 59%X = F, 98%

Ph

O

X

Ph

O

83%

Ph

O

Ph

X = OMe, 93%X = CN, 74%X = Ac, 90%

O

Ph

O

X = NHBoc, 85%X = CO2Me, 97%

Ar B(OH)2

X X

Ph

32 examples

Scheme 8 Garg’s Ni-catalyzed Suzuki cross-coupling of amides by N–C cleavage

59%

R

O

N

Boc

BnAr

O

R

Ni(cod)2 (5 mol%)SIPr (5 mol%)

K3PO4, H2Otoluene, 50 °C, 24 h

+

X = H, 96%X = CO2Me, 77%X = morpholinyl, 81%

Ph

O

XX = OMe, 95%X = CF3, 81%X = F, 88%

Ph

O

X

Ph

OMe

51%

Ph

96%

O

Ph

O

80%

Ar Bpin

N

Me

N

O

Me2N OMe Me

N

O

HN

O

Bn

BocBn

O

O

O

O

Me

Me Me

3-furylBpinNi(cod)2 (10 mol%)

SIPr (10 mol%)

K3PO4, H2Otoluene, 50 °C

[92% yield]

• iterative N−C cross-coupling

O

HN

O

OBn

1. Boc2O2. (–)-menthol


toluene, 80 °C[57% yield]

29 examples

Ar

O

N

O

O

Ar

O

ArNiCl2(PPh3)2 (5 mol%)

THF–Et2O, 23 °C, 12 h+ Ar ZnCl

35 examples

92% 79% 57%

96%

88%

O O OMe

S

O

O

F3C

OMe

N

Me

52% 74%

67%

O O

O

F

Me

MeO NMe2

OMe

Cl


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Scheme 10 Garg’s Ni-catalyzed acyl-alkyl Negishi cross-coupling of amides by N–C cleavage

3.3 Esterification and Amidation via N–C Cross-Coupling

In their seminal 2015 report, the Garg group reportedesterification of amides using Ni(cod)2 and SIPr in tolueneat 80 °C (Scheme 11).37,38 A series of aromatic amides (e.g.,anilides, N-Boc/alkyl) and an impressive range of alcoholsunderwent the cross-coupling in high yields and with re-tention of configuration when chiral substrates were used.From DFT calculations, it was suggested that the rate-deter-mining step of the reaction involves oxidative addition ofthe N–C amide bond into Ni(0)-NHC via a three-membered

transition state (not shown). Interestingly, this mechanismappears to be different from the Pd-catalyzed Suzuki andNi-catalyzed decarbonylative Suzuki reactions through N–Camide cleavage. Importantly, the putative transition statesuggests that less distorted amides might become availableas substrates for metal-catalyzed N–C activation reactions.The synthetically useful order of reactivity: N-Me,Ar-benz-amide > N-H,Ar-benzamide, N-Me,alkyl-benzamide, t-Bu-alkyl ester was demonstrated.

More recently, this protocol has been extended to trans-amidation of aryl N-Boc/alkyl amides using Ni(cod)2 andSIPr in toluene at 35–60 °C (Scheme 12).39 Heteroatom-con-taining, aromatic, sterically hindered and chiral aminesreadily furnished cross-coupling products in high yields.High chemoselectivity and the mildness of these proce-dures are noteworthy.

Scheme 12 Garg’s Ni-catalyzed transamidation by N–C cleavage

4 Decarbonylative Amide N–C Cross-Cou-pling

The general mechanism for decarbonylative amide N–Ccross-coupling is shown in Scheme 13. In general, decarbo-nylative cross-couplings40 are significantly more challeng-ing than acyl cross-couplings as the success must accom-modate selective metal insertion into the N–C bond, andcontrolled decarbonylation. The major advantage of usingamides as aryl electrophile equivalents involves low priceand stability of amide precursors (air, moisture), halide-free cross-coupling manifolds, and the potential for orthog-onal C–N/C–X cross-coupling. To date, four previously un-known reactions of amides by decarbonylative cross-cou-pling have been reported (cf. ketone synthesis by acyl cross-coupling). This mode of amide bond activation has beenachieved using Pd, Ni and Rh catalysis.

Ar

O

N

Ts

MeR

O

Ar


THF, 23 °C, 24 h+ R ZnX

74% X = NMe2, 87%X = F, 73%

80%

81%

O O O

O

80% 72%

O O

X = Br, Cl R = Bn, 1°, 2° alkyl

Ph PhPh

X

MeMe

Me

15 examples

Scheme 11 Garg’s Ni-catalyzed esterification of amides by N–C cleav-age

Ar

O

N

R''

R'OR

O

Ar


toluene, 80 °C, 12 h+ RO H

82% 64%

88%

O

OMe

O

OCy

O

Ot-Bu

O

O

49% 67%

O

O

O

O

• R'R'' = Ph, alkyl; Ts, Me; Boc, alkyl

XX = H, 88%X = MeO, 90%X = CF3, 80% Me

Me Me

O BocN

• N–O cross-coupling of amino acids

Ph N

O

Ph

Ot-Bu

O

NH

Ot-Bu

O

Ph

(−)-mentholNi(cod)2 (10 mol%)

SIPr (10 mol%)

toluene, 80 °C, 12 h

99% ee

70%

79%, 96% ee

Ph

O

OR

+

31 examples

Ar

O

N

Boc

RN

O

Ar

Ni(cod)2 (5–10 mol%)SIPr (10 mol%)

THF, 35–60 °C, 14 h+ N H

91% X = CF3, 92%X = morpholinyl, 83%

X = F, 92%X = Me, 92%

74%

O

N

O

N

O

N

O

N

90% 58%

O

NH

O

NHN

O

Ph

Me

O OX

X

Ad

• R = Me, Bn

N

Boc

NH

O

Ot-Bu

O N

Boc

N

O

t-BuO2C

97% 74%

R2

R1R1

R2

24 examples


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Scheme 13 Cross-coupling of amides via aryl-metal intermediates

4.1 Heck Cross-Coupling

In 2015, we demonstrated the first decarbonylativecross-coupling by amide N–C bond cleavage using catalyticPdCl2 and LiBr in NMP at 160 °C to deliver functionalizedolefins in high yields and with excellent selectivity (Scheme14).41 This Heck protocol was characterized by a broad sub-strate scope with respect to both coupling partners. A di-verse array of electrophilic functional groups, such as chlo-rides, bromides, esters, ketones and even aldehydes re-mained intact under the reaction conditions, attesting tothe high selectivity of the N–C amide bond cleavage. More-over, this reaction is effective for the cross-coupling of sty-renes, acrylic esters, amides, nitriles, α,α-disubstituted ole-fins, cyclic and aliphatic olefins. In addition, the coupling ofan α,β-unsaturated substrate afforded the diene productwith excellent selectivity. Through kinetic studies, we es-tablished that the reactivity of amides in comparison withother aroyl precursors is in the following order: Ar–C(O)NR2≈ (Ar–CO)2O >> Ar–CO2R. Moreover, the order of reactivitywith respect to aryl halides is as follows: Ar–I > Ar–C(O)NR2>> Ar–Br. The reaction was applied to the gram-scale syn-thesis of a common UV-B sunscreen. Considering the indus-trial role of olefins, the reaction represents an exciting ad-vance in decarbonylative Heck reaction protocols.

4.2 Suzuki Cross-Coupling

The Suzuki biaryl synthesis is among the most import-ant synthetic reactions as a result of its efficiency, opera-tional simplicity and reliability.11,15 In 2016, we disclosedthe first decarbonylative Suzuki cross-coupling by N–Cbond cleavage using bench-stable Ni(PCy3)2Cl2 and Na2CO3in dioxane at 150 °C (Scheme 15).42 Interestingly, the reac-tion proceeded with high decarbonylation selectivity, whilethe insertion occurred selectively at the N–C bond, withcleavage of the alternative σ N–C bond not observed underthese reaction conditions. The reaction proved to be re-markably robust to the electronic nature of the reaction

components. A series of electron-neutral, electron-donatingand electron-withdrawing substituents on the amide andthe boronic acid coupling partner underwent the reactionin high to excellent yields. The synthesis of fluorine-con-taining biaryls was accomplished using electron-deficient,

Mechanism: amide aryl N−C cross-coupling

MnLmNR

O

R1

R2

Y R

R M

ON R2

R1

L L

– YX, – LR M

OR

L

RM

R

L L

R R

X = halide or NR1R2

L = CO, PR3

n+2

n+2

n+2

selective N−CO activation

transmetalation

reductive elimination

decarbonylation

Scheme 14 Pd-catalyzed decarbonylative Heck cross-coupling of am-ides by N–C cleavage reported by our group

Ar

O

N

O

O

Ar

PdCl2 (3 mol%)LiBr (12 mol%)

NMP, 160 °C, 15 h+

28 examples

R1

R2

H

HR2

R1

H

CONHt-Bu CN

86% 93%

MeO

Ph

75%

X = F, 84% X = Me, 91%

X

Ph

X

Ph

X

Ph

OHC

X = H, 86%X = MeO, 81%X = CF3, 79%

X = Br, 71%X = CN, 77%X = NO2, 76%

75%

Ph

MeO85%

UV-B sunscreen

O

O

Hex

Et

Scheme 15 Ni-catalyzed decarbonylative Suzuki cross-coupling of am-ides by N–C cleavage reported by our group

Ar

O

N

O

O

Ni(PCy3)2Cl2 (5 mol%)Na2CO3

dioxane, 150 °C, 12 h+

37 examples

Ar B(OH)2 Ar Ar

CF3

80%

CF3

70%

CF3

46%O

H

F

73%

F3C

87%O

Me

F3C

N74%

F3C OMe

F

CF3

69%S

CF3

81%

74%

77%

F3C

Me

MeO

O

MeO


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generally less reactive in transmetalation boronic acids,highlighting the potential of this protocol. In terms of func-tional group tolerance (esters, ketones, aldehydes, hetero-cycles, ethers), the reaction showed good complementarityto C–O couplings, while using the bench-stable catalyst sys-tem and readily available amide precursors. StoichiometricESI-MS measurements were used to detect the presence ofNi-aryl, as well as ArCONiCO3

2– intermediates, suggesting akey role of carbonate to facilitate transmetalation.

4.3 C–H Activation

The first example of directed sp2 C–H bond functional-ization with amides as coupling partners was reported byour group in 2016 using catalytic [Rh(cod)Cl]2 in toluene at150 °C (Scheme 16).43 Using this protocol, aryl, vinyl andeven alkyl amides underwent efficient insertion/decarbon-ylation to provide direct C–H functionalization productswith substrates containing a variety of directing groups, in-cluding quinolines, pyridines, pyrazoles, pyrimidines, 2-carbonylpyridines and imines. Sensitive functionalities(bromide, aldehyde, ketone, ester) were well-tolerated un-der the reaction conditions. Notably, C–H activationthrough the inherently difficult six-membered metallacycle

was readily accomplished, while the use of imines fur-nished synthetically valuable biaryl aldehydes after hydro-lysis. Perhaps most remarkably, the turnover number of>1,000 demonstrated in this reaction is the highest report-ed to date in amide N–C activation reactions, a findingwhich bodes well for the application of amides as couplingpartners in a broad range of C–H activation protocols.

4.4 Decarbonylative Borylation

In 2016, the Shi group reported the first decarbonylativeborylation of amides by N–C bond cleavage in the presenceof B2nep2, Ni(OAc)2·4H2O, commercially available 1,3-dicy-clohexylimidazolium chloride (ICy). NaOt-Bu and K3PO4 intoluene/hexane at 150 °C (Scheme 17).44 The broad func-tional group tolerance of this protocol is noteworthy. Theauthors found that aryl N-Boc/alkyl amides afforded thehighest yields in the reaction. Vinyl and benzyl borylationby amide scission was also accomplished using this meth-od. From a stoichiometric study with Ni(cod)2, the NHC li-gand, NaOt-Bu and K3PO4 in toluene/hexane at 35 °C, thenickel-acyl species was isolated and the structure was de-termined by X-ray crystallography. The acyl-nickel interme-diate was found to be stable at room temperature. The com-plex exhibited similar reactivity to that observed in the bor-ylation reaction, and was converted into the final product inthe presence of K3PO4 at 60 °C. The isolation of the Ni-acylcomplex suggests that ligand exchange on the Ni(II) mightbe facile, while decarbonylation/transmetalation might belimiting. The study provides valuable insight into the amideN–C cross-coupling. The complex was found to be catalyti-cally active in the N–C borylation.

5 Transition-Metal-Free Activation of Amide Bonds

Recently, there has been a strong impetus to developtransition-metal-free carbon–carbon bond-forming reac-tions.45 Metal-free reactions are often cheaper than themetal-catalyzed variants, while removal of trace metal im-purities can provide a significant manufacturing issue. Inthis context, we considered the use of amides as acyl equiv-alents in the classic Friedel–Crafts reaction. We found thatwhen N-glutarimide amides were treated with TfOH in thepresence of an appropriate arene at room temperature or at60 °C for electron-deficient arenes, the corresponding dia-ryl ketones were formed in good yields and with excellentregioselectivity (Scheme 18).46 The reaction showed goodfunctional group compatibility, tolerating sensitive arylchlorides and bromides on either of the coupling partners.

Scheme 16 Rh-catalyzed decarbonylative C–H activation with amides by N–C cleavage reported by our group

R

O

N

O

O

[Rh(cod)Cl]2 (5 mol%)

toluene, 150 °C, 15 h+

N

Ph Ph Ph

Ph

87% 96% 64% 60%R = 2,6-i-Pr2-C6H3

Ph O

NPh

NR

H

81%

N N Br N CHO

NNN

Me

91% 89% 91%

64%, R = 4-MeO86%

R2N

R1

R3

H

R2N

R1

R3

R

• R = Ar, vinyl, alkyl

N

N

R

34 examples

Ph


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Scheme 17 Ni-catalyzed decarbonylative borylation of amides by N–C cleavage reported by Shi (Bnep = 5,5-dimethyl-1,3,2-dioxaborolane; Np = naphthyl

To our knowledge, this method represents the first gen-eral Friedel–Crafts acylation using acyclic amides as sub-strates.

6 Mechanistic Studies

In our general mechanistic hypothesis, low-valent metalinsertion into the N–C amide bond can occur only after theamide has been destabilized (Scheme 1B). This is in agree-ment with the energetic barrier required to activate other-wise inert planar amide bonds. To gain insight into thestructures of amides undergoing N–C cross-coupling, weperformed detailed mechanistic investigation of theground-state amide distortion in relevant amides (Scheme19).47,48

Scheme 19 Ground-state distortion in amide bond N–C cross-cou-pling

Using DFT and crystallographic studies, we determinedthat N-acyl-tert-butyl carbamates (Boc) and N-acyl-tosyl-amides (Ts), two classes of amides that have been used asprototypes in the amide bond cross-coupling, contain sig-nificantly distorted amide N–C bonds in the ground state(Scheme 19A).47 For example, N-Boc/alkyl and N-Ts/Ar am-ides that have been shown to be particularly reactive in am-ide N–C cross-coupling feature amide bonds approachingone-third maximum amide distortion (τ = 32.06°,χN = 17.36°, τ = 30.39°; χN = 22.28°, respectively). We deter-mined that these N-Boc/alkyl and N-Ts/Ar amides can freelyrotate around the N–CO axis.

Furthermore, we established that N-glutarimide amidesemployed by us as models for N–C cross-coupling containuniformly twisted (close to τ = 90°) amide bonds irrespec-tive of the steric demand at the amide carbon side (Scheme19B).48 These N-glutarimide amides are distorted by a newdestabilization mechanism of the amide bond, which fea-tures an inverted rotational profile of the amide linkage.The high reactivity observed in N–C activation reactions ofN-glutarimide amides correlates with structural ground-state distortion. Collectively, these results strongly supportthe amide bond destabilization as a blueprint for activationof amides toward transition-metal-catalyzed N–C bondcleavage.49,50

Ar

O

N

Boc

Me

Ni(OAc)2⋅4H2O (10 mol%)ICy (15 mol%)

NaOt-Bu (15 mol%)

K3PO4, toluene/hexane 150 °C, 24 h

+ B2nep2

69%

42%

Bnep Bnep Bnep

Bnep

45% 56%

X X = H, 72%X = MeO, 74%X = CF3, 70%X = 4-Me2N, 66%

• Acyl-nickel(II) complex

Ni(cod)2 (1 equiv)ICy (2 equiv)

NaOt-Bu (2 equiv)

K3PO4, toluene/hexane 35 °C, overnight

Ar Bnep

30 examples

O

O

F

F

X

X = CO2Me, 71%X = CONHMe, 67%

N

Me

PhBnep

Ph

Bnep1-Np

Me

NO

Me

Boc

59%, X-ray Me

NiO

CyI

ICy

Cl

Scheme 18 Transition-metal-free acylation of arenes with amides re-ported by our group (rr = regioisomer ratio)

R

O

N

O

O

TfOH

23 °C, 15 h

+

21 examples

64% 57%, rr >95:564%, rr >95:5

Ph

O

Ph

O

Ph

O

75%

93% 64%

68%

MeO2CBr

Ph

O

S

Ph

OMe

MeMe

Ph

O

Br

Ph

O

MeO

Ar H R

O

Ar

Ph

O

83%

Cl

Ph

O

X

X = OMe, 77%X = CF3, 97%

Boc

NR'

O

R N

O

R

Ts

R'

A. N-Boc/R and N-Ts/R amides: acyclic twisted amides

B. N-glutarimide amides: fully perpendicular twisted amides

R = Ph, R' = Metwist = 32°χN = 17°

R = Ph, R' = Phtwist = 30°χN = 23°

N

O

R

O

O

R = Phtwist = 90°

χN = 0°N

O

R

O

O

R = Phtwist = 50°χN = 10°


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7 Conclusions and Outlook

In conclusion, the field of amide bond N–C cross-cou-pling has experienced an exponential growth over the pasttwo years and huge conceptual advances have been made inthis area. The results reviewed here demonstrate that theformation of carbon–carbon, carbon–oxygen, carbon–ni-trogen and carbon–boron bonds has been successfully ac-complished. These new methods are of considerable inter-est given the central importance of amides in organicchemistry and biology. At present, steric distortion and/orelectronic activation appear to be required for the efficientN–C metal insertion, in agreement with Pauling’s reso-nance theory. An especially exciting functionalization in-volves the use of simple anilides, as in the Ni-catalyzed es-terification. Furthermore, the progress in decarbonylativecross-couplings is noteworthy. Future research in the fieldwill need to address the practical aspects of the amide N–Cbond cleavage. Moreover, mechanistic investigations fo-cused on the interplay between catalysts and substrateswill enable the design of more efficient catalytic processes.We are convinced that the amide bond N–C activation plat-form will reach its maturity in the coming years. Ultimately,general reactions involving amide N–C bond activation willbe of significant utility to organic chemists.

Acknowledgment

Financial support was provided by Rutgers University. The Bruker 500MHz spectrometer used in our studies was supported by the NSF-MRIgrant (CHE-1229030).

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cross-coupling of amides by n–c bond activation...scheme 2 cross-coupling of amides by n–c bond...

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