Metalloporphyrin Catalyzed C–H Amination - ACS Catalysis (ACS

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Metalloporphyrin Catalyzed C-H Amination Ritesh Singh, and Anirban Mukherjee ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00009 • Publication Date (Web): 13 Mar 2019 Downloaded from http://pubs.acs.org on March 13, 2019

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ACS Catalysis

Metalloporphyrin Catalyzed C–H Amination Ritesh Singh*a and Anirban Mukherjeea aDepartment

of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER-Raebareli), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow (UP)- 226002, INDIA

ABSTRACT: Direct C–H bond functionalization to form C‒N bonds via nitrenoid insertion is one of the most effective strategies to construct N-functionalized molecules of importance. In this context, metalloporphyrins have established itself as an effective catalytic system for such transformation following outer sphere pathway. In past few years C(sp3)–H bond amination has progressed leaps and bounds tackling the chemo-/regioselectivity issue not only in small molecules but also in complex molecules through late stage functionalization, furnishing valuable N-scaffolds. It is only very recently that the bio-catalytic approach with metalloporphyrin based enzymes have emerged as promising research area demonstrating very good regio- and stereoselectivity towards development of environmentally benign C–H amination processes. Importantly, the progress in aromatic C–H bond amination has also gained prominence lately under metalloporphyrin catalysis. This review covers till date development achieved in metalloporphyrin catalyzed C–H amination, including the very nascent bio-catalytic C–H bond nitrenoid insertion, besides providing an insight on the mechanistic aspects as well. KEYWORDS: C–H amination, metalloporphyrin, nitrene insertion, metalloradical catalysis, N-scaffolds 1. INTRODUCTION Nitrogen bearing molecules constitutes core of several natural products, therapeutic drugs, materials and agro-/fine chemicals (Figure 1).1-2 Besides, N-heterocycles often serves as ligands for catalytic reactions and also find usage as a chiral template for enantioselective reactions.3 Thus, construction of Nfunctionalized molecules is of significant importance to synthetic organic/medicinal chemists. Consequently, there is a continuous quest for development of new methods to access N-compounds. C–H bond functionalization has emerged as one of the prominent ways to construct C‒N bond from direct C–H bonds. This strategy provides a unique disconnection approach without requirement of any preinstalled functional groups, thus providing one of the most atom economical methods for construction of N-scaffolds. O HN

O S

O O S NH2

CF3 Naturetin anti-hypertensive agent

O

O N S N N H

H N

SO2NH2

S O O Doburil oral diuretic

Sulfadiazine antibiotic

H 2N

Cl

HN

Scheme 1. Metalloporphyrin catalyzed C–H amination pathway

O

N O O

N

O

NH

O NH2 Carbamazepine anti-epileptic

OH

NH

O O N Quinine anti-malaria

H

HO Codeine analgesic

S

O

N

Penicillin G antibiotic

OH

N O N H

H

R [M(Por)] (regenerates)

R1

O

HO

O

R1 X R2 N + R3 H N-scaffold (P)

N

Horsfiline analgesic effect

O

N

Substantial advancement has been made in this direction by effective utilization of various transition metals promoting efficient direct C–H bond amination.4 In this context metalloporphyrins have established themselves as a robust and unique catalytic system for such transformation. In fact, the significant progress achieved in the area of direct C–H bond amination stems from some very early works carried out by metalloporphyrin catalyst (MPC) as P450 biomimetic model.5 Metalloporphyrin catalyzed C–H amination occurs via outer sphere pathway,6a wherein initial co-ordination of metal porphyrins with aminating agents generate high valent metalnitrenoid species, which subsequently undergoes C–H bond insertion in substrates (S) providing desired N-scaffolds (P) (Scheme 1). Such a pathway is known to proceed through different mechanistic manifolds viz. concerted asynchronous or stepwise (hydrogen atom abstraction and radical rebound [HAA/RB] or electrophilic substitution [ES]) pathways (in aromatic system).

O

Gelsemoxonine natural alkaloid

Figure 1. Representative N-containing natural and synthetic biorelevant molecules

R

R2 H R3 S [M(Por)=N-X] Metal nitrenoid

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NX

:N-X

[M(Por)]

M

R Metal-nitrenoid

R

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

Owing to metalloporphyrin ’ s unique structural arrangement wherein a metal ion is snugly associated with the porphyrin ligand, it often leads to high selectivity and turnover number.7 Metalloporphrin based catalytic system differs from other transition metal based catalytic systems in a way, such that no dissociation of metals is seen during the catalytic cycle event. Besides, the cis-coordination site being unavailable allows lesser side product formation. Further, metalloporphyrins have shown distinct capability in catalyzing nitrene-transfer reactions on C–H bonds from N-precursors like carbonazidates and sulfamoyl azides, on which other metal catalysts remain unsuccessful (vide infra).4i,6b Thus, MPC holds significant promise toward development of effective C–H amination processes. Earlier reviews on metalloporphyrin catalyzed direct C–H bond to C‒N bond formation appeared almost a decade back as part of exhaustive review on metalloporphyrin catalyzed transformations.7 However, in light of significant body of work that appeared in past few years especially in the area of biocatalytic C–H to C‒N bond transformations as well as aromatic C–H bond amination, we believe a comprehensive review dedicated solely to account the advancements in C–H bond nitrenoid insertion enumerating the historical growth and future prospect would be of immense interest to researchers which will be helpful in further growth of this area. With the idea of providing a complete update in metalloporphyrin catalyzed C–H amination till date, reports prior to 2011 have been only summarized in this piece. This review will help understand the wide perspective and consequently the importance of the metalloporphyrin catalysis (MPC) in direct C–H bond amination reactions. For the convenience of our discussion we have two broad sections in this article; intermolecular and intramolecular reactions with synthetic catalysts which subsequently is divided in C(sp3)–H and C(sp2)–H amination reactions. Finally, a section on bio-catalytic methods for C–H bond nitrene transfer has been delineated. Structures of porphyrin ligands used in this review article are depicted in Figure 2. Scheme 2. Mechanistic manifolds in metalloporphyrin catalyzed C–H amination

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as a ground work for Breslow and Gellman, who in 1982 gave a seminal report9 on tosylamidation of unactivated C–H bond in cyclohexane 2. In this work they reported MnIII(TPP)Cl and FeIII(TPP)Cl as potential catalysts for the formation of Ncyclohexyl toluene-p-sulfonamide 3 from (tosyliminoiodo)benzene (PhI=NTs) 110 (Scheme 3). With 50 mmol of the iodo-compound the percentage of yield in Mncatalysis was 136% whereas in case of Fe-catalysis the yield was only 62% with respect to the porphyrin catalyst. When CH2Cl2 was replaced by benzene as co-solvent, it led to the lower yield with both the catalyst. A reaction with MnIII(TPP)Cl in CH2Cl2 under the same condition with 125 mmol of iodo-compound furnished 310% yield with respect to the catalyst. Formation of tosylamidated product 3 was also observed with MnIII(TPP) acetate in cyclohexane-benzene solvent system. Ar

tBu

N M Cl N N

tBu

N Ar

N

Ar

Ar = M(TPP)Cl

M(TMP)Cl

NH

HN

N

N

cer con

R-H + [M(Por)

N-X]

stepwise

N

N

NH

hydrogen atom abstraction ste p

wi

se

[MnIII(tBuPc)]Cl

N N

N Ru CO N

O

[M(Por*)(L)(L' )] Mn = RuII or MnIII L = CO or OH L' = EtOH or MeOH

Co(P1)

RuII(TTP)(CO)

F Cl

Cl

Cl N

Cl

N

N Mn SbF6 N

Cl

N

N

Cl

N Cl

Cl

N N

M

N

N

Cl Cl

R



R M(Por) N H X electrophilic addition

2. INTERMOLECULAR AMINATION WITH METAL CATALYST 2.1 C(sp3)–H Bond Insertion Initial reports on bio-mimetic oxene transfer for C–H hydroxylation catalyzed by iron or manganese porphyrin5,8 served

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F

F

F

F

Cl Cl

Cl

Mn(III)(ClPc)

X-NH

tBu

FeIII[Pc]Cl

HN

O

asynchronous R M(Por) N H X radical rebound

N tBu

N L' N Mn N L N

Co

Cl

M(Por) N H X

N N

N Mn Cl N N N

N N

N

O

O

Cl

ted

Cl

M(TDCPP)Cl

N

R

N N Fe Cl N

Cl Ar =

Ar =

N

N

Ar

F

F

F

F

N Fe Cl N N

N

F

F

F

F

F F

Cl M(OEP)

[FeIII(F20TPP)Cl

F

F

F

F

F

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ACS Catalysis

H O

O N N

O

H

O NH

NH

Co

HN

N

F

F

F

F

N

O

O H

CO(P4)

F

F N Fe Cl N N

N

F

F

F

F NMe2

F

F

F

F

NMe2

Fe(TF4DMAP)Cl

N N

III

Fe (TDCPP)(IMe)2I

N

N

Ar = 2,6 Cl2C6H3 IMe =

NMe2 F

Me2N HN

O

H

O

F

Ar

Ar

N M N

N N

Ar

N

N

Ar = 4-F-C6H4 Ar

N BIMe =

N

RuII(4-F-TPP)(BIMe)2I

Figure 2. Structure of various metalloporphyrins used in this review Scheme 3. MnIII- and FeIII-porphyrin catalyzed tosylamidation of cyclohexane

point of view (Scheme 5). It was found that tosylamidation was highly selective toward tertiary C–H bonds in saturated alkanes. Che and co-workers reported another work on asymmetric amidation of saturated C–H bonds catalyzed by chiral ruthenium and manganese porphyrins (Scheme 6).13 They demonstrated that RuII(Por*)(CO)(EtOH) and MnIII(Por*)(OH)(MeOH) porphyrins are potent catalyst towards such asymmetric amidation reactions of alkanes 11 with PhI=NTs giving products 12. Besides, they also showed that reaction of [RuII(Por*)(CO)(EtOH)] with 2 equiv. of PhI=NTs in CD2Cl2 at room temperature gives rise to the complex [RuVI(Por*)(NTs)2], a seminal example of a chiral imido metalloporphyrin, showing good catalytic activity towards the enantioselective amidation reaction of saturated C–H bonds. Effect of temperature and substrate sterics on yield (up to 78%) and enantioselectivity (up to 58% ee) was observed in this study, with less sterically hindered substrate giving higher yield and better enantioselectivity.

Scheme 5. Proposed pathway in RuVI-porphyrin catalyzed amidation

O O H MnIII(TPP)Cl or FeIII(TPP)Cl (2.5 mmol) S N IPh + S N O O H CH2Cl2 - Cyclohexane (1:1), 3 h (tosyliminoiodo)-benzene Cyclohexane N-cyclohexyltoluene-p-sulphonamide 2

1

Ts HN

H

CR3

3 MnIII(TPP)Cl PhI=NTs : 50mmol

Ru(Por)

136%

FeIII(TPP)Cl

H CR3 9 NTs

62%

MnIII(TPP)Cl in CH2Cl2 PhI=NTs : 125 mmol Time: 4.5 h

VI

Ru (TPP)(NTs)2 310%

Scheme 4. Metalloporphyrin catalyzed allylic amination MnIII

PhI=NTs Mn (TDCPP)(ClO4) III

NHTs 4

5

NHTs

6 NHTs

TsHN 7

NHTs

RuVI(Por)

Ru(Por) NTs

NTs

In 1988, Mansuy and co-workers reported amination of rather activated allylic C–H bond in alkene 4 by PhI=NTs.11 They demonstrated that manganese-porphyrin was the efficient catalyst which manifests different chemoselectivity and predominantly leads to the allylic N-tosylamination (5, 6, 7 and 8) of alkenes. (Scheme 4).

MnIV-NHTs

=

CR3

NTs

8

On comparing the yield of N-tosylaziridines and allylic Ntosylamines with different manganese and iron porphyrin catalysts consecutively with cis and trans hex-2-ene, it was found that the ratio of N-tosylamines to N-tosylaziridine was differing widely with the nature of catalyst and consequently MnIII(TPP)(ClO4) appeared to be the best catalyst for allylic N-tosylamidation with almost 40% yield with both cis and trans hex-2-ene verging no formation of N-tosylaziridines. In 1999, Che and co-workers reported amidation (10) of alkanes 9 by bis(tosylimido)ruthenium(VI) porphyrins12 from a mechanistic

Hpz

NHTs pz = Dichloromethane containing pyrazole

RuIV(Por) pz

R3C NHTs 10

Selected Examples NHTs

NHTs

NHTs

NHTs 10a

10b

10c

10d

Yield with RuVI(TPP)(NTS)2

9%

78%

84%

52%

Yield with RuVI(OEP)(NTS)2

11%

80%

88%

60%

In 1999, Cenini and co-workers established [RuII(TPP)(CO)]- or [CoII(OEP)]-catalyzed intermolecular allylic amination with pnitrophenyl azide under reflux condition.14 Following this, in 2000 Breslow and co-workers reported amidation of equilenin acetate 13 furnishing 11-β aminated product 14 with 47% yield, catalyzed by MnIII(F20TPP)Cl (Scheme 7).15 This was the seminal example of metalloporphyrin catalyzed regio- as well as stereo-specific amidation of natural product where (tosyliminoiodo)benzene (PhI=NTs) acts as a nitrogen donor. Scheme 6. Metalloporphyrin catalyzed asymmetric amidation of saturated C–H bond

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1, [RuII(Por*)(CO)(EtOH)] or 2, [MnIII(Por*)(OH)(MeOH)] H R2

PhI=NTs H

R1

VI

[Ru (Por*)(NTs)2]

11

Page 4 of 15

Me3SiO R1

NHTs

R1 * H R2

H

12

TFAA

12b

Yield 82% ee 47%

Yield 72% ee 54%

R2

R3

R2 18

Scheme 7. Amidation of equilenin acetate TsHN Mn(TFPP)Cl, PhI=NTs CH2Cl2

R1

O NHCOCF3

Another work on effective amination of saturated C–H bonds was reported by Che et al., with electron deficient Mn- and Ruporphyrins where the direct amination involves catalytic nitrogen atom transfer.16 In 2000, Cenini et al., also reported their work on the formation of secondary amines with new synthetic strategy that includes aryl azide for the direct amination of benzylic C–H bonds by using the complex of CoII-porphyrin.17

O

R2

NHCOCF3

R1

O

12a

16

Selected Examples

NHTs

MeO

13

Ru

17

NHTs

O

R2

15

NHCOCF3

OH

Selected Examples

O

O R1

up to 58% ee

R3

H

N

H

O

O O 14

In 2002, Che et al., reported chiral Mn- and Ru-porphyrin catalyzed amidation of saturated C–H bonds that involves asymmetric nitrogen atom transfer to the hydrocarbons.18 Another work from the Che laborartory reported intramolecular amidation of C(sp3)–H bonds with sulfamate ester substrates catalyzed by ruthenium porphyrins in high diastereo- as well as enantioselectivity.19,20 Thereafter, in 2003, Cenini and co-workers proposed a synthetic and mechanistic study on CoII-porphyrin catalyzed direct C–H bond amination with aryl azides.21 An elegant RuVI-porphyrin catalyzed transfer of ‘NCOCF3’ in O-silyl enol ether 15 and C–H bond of indan 17 was reported by Che et al., via trifluoroacetic anhydride (TFAA) activated approach of nitride RuVI-porphyrin complexes providing aminated products 16 and 18 respectively in good yields (Scheme 8).22

NHCOCF3

NHCOCF3

16a

16b

18a

75%

84%

63%

Prevalence of metal-nitrenoid intermediates had been postulated for the reactions undergoing metalloporhyrin catalyzed C–H amination. However, an unambiguous proof for such an intermediate was provided by Gallo and co-workers via X-ray crystallography of ruthenium bis-imido porphyrin complex as an active intermediate species in allylic and benzylic C–H nitrene transfer reactions with Ru(TPP)(NAr)2 [where, Ar = 3,5(CF3)2C6H3].23 Catalytic prowess of CoII-Porphyrin was further demonstrated by Zhang et al. in their early reports of benzylic C– H bond amination wherein they used bromamine-T and 2,2,2trichloroethoxycarbonyl azide (TrocN3) as nitrene source.24,25 Subsequently, in the year 2010, Zhang and co-workers reported formation of six and seven membered cyclophosphoramidates with phosphoryl azides by using CoII-porphyrin system.26 Electron deficient Fe-porphyrin [FeIII(F20TPP)Cl] was demonstrated to be an effective catalytic system for amination/amidation of allylic C–H bonds using pnitrobenzenesulfonyl azide (PNBSA) and TsN3 respectively by Che and co-workers.27 Direct functionalization of saturated C–H bonds in alkyl substrates were also accomplished by same iron porphyrin catalyst using PNBSA as nitrogen source. Above mentioned reports have been covered in detail in earlier reviews.7 Scheme 9. CoII-(Por) catalyzed C–H amination pathway O O

Ph

O

CoII(Por)

HN

O N N N

20 R1 O

O

Ph

O NH

Scheme 8. Amidation of silyl enol ether and indan

+

O N N N

R1

CoII(Por)

CoIII(Por) O O

Ph H

R1 19

N

N2

CoIII(Por)

A thorough study shedding light on mechanistic details on CoII– porphyrin catalysis in benzylic C–H bond amination (20) of different substrates 19 like toluene, tetralin etc. was reported by Zhang et al., in 2011 (Scheme 9).28 The density functional theory (DFT) calculations were performed with a series of azides viz. N3C(O)OMe, N3SO2Ph, N3C(O)Ph and N3P(O)(OMe)2 and

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ACS Catalysis

porphyrins like simple porphyrin (Por), TPP, TPFPP, and TDClPP (Figure 3). R NH

N

N

HN

R

Por; R=H TPP; R = Ph R TPFPP; R = C6F5 TDClPP; R = o-Cl2C6H3

R

Figure 3. Ligands used for DFT study in mechanistic investigation of CoII radical catalysis The computational outcomes showed the co-ordination of azide to the metal center, leads to the formation of nitrene radical intermediate; which was also confirmed by electron paramagnetic resonance (EPR) spectroscopy. Now this metallo-nitrene radical intermediate eventually abstracts proton from the benzylic position followed by the formation and dissociation of metalloamine complexes. In 2012, Gallo and co-workers reported a synthetic as well as mechanistic study on allylic amination of olefins 21 by aryl azides with Ru-porphyrin, [RuII(TPP)(CO)], as a potential catalyst (Scheme 10).29 Mechanistic insight revealed, the nitrene transfer step involves both mono- and bis-imido species. Aryl azides with less electron withdrawing behaviour prefers the formation of mono-imido complex and with strong electron withdrawing substituents the mono-imido complex readily reacts with the azide giving rise to the formation of oxidized bis-imido complex, acting as a catalyst. The percentage yield of the products 22 was relatively much higher in case of neat olefin as a solvent than benzene.

Scheme 10. RuII-porphyrin catalyzed allylic amination H R2

R2

ArN3 , RuII(TPP)(CO) 21

R1

R1

Benzene, reflux

NHAr 22

Selected Examples NHAr

NHAr

22c

22a

22b

Ar = 3,5-(CF3)2C6H3 benzene : 26% olefin : 75%

Ar = 3,5-(CF3)2C6H3 benzene : 42% NHAr

22d Ar = 3,5-(CF3)2C6H3 benzene : 33% olefin : 51% Ar = 4-NO2C6H4 benzene : 32% olefin : 45%

NHAr

Ar = 4-NO2C6H4 benzene : 30%

porphyrin

[Ru(4-F-TPP)(BIMe)2],

effecting very high nitrene

C–H insertion activity (24) on unactivated hydrocarbons 23. Theoretical experiment revealed the influence of strong σ donating effect of the trans NHC ligand for the decomposition of azides under mild conditions for amination process (Scheme 11). An asymmetric C–H nitrene transfer was also achieved in the same report using a chiral Ru-porphyrin catalyst giving decent enantioselectivity (70% ee).30 Following fundamentally similar pathway Betley et al. also reported direct benzylic C–H bond amination with aryl azide using his unique non heme FeIIdipyrrinato catalyst giving modest turnover number (12 TON) via radical Fe-imido intermediate.31 Groves and co-workers reported late stage azidation of secondary, tertiary and benzylic C(sp3)–H bonds in compounds 25 with MnIII-porphyrin (Mn(TMP)Cl) using aqueous NaN3 under open air condition providing products 26 with potential utility in drug discovery and chemical biology research (Scheme 12).32 A radical pathway was proposed for the azidation of C–H bonds. In 2018, White and co-workers came up with a new catalytic system, MnIII(ClPc), capable of selectively aminating benzylic C(sp3)–H bonds in 27 with very good reactivity and functional group tolerance (28), allowing the late stage functionalization of bioactive molecules and natural products as well (Scheme 13).33 Mechanistic pathway involves the formation of electrophilic metallo-nitrene intermediate, which is in contrast with other catalytic systems, containing base metals, which proceed via non-electrophilic metallo-radical intermediate, inefficient for site selective aminations. The catalytic system was tolerable even to the presence of Lewis and Bronsted acid complexed amine functionality in those substrates for which C–H bond would rather be very difficult to achieve. Very recently, Che et al. showed the capability of a biocompatible Fe-porphyrin [FeIII(TF4DMAP)Cl] for efficient intermolecular benzylic C(sp3)−H amination (30) on compounds 29 using aryl azides. With just 1 mol% of catalyst loading the reactions display high chemo- and regioselectivity on a broad range of substrates and is also effective for late-stage functionalization of complex natural and bioactive molecules (Scheme 14).34 Scheme 11. RuII-Porphyrin catalyzed amination using pentafluorophenyl azide R H 23

+

C6F5N3

Ru(4-F-TPP)(BIMe)2(0.5 mol%)

R

CH2Cl2, reflux, 12 h

Selected Examples

NHC6F5

NHAr

NHC6F5 22e

24a

Ar = 3,5-(CF3)2C6H3 benzene : 24% olefin : 34% Ar = 4-NO2C6H4 benzene : 22% olefin : 28%

90%

NHC6F5 24

NHC6F5 24b 92%

24c 93%

Scheme 12. Mn-Porphyrin catalyzed aliphatic C–H azidation

The excellent versatility of Ru-porphyrin complex was further demonstrated by Che et al. using Bis(NHC)ruthenium(II)-

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Although significant progress has been made in C(sp3)–H nitrene insertion via metalloporphyrin catalysis, in comparison, C(sp2)–H bond amination via nitrenoid insertion has received less attention. In this regard, Che and co-workers gave a seminal report of direct intermolecular amination of aromatic C(sp2)–H bonds with [RuII(TTP)(CO)] in aromatic heterocycles 31 with iminoiodinanes under mild conditions giving moderate to high yield of aminated products 32 (Scheme 15).35

Mn(TMP)Cl, NaN3 R

H 25

R N3 26

PhIO, EtOAc, rt, 3-12 h

Selected Examples N3

N3 N3 26a

26b

26c

54%

38%

45%

Scheme 15. [RuII(TTP)(CO)] catalyzed amidation of aromatic heterocycles

OH

N3

Page 6 of 15

N3

O 26d

26e

56%

50%

RuII(TTP)(CO) PhI=NR1 / NH2Ns + PHI(OAc)2

X CH2Cl2, 4 Å MS, 31 X = O, S, NR R = Ph, (p-Me)C6H4, (p-OMe)-C6H4, (p-NO2)-C6H4 etc.

Scheme 13. [MnIII(ClPc)] catalyzed selective amination of benzylic C–H bond H R1

C6H6 , 5 Å MS, 40 oC

R2

R1

32a 73%

Selected Examples NHTces

NHTces

N H

OAc O

O

28a

28b

67%

69%

NHTces

NHTces

CF3

O

NHTces

O

CF3 28e 76%

NH3+

O O S N

HH

O AcO

O

O

O

H

NHTces

NHTces 28i 65%

28h 69%

Scheme 14. [FeIII(TF4DMAP)Cl] catalyzed C–H amination R R1 R2

R

[FeIII(TF4DMAP)Cl](1 mol%),

N3

H +

4 Å, ClCH2CH2Cl, reflux, 12 h

29

H N

R1 R2

CF3

HN N H

HN CF3

CF3

30a 91%

F

F

Cl

CF3 O 30c 95%

30b 93%

Br

F HN N H

Cl

30d 76%

F 30e 93%

F

S 32e 60%

TsHN

NNs2

NHTs

NHTs N NHTs O 32h 50% 32g 84%

NO2 32i 87%

Scheme 16. Diimination of indole via RuII-porphyrin catalysed aromatic C(sp2)–H bond amination

30

CF3

32d 80%

NHTs

Selected Examples CF3

NTs2

N Ts

Diimination of indole 33 using intermolecular C(sp2)–H nitrenoid insertion was achieved by the same group, using RuII-porphyrin (RuII(TTP)(CO)]) under reflux, providing products in good yields (up to 94%). Involvement of ruthenium bis/mono-imido porphyrin complex was proposed via in initial aziridine formation 34′ with subsequent ring opening providing unstable diamine intermediate 34″, which undergoes dehydrogenation to furnish diimine product 35 (Scheme 16).36

28g 56%

H O

NTs2

BF3-

H

H

33%

TsHN TsHN

S 32c

32b 58%

32f 82%

NHTces N O S Ph O 28f 65%

NTs2

N Ph

28d 60%

N

O

N

28c 53%

NHTces

NTs2

O

28

8-16 h

27

X 32 R1 = Ts, Ns R2, R3 = H, Ts, Ns

Selected Examples

NHTces

Mn(III)(ClPc) PhI=NTces

R2

NR2R3

N H 30f 48%

2.2 C(sp2)–H Bond Insertion

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ACS Catalysis condition to synthesize cyclic thiadiazinane scaffold 39 which was further utilized in the synthesis of 1,3-Diamines 40 (Scheme 18).42 A ‘radical nitrene’ intermediate was invoked in this transformation which was supported by a cyclopropyl tethered probe.

NAr

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

R2

N R1

33

[RuII(TTP)(CO) (2 mol%)

+

NAr

R2

ArN3 ClCH2CH2Cl, reflux nitrene insertion/ aziridation

N R1

35

hydrogen abstraction NHAr

NAr R2

ring opening

N R1

Selected Examples NO2

N

NO2

N

N

Catalyst

N

NO2

35b 89% yield 100% conv.

O O S NH

CH3CN or CH2Cl2 37

Yield

FeIII(TPP)Cl MnIII(TPP)Cl

NO2

35a 90% yield 100% conv.

intramolecular

Catalyst

36

N

N Bn

77% 16%

NO2

35c 94% yield 100% conv.

Scheme 18. Intramolecular C–H amination followed by the formation of 1,3-Diamine

CF3

O

O O S N IPh H

NO2

N N

N

catalyzed

34'' R1

34'

N

Scheme 17. Metalloporphyrin nitrene C–H insertion

NHAr

R2

CF3

NO2

N

N N

N

N 4-Tol 35d 90% yield 100% conv.

N Bn NO2

F3C 35e 86% yield 100% conv.

CF3

N CF3

O O N3 S N R1 H

N CF3

N

R2

CoII(Por*) (2 mol%)

R4

PhCF3, 4 Å MS 40 oC, 20 h

R3

R4

CF3

R3 38

35f F3C 91% yield 100% conv.

R1

+ N2

R2 39

NH

NH2(CH2)3NH2 reflux, 3 h

NH2

R4 R3 1,3-Diamine 40 Por* = D2h-symmetric porphyrin 3,5-DitBu-IbuPhyrin (P1) Selected Examples

After developing a method of metalloporphyrin catalyzed intermolecular C–H amination, Breslow and Gellman in 1983 gave a pioneering report of intramolecular C–H amination with metalloporphyrin catalyst by accessing benzosultam 37 (Scheme 17).37 The corresponding (iminoiodo)benzene derivative 36 was prepared from 2,5-diisopropylbenzenesulfonamide with phenyliodine(III) diacetate (PIDA) with KOH/MeOH. MnIII(TPP)Cl, was found to be inferior as compared to FeIII(TPP)Cl as catalyst for the insertion reaction which is in contrast to earlier model systems38 but analogous to the natural enzymatic system. In an approach to achieve high catalytic efficiency a solid support polyethylene glycol (PEG) based Ruporphyrin [(RuII(F20-tpp)(CO)] catalytic system for intramolecular amidation of sulfamate esters was reported by Che at al. in 2006, affording cyclic sulfamidates.39 In 2007, Zhang et al., demonstrated the intramolecular direct C–H bond amination with CoII-porphyrin using arylsulfonyl azides providing biologically relevant benzosultams.40 In one of the reports in the year 2008, Che et al., provided some mechanistic rationale via computational studies on ruthenium-porhyrin complex [Ru(por)(CO)]-catalyzed intramolecular C–H bond amidation of sulfamate ester.41 1,3-Diamines are important scaffolds in natural product and they also serve as crucial building blocks in synthetic organic chemistry. In 2010, Zhang and co-workers used sulfamoyl azides 38 as susbtrate to achieve intramolecular C–H bond amination with CoII–porphyrin as a catalyst under neutral and non-oxidative

O S O N R1

R2

3. INTRAMOLECULAR AMINATION WITH METAL CATALYST 3.1 C(sp3)–H Bond Insertion

H N

H N

O S O N

O O N O S HN

39a 95% H N

H N

O

39e 89%; trans/cis > 20/1

MeO

39c 96%

39b 99% O S O N

O S O N

H N

O S O N Bn 39d (> 80%)

H 2N

Et NH2 N H 40a 82%

Bn

N H

Bn

40b 60%

Building on their previous work in metalloradical nitrene insertion in C–H bonds, Zhang and co-workers reported stereoselective amination of electron deficient aliphatic C–H bond using CoII–pophyrin as catalyst under redox neutral condition (Scheme 19).43 Under metalloradical catalysis (MRC), N-benzyl sulfamoyl azides 41 effectively undergoes intramolecular amination at α-C(sp3)–H bond to esters, ketones, nitriles and amide producing products 42, with high regio- and diastereoselectivity. It was found that CoII(P1) was the better catalyst for the amination than CoII(TPP), producing greater percentage of yield. During the same period White and co-workers identified a non-toxic and inexpensive, iron porphycine [FeIIIPc] (Pc = phthalocyaninato, nitrogen analogue of porphyrin) as a potential catalyst showing very good chemo- as well as site-selectivites in allylic C(sp3)–H amination reaction (44a and 44b) over aziridination. The system also effectively aminated (44c and 44d) stronger 3º and 2º aliphatic-, ethereal-, and benzylic- C–H bonds

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

on various sulfamate esters 43 (Scheme 20).44 Intramolecular Kinetic Isotope Effect studies conducted using a deuterated substrate resulted in KIE = 2.8. Further probing of mechanism using Z/E alkene (20:1) probe gave scrambled product (Z/E = 9:1), thus indicating a different mechanism prevailing in this catalytic system, which is in contrast to the concerted asynchronous mechanism prevalent in Rh2(OAc)4 catalyzed C–H amination under similar conditions and substrate. Scheme 19. Stereoselective amination by metalloradical catalysis O O O R1 S S R1 [Co(P1)] (2 mol%) N NH N R4 N3 + N2 H R4 C6H6, 4 Å MS, 40 oC, 20 h R2 R2 EWG EWG R3 R3 EWG = C(O)NR2, C(O)OR, C(O)R, CN 42 41

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approach for synthesis of high‐yielding functionalized propargylamine derivatives 46. White and co-workers reported a unique manganese catalyst which can intramolecularly aminate (46) various aliphatic C–H bonds including propargylic and 1º aliphatic systems (Scheme 22).46 The catalytic system they used was MnIII(tBuPc), which manifested high reactivity and chemoselectivity in sulfamoyl substrates 45. It selectively aminated C(sp3)–H bonds in allylic substrates bearing reactive π functionality. Scheme 21. Chemoselective amination of propargylic C(sp3)– H bonds

O

N3

O O R1 S N H R4 R2 R3 45

Selected Examples

R1

[Co(P1)] (2 mol%)

R5

O O S NH

N

R2

C6H6, 4 Å MS, 40 oC, 20 h

R3 46

R4

R5

Selected Examples

O O S BnN NH

O O S BnN NH

CO2Et

O O S BnN NH

CO2NH2

42a 98%

CN EtO2C

42b 97% O O S NH

O O S BnN NH

42c 99%

H

42f 95%; dr: >99/1

43

PhI(OPiv)2 (2 equiv.)

O HN R1

PhMe/MeCN(4:1) rt, 6 h

O O S

S

O O S O N

O O

44 Amination

O O S Me HN O

O Me

44a 70% Z : E > 20 :1 21a : 22a > 20 :1

Me 44b 53% Z : E > 20 :1 21b : 22b > 20 : 1 O S

O O S NH

+

R1

46e 95%

H

H

Scheme 22. [MnIII(tBuPc)]Cl catalyzed C–H amination R2

O O S H 2N O H R1 R3 R2 47

R2 Aziridination

O O S HN O

O

[MnIII(tBuPc)]Cl AgSbF6

HN

R1 R2

PhI(OPiv)2, 4 Å MS C6H6/MeCN rt, 8-24 h

Selected Examples Me

Me

HN

H

Their approach allowed late stage functionalization of complex molecules. Mechanistic investigation revealed that nitrene transfer follows the pathway between concerted C(sp3)–H insertion as in the case of reactive noble metals like rhodium and stepwise radical C(sp3)–H abstraction as in case of base metals like iron.

Selected Examples

HN

46c 92%

Br

N

46d 92%

42g 91%; dr: 86/14

[FeIIIPc]Cl (10 mol%) AgSbF6 (10 mol%)

R2

46b 92%

O

Scheme 20. Intramolecular allylic C–H amination via iron porphyrin catalysis

R1

Et OH O O S BnN NH

All the percentage of yield is with Co(P1), where P1 = 3,5-DitBu-Ibuphyrin

O O S O NH2

O O S NH

N

H

O

42e 91%; dr: 76/24

46a 97%

O O S BnN NH

BnN

O

O O S NH

BnN

CO2Et

42d 99%; dr: 85/15

O O S NH

BnN

O O S NH

BnN

Me

44c 66% Z : E = 17 : 1

O O S HN O

S

O O

48

R3

O O S O

O O O S H

O O S O

HN

HN

HN H

48a OTBDPS 71%

O O

48b 63%

O O HN S O

* 44d S configuration, 42%, Z : E = 5: 95 R configuration, 45%, Z : E = 97 :3

48c 86%

H

O O HN S O

O O S HN O

48d 50%

H

O

O TMS 48e 60%

Further, in 2014, Zhang and co-workers under metalloradical catalysis, reported a chemoselective intramolecular amination of propargylic aliphatic C–H bonds using CoII-porphyrin catalytic system with N-(bis)-homopropargylic sulfamoyl azide substrates 45 (Scheme 21).45 This metalloradical amination was suitable for both secondary and tertiary propargylic C–H substrates with high functional‐group tolerance, thus providing a straightforward

O 48f 64%

48g 64%

OMe

H

O O S N O H

H 48h 76%

In 2016, Zhang et al., reported metalloradical catalysis (MRC) in achieving bioactive five membered cyclic sulfamides by using CoII–porphyrin under redox neutral condition (Scheme 23).47 The complex [Co(P1)] was found to be a potent catalyst giving intramolecular chemoselective 1,5-C(sp3)–H aminated products 50 with high yield and stereospecificity, tolerating different functional groups in sulfamoyl azides 49. Additionally, it also allowed the late stage functionalization of complex molecules.

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ACS Catalysis

The amination reaction was proposed to go via radical mechanism through the formation of CoIII –aminyl radical intermediate. Scheme 23. Direct C(sp3)–H amination via metalloradical catalysis for five membered cyclic sulfamides R2 O O R2 R3 Co(P1) S R3 N R1 N3 N HN S C6H6, 4 Å MS, 40 oC, 20 h 49 R1 H 50 O O

Scheme 25. FeIII(TDCPP)(IMe)2 catalyzed C(sp3)–H amination R1

Bn N Bn HN S O O 50a 92%

Bn N

S NH O O 50c 50%

50b 62%

Ph

Bz N

O

3

51

H R2

N Bn HN S O O

O O S NH

N

where Por* = 2,6-DiMeO-QingPhyrin

+ N2

H R2

MTBE, 4 Å MS, rt, 48 h 52

Selected Examples O O S NH

BnN

Ph H

52a 93%; 90% ee

O O S EtN NH H 52d 92%; 92% ee

O O S NH

O O S NH

BnN

BnN

Cl

O H 52b 93%; 84% ee

i

O O S NH

PrN

R2

n-1 R 3 R4 N Boc 54

MeO2C

N Boc

54b Conv.:>99% Yield: 50%(80)

N Boc

N Boc

N Boc 54c Conv.:>99% Yield: 95%

54d Conv.:>99% Yield: 75%(88)

54e Conv.:>99% Yield: 90% (syn/anti 5:1)

Yield in parentheses is obtained under microwave condition

50g 95%

R1

Boc2O (1 equiv.), PhMe, reflux, 115 oC

54a Conv.:>99% Yield: 74%(90)

Scheme 24. Enantioselective C(sp3)–H amination under metalloradical catalysis

[Co(P4)] (2 mol%)

R1

Ph

Very recently Zhang et al., gave a highly enantioselective method to access biologically important cyclic sulfamides 52 through intramolecular C(sp3)–H amination of N-substituted sulfamoyl azides 51 under metalloradical catalysis using chiral D2 symmetry CoII-porphyrin. These sulfamides were readily extended to access synthetically valuable chiral 1, 3-diamines with original enantiopurity (Scheme 24).48

O O S R1 N H N

FeIII(TDCPP)(IMe)2(10 mol%)

N Boc

N

BzO

N3 R4

Selected Examples

Ph

50d 89%

BzO

98%

R3

S NH O O

O

S NH OO 50f

O

O Bn N

O

Bn N

50e 92%

n

n = 2, 3 53

OEt

NMe2

Bn N O S N O H

O O S NH Bn N

H R2

Selected Examples

Ph

95% yield).50 Reaction was amenable to several complex natural products like nornicotine, cis-octahydroindole and leelamine leading to their N-derivatives (Scheme 25). In a recent work, Che group further bettered the intramolecular amination of alkyl azides using [Fe(TF4DMAP)Cl] with just 3 mol% of catalyst loading, demonstrating the profound effect of ligand on MPC.33

H 52c 91%; 92% ee

O O S NH

BnN

C6H13

H

H

52e 89%; 93% ee

52f 88%; 89% ee

3.2 C(sp2)–H Bond Insertion Che and co-workers demonstrated the nitrene transfer ability of electron deficient iron porphyrin [FeIII(F20TPP)Cl] through intramolecular aryl C(sp2)–H bond amination using aryl azides 55 as nitrogen source leading to the formation of indole scaffold 56(Scheme 26).51 Reaction was proposed to proceed via of ironnitrene/imido intermediate, although no evidence for putative mechanistic pathway was reported. In the same report, intramolecular alkene C(sp2)–H amination was also demonstrated with same iron–porphyrin catalyst under reflux condition with tethered azides 57, giving good yields of corresponding indole derivatives 58 (Scheme 27). Recently, in 2018 Singh and co-workers reported a heme based catalytic system for intramolecular chemoselective C(sp2)–H bond amidation of aryl N-tosyloxycarbamates 59 in order to achieve benzoxazolones 60 (Scheme 28) through nitrene intermediate.52 Density functional Theory (DFT) study revealed that the reaction likely proceeds via Electrophilic Aromatic Substitution (EAS) pathway. This is the seminal example where an inexpensive and a biocompatible catalyst [FeIII(TPP)Cl] is used in chemoselective aromatic C–H amidation at ambient temperature. The mechanism proposed in this work is distinct from the earlier reported electrocyclic53 and stepwise HAA/RB54 mechanism proposed in azide based substrates. Scheme 26. [FeIII(F20TPP)Cl] catalyzed aromatic C(sp2)–H amination reaction O

55

Inspired by Betley’s report of FeII-dipyrrinato complex catalyzed N-heterocycle synthesis through intramolecular aliphatic C–H amination using azides as N-source,49 Che et al. synthesized an iron(III) porphyrin bearing axial N-heterocyclic carbene ligands [FeIII(TDCPP)(IMe)2] and demonstrated selective intramolecular amination (54) of benzylic, allylic, secondary, and primary C(sp3)–H bonds present in array of alkyl azides 53 under thermal and microwave-assisted conditions with very good yields (up to

[FeIII(F20TPP)Cl (2 mol%)

OMe

R H

N3

O

O N H

Cl 56b 85%

OMe

Cl

Cl O OMe

N 56 H

ClCH2CH2Cl, reflux

Selected Examples

N H 56a 93%

O R

OMe

N H 56c 88%

OMe

Scheme 27. [FeIII(F20TPP)Cl] catalyzed alkene C(sp2)–H amination reaction

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ACS Catalysis O

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

R 57

N3

O

[Fe(F20TPP)Cl (2 mol%)

OMe H

R

N 58 H

ClCH2CH2Cl, reflux

OMe

N H 58a 89%

O

OMe

F

O

O

58b 89%

N H

OMe

O

O

HN 59

OTs

OMe

R1

C(sp2)–H

O O S NH

N H 60

DCE, 25 C, 4 Å MS

62a TTN: 26

Selected Examples

O O

O O 3

R = OMe, 96% R = Me, 95% R = F, 81%

60b 92%

N H

60c 77%

60d 92% O

O H

H

H N

NH

O

N H

H

O

H

+ O

O 60e

1.2

NH

: 1 O

79%

R2 R3

62

O O S NH

O O S NH * H 62b TTN: 383(P411BM3-CIS-T438S) ee: 89%(P411BM3-T268A)

62c TTN: 36

O

O

O

O N H 60a

R

DMSO, Kpi (pH 8.0) R1 rt, 24 h

3 examples up to 89% ee up to 383 TTN

bond

O

R1

o

O O S NH

P411BM3 (0.1 mol%)

R1

61

O FeIII(TPP)Cl, K2CO3

R1

R1 O O S N3

58c 91%

Scheme 28. Chemoselective aromatic amination of aryl N-tosyloxycarbamates R1

O N H

perhaps the orientation of the substrate inside the active site of enzyme was responsible for the differential activity observed in bio-catalytic nitrenoid C–H insertion. Scheme 29. Arnold’s Cytochrome P411BM3 catalyzed C(sp3)–H amination

Selected Examples O

Page 10 of 15

Mechanistic pathway may involve the formation of FeIV- imido species followed by the productive nitrene insertion pathway to give the desired benzosultam or it may get reduced directly via unproductive pathways to give side product benzenesulfonamide. This side product could also be formed via hydrolysis of FeIVimido, forming high valent FeIV-oxo species followed by reduction generating back the catalytic ferrous (FeII)-heme (Figure 4).

60f FeIII CysS

O O

O

O 60g 82%

O

N H 60h 75%

N H

2e-, 2H+

N H

FeII

60i 79% R

4. BIO-CATALYTIC C-H AMINATION

H 2O

1e-

O

O O S NH

O O S N3

CysS R ArSO2NH2

O H

FeIV

2e-,2H+

Inspired by marvelous oxene transfer activity demonstrated by Cytochrome P450, a heme (FeIII-poprhyrin) containing enzyme on unactivated C–H bond of hydrocarbons, Breslow et al., demonstrated the nitrene transfer ability of microsomal Cytochrome P450, via both intramolecular C–H bond amination using [[(2,5-diisopropylphenyl)sulfonyl]imino] phenyliodinane as substrate to form 2,3-dihydro-3,3-dimethyl-6-isopropyl-l,2benzisothiazole 1,l-dioxide (2.2 TTN) as well as analogous intermolecular nitrene transfer on C–H bond in cyclohexane with less than 1 TTN of amidated product.55 However, it was not until 2013, i.e. almost four decades later, the 2018 Nobel Laureate Prof. Arnold’s group with engineered Cytochrome P411 (P411BM3-CIST438S) (axial cysteine ligand replaced with serine) (Scheme 29)56 and Prof. Fasan’s laboratory in 2014,57 with engineered Cytochrome P450BM3 (FL#68(T268A), independently demonstrated an efficient and practical bio-catalytic method for intramolecular C(sp3)–H amidation on aryl sulfonyl azides 61, furnishing benzosultams 62 with high turnover numbers (~400 TTN). Wherein Arnold’s work reported high enantioselectivity (up to 89% ee) on a prochiral substrate; Fasan’s work demonstrated similar enantioselectivity (up to 91% ee) on both racemic and prochiral substrate 64 (Scheme 30). Fasan’s report also demonstrated the effect of sterics as well as electronic effect on P450 catalyzed nitrene transfer activity. It was proposed that

CysS

Ar S O N O

N2 ArSO2NH2

IV

Fe CysS

H 2O

Figure 4. Proposed benzosultam formation

mechanism

for

P450BM3

catalyzed

Subsequently, Fasan et al., in another report demonstrated the nitrene transfer capability of engineered Myoglobin on arylsulfonyl azides 63 to synthesize benzosultams 64, although with lower activity (up to 200 TTN) and enantioselectivity (up to 60% ee) as compared to Cytochrome P450 (Scheme 30). In the same report they also showed that artificial Mb with Cobalt and Manganese protoporphyrin IX as cofactors (Co- & Mn-(por)) also serves a viable C–H amination catalysts showing distinct activities than their synthetic counterparts.58 Rate limiting C(sp3)–H phenomenon occurring in the mechanism was confirmed by positive kinetic isotope effect (KIE = 4.5). Directed evolution59 has revolutionized the bio-catalysis and has allowed generation of such engineered variants which could demonstrate efficient activity and complementary selectivity of C–H bonds in substrates. In 2014, Arnold and co-workers reported divergent regioselectivity with two different engineered variants of P450BM3

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ACS Catalysis

leading to the amination of benzylic- and homo benzylic-C(sp3)– H bonds giving 5- and 6-membered cyclic products 66 and 67, respectively from sulfonyl azide substrates 65 (Scheme 31).60 Fasan and co-workers further reported Cytochrome P450 catalysis in effective formation of oxazolidinone 69 by cyclization of carbonazidate substrates 68 (Scheme 32).61 Scheme 30. Fasan’s Cytochrome P450BM3 and Mb catalyzed C(sp3)–H amination R1

O O S NH

R2

Mb (0.2 mol%)

Kpi (pH7.0) R 5 rt, 18 h

R5

64 R3 R4 4 examples up to 60% ee up to 200 TTN

Scheme 32. Cytochrome P450BM3 catalyzed oxazolidinone formation

R1 O R1 O O O P450BM3 R2 S S (0.2 mol%) NH N3 H Kpi (pH 8.0) R5 R4 rt, 16 h R 64 3 R4 63 R3 9 examples up to 91% ee up to 388 TTN

R2

68

O O S NH 64b

64a

O O S NH

MeO2C

64d

MeO2C

TTN: ~30 (P450(FL#62)

69a 100 TON

36% ee : Mb(H64V) 66% ee: P450 #139-3 O O S NH

67

R1

O O S N3

R

Variant B 65

O O S NH 66a

Et

ee: 99%

n-Bu

O O S NH

Variant A

R1

66

O O S NH

O O n-Bu S NH : Et 67b ee: 99%

O

66b ee: 99%

Variant B TTN: 361; 97:3

TTN: 178; 90:10

Variant A TTN: 181; 30:70

TTN: 128; 30:97

69d ~3 TON

69c ~4 TON

P450(FL#62)

n-Pr

In this report, they also conducted experiments to underpin the mechanism prevalent in enzyme catalyzed C–H amination. Intramolecular kinetic isotopic effect (KIEintra = 4.7) and intermolecular kinetic isotopic effect (KIEinter = 2.7-5.3) along with observation of scrambling of Z-alkene carbonazidate probe to E-alkene oxazolidinone revealed that the C–H bond cleavage step is rate determining one and the reaction proceeds via nitrene insertion followed by hydrogen atom abstraction and radical recombination (HAA/RB) similar to the mechanism prevalent in mono-oxygenation of hydrocarbons carried out by Cytochrome P450. Lack of stereo/enantio induction in the chiral products obtained was attributed to putative long lived radical intermediate forming in the mechanistic pathway of this C–H amination process. In 2017, Hartwig and co-workers reported that P450 ’ s derived from a thermophilic organism containing an iridium

N3

68b O E-carbonazidate

O

KPi (pH 8.0) rt, 16 h

HN

O

69e E-oxazolidinone

P450(FL#62) KPi (pH 8.0) rt, 16 h

Scheme 33. Ir(Me)-PIX CYP119 catalyzed intramolecular C– H amination R1 O O S N3 CYP119 ((Ir(Me)-PIX) (0.33 mol%) H buffer (pH 6.0) 70

R2

O O n-Pr S NH : 67a ee: 99%

O

Ph

Selected Examples

n-Pr

H N

O

O

TTN: ~2 (P450(#139-3)

P411BM3 R R1

N3 O

68a Z-carbonazidate

Scheme 31. P450BM3 catalyzed divergent regioselectivity P411BM3

H N

O

69b 6 TON

O

64f

TTN: ~15 (P450(FL#62)

69

Mechanistic Experiment for HAA/RB

Ph

64e

R2

O HN

O

O

R1

KPi (pH 8.0) rt, 16 h

O

O

64c

TTN: 388 (P450(FL#62)) 60% ee: Mb(H64V,V68A) 91% ee: P450 #139-3 (T268A) TTN: 200 (Mb(H64V)) O O S NH

HN

O O S NH

MeO2C

HN

N3 P450(0.05 mol%)

O

R2

Selected Examples O

O O S NH *

O O S NH

O

R1

Selected Examples

R

porphyrin cofactor (Ir(Me)-PIX) could enantioselectively catalyze intramolecular C−H bond amination reactions of sulfonyl azides 70 to benzosultams 71 with yields reaching up to 98% (up to 300 TON) (Scheme 33).62 It was interesting to observe that Irprorphyrin itself is totally inert toward C–H amination. They also demonstrated that by judicious mutations in the amino acid sequence of enzyme, C–H amination activities as well as enantioselectivity could be fine tuned as well.

R3

R1 R2 R3

O O S NH

71

Selected Examples O O S NH 71a 201 TON er: 84:16

Et

Et

O O S NH 71b 192 TON er: 95: 5

O O S NH

Et 71c 129 TON er: 84:16

Scheme 34. P411CHA catalyzed intermolecular benzylic C–H

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

amination H

NHTs R2 Cytochrome P411CHA

R1 72

whole cells TsN3

R1

R2

73 up to 99% ee 1300 TON

Selected Examples NHTs

NHTs

NHTs

NHTs O

MeO 73a 86% yield 670 TON >99% e.e.

73b 80% yield 640 TON 96% e.e.

73c 81% yield 710 TON >99% e.e

73d 80% yield 730 TON

A significant contribution in the area of asymmetric intermolecular C–H amination potential of engineered cytochrome P411CHA was demonstrated by benzylic C–H to C-N bond formation with high enantioselectivity using Tosyl azide as nitrene source on various aromatic substrates 72 (Scheme 34).63 This heme containing biocatalyst was capable to produce valuable benzylic amines with turnover number (TON) up to 1300. 5. CONCLUSIONS AND OUTLOOK Metalloporphyrins either in synthetic or bio-catalytic form has created their niche as efficient catalytic system in the direct C–H bond amination via nitrene insertion. Of note is the fact that the transformation occurs via mechanistically different outer-sphere manifold as compared to most of other transition metal catalyzed non-porphyrin-based catalysts. Such MPC are efficient in effecting amination of both the aliphatic C(sp3)–H as well as the C(sp2)–H bonds, furnishing biologically relevant N-scaffolds with high functional group diversity. Since the seminal report of Breslow ’ s FeIII-porphyrin catalyzed nitrene C–H insertion, researchers have made a variety of changes in the porphyrin system to enhance the C–H amination efficiency of MPC i) by incorporating bulkier ligand substitution, inducing optimum steric effect which gives enough stabilization not to devoid of the planarity; hence better shape selectivity leading to regioselective C–H bond functionalization; ii) by tweaking the electronic properties of porphyrin ligand with electron withdrawing groups like Fluorine on TPP or the use of more electron withdrawing pthalocyanine ligand systems which probably increases the electrophilicity of metal-nitrene intermediates to facilitate the decomposition of relatively unreactive N-precursors. The axial ligands in metalloporphyrin catalysts have also been found to play a critical role in activating the reaction intermediates for C–H bond amination. Initial progress in MPC based C–H amination relied heavily on N-sulfonyl based nitrene precursors especially iminoiodinane (PhI=NTs) using Fe, Mn and Ru porphyrins perhaps owing to prevalence of sulfonyl amine moieties in biologically active molecules (vide supra), besides the virtue of relatively efficient decomposition of highly activated sulfonyl amine based nitrene precursors as compared to other Nprecursors. The reluctance of environmentally benign nitrene sources to undergo C–H bond insertion under non-oxidative and redox-neutral conditions like azides (R-N3) and difficulty

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encountered in aromatic C–H bond amination led to the development of different metal based porphyrin systems for eg Ru and Co-porphyrins. Although Che ’s group were able to catalyze inter/intramolecular C–H bond nitrene insertion from azide precursors using electron deficient Fe-porphyrins in an attempt to provide an environment benign method with earth abundant iron, Zhang et al ’ s contribution in development of Co-porphyrins for introduction of N-functionality with sulfonyl azides, sulfamoyl azides and bromamine-T via metalloradical pathway is noteworthy. At the same time White et al ’ s efforts toward aliphatic C–H amination has culminated in pthalocyanine complex based Fe- and Mn porphycene catalysts (porphyrin analogs), driven from economical and environment friendly point of view. Clearly, incorporation of various metals in porphyrins demonstrated that C–H amination activity as well as selectivity could be modulated. Bio-catalytic transformation with tailor-made variants has recently demonstrated unique and impressive chemo-, regio-, and stereoselectivity. This provides a unique opportunity to explore such bio-catalytic systems for development of environmentally benign C–H amination processes to generate biologically and industrially relevant molecules. Progress till date provides good insight of the catalytic nature of metalloporphyrins, which creates opportunity for researchers to use such catalytic systems for further developments in the area of aromatic C–H amination, a form with only handful of reports. Besides, it will be interesting to find out a bio-catalytic system which could transform aromatic C–H bonds to C‒N bond in order to increase the chemical tool box of metalloporphyrins in context of C–H amination reactions for which no such precedence is there. On a critical note, although metalloporphyrin based catalytic systems have found less usage in total synthesis of natural products or industrial applications, things have started to change and it will be just a matter of time that metalloporphyrin based catalytic system will be embraced in various applications in organic synthesis.

ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author [email protected]; [email protected] Notes The authors declare no competing financial interests.

ACKNOWLEDGMENTS This work was supported by the DST INSPIRE grant. RS thanks DST (Department of Science and Technology) for INSPIRE faculty award. A. M. thanks NIPER-R for doctoral fellowship. Director (Dr. S. J. S. Flora), NIPER-Raebareli is gratefully acknowledged for his constant motivation and providing necessary infrastructure. This is NIPER-R Communication/056.

REFERENCES 1. (a) Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem., Int. Ed. 2007, 46, 8748-8758. (b) Diethelm, S.; Carreira, E. M. Total Synthesis of (±)-Gelsemoxonine. J. Am. Chem. Soc. 2013, 135, 8500-8503. (c) Newcomb, E. T.; Knutson, P. C.; Pedersen, B. A.; Ferreira, E. M. Total Synthesis of Gelsenicine via a Catalyzed

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

ACS Catalysis

Cycloisomerization Strategy. J. Am. Chem. Soc. 2016, 138, 108-111. (d) Amino Group Chemistry: From Synthesis to the Life Sciences. 2008; p 408. (e) Hili, R.; Yudin, A. K. Making Carbon-Nitrogen Bonds in Biological and Chemical Synthesis. Nature Chemical Biology 2006, 2, 284-287. (f) Vidaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles Among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257-10274. (g) Feng, M.; Tang, B.; Liang., S. H.; Jianga, X. Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200–1216. 2. (a) Ribeiro, C. J. A.; Amaral, J. D.; Rodrigues, C. M. P.; Moreira, R.; Santos, M. M. M. Synthesis and Evaluation of Spiroisoxazoline Oxindoles as Anticancer Agents. Bioorg. Med. Chem. 2014, 22, 577-584. (b) Swensen, A. M.; Herrington, J.; Bugianesi, R. M.; Dai, G.; Haedo, R. J.; Ratliff, K. S.; Smith, M. M.; Warren, V. A.; Arneric, S. P.; Eduljee, C.; Parker, D.; Snutch, T. P.; Hoyt, S. B.; London, C.; Duffy, J. L.; Kaczorowski, G. J.; McManus, O. B. Characterization of the Substituted N-Triazole Oxindole TROX-1, a Small-Molecule, State-Dependent Inhibitor of Ca2+ Calcium Channels. Molecular Pharmacology 2012, 81, 488-497. (c) Abbadie, C.; McManus, O. B.; Sun, S.-Y.; Bugianesi, R. M.; Dai, G.; Haedo, R. J.; Herrington, J. B.; Kaczorowski, G. J.; Smith, M. M.; Swensen, A. M.; Warren, V. A.; Williams, B.; Arneric, S. P.; Eduljee, C.; Snutch, T. P.; Tringham, E. W.; Jochnowitz, N.; Liang, A.; Euan MacIntyre, D.; McGowan, E.; Mistry, S.; White, V. V.; Hoyt, S. B.; London, C.; Lyons, K. A.; Bunting, P. B.; Volksdorf, S.; Duffy, J. L. Analgesic Effects of a Substituted N-Triazole Oxindole (TROX-1), a State-Dependent, Voltage-Gated Calcium Channel 2 Blocker. J. Pharmacol. Exp. Ther. 2010, 334, 545-555. 3. Quaranta, L.; Corminboeuf, O.; Renaud, P. Chiral Relay Effect:  4Substituted 1,3Benzoxazol-2-(3H)-ones as Achiral Templates for Enantioselective Diels−Alder Reactions. Org. Lett. 2002, 4, 39-42. 4. (a) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017, 117, 9247-9301. (b) Müller, P.; Fruit, C. Enantioselective Catalytic Aziridinations and Asymmetric Nitrene Insertions into C–H Bonds. Chem. Rev. 2003, 103, 2905-2920. (c) Collet, F.; Dodd, R. H.; Dauban, P. Catalytic C–H Amination: Recent Progress and Future Directions. Chem. Commun. 2009, 14, 5061-5074. (d) Zalatan, D. N.; Du Bois, J. MetalCatalyzed Oxidations of C–H to C‒N Bonds. Top. Curr. Chem. 2010, 292, 347-378. (e) Roizen, J. L.; Harvey, M. E.; Du Bois, J. MetalCatalyzed Nitrogen-Atom Transfer Methods for the Oxidation of Aliphatic C–H Bonds. Acc. Chem. Res. 2012, 45, 911-922. (f) Uchida, T.; Katsuki, T. Asymmetric Nitrene Transfer Reactions: Sulfimidation, Aziridination and C–H Amination Using Azide Compounds as Nitrene Precursors. Chem. Rec. 2014, 14, 117-129. (g) Alderson, J. M.; Corbin, J. R.; Schomaker, J. M. Tunable, Chemo- and Site-Selective Nitrene Transfer Reactions through the Rational Design of Silver(I) Catalysts. Acc. Chem. Res. 2017, 50, 2147-2158. (h) Darses, B.; Rodrigues, R.; Neuville, L.; Mazurais, M.; Dauban, P. Transition Metal-Catalyzed Iodine(III)-Mediated Nitrene Transfer Reactions: Efficient Tools for Challenging Syntheses. Chem. Commun. 2017, 53, 493-508. (i) Hazelard, D.; Nocquet, P.-A.; Compain, P. Catalytic C–H Amination at its Limits: Challenges and Solutions. Org. Chem. Front. 2017, 4, 2500-2521. 5. Groves, J. T.; Nemo, T. E.; Myers, R. S. Hydroxylation and Epoxidation Catalyzed by Iron-Porphine Complexes. Oxygen Transfer from Iodosylbenzene. J. Am. Chem. Soc. 1979, 101, 1032-1033. 6. (a) Dick, A. R.; Sanford, M. S. Transition Metal Catalyzed Oxidative Functionalization of Carbon–Hydrogen Bonds. Tetrahedron 2006, 62, 2439-2463. (b) Lebel, H.; Huard, K.; Lectard, S. N-Tosyloxycarbamates as a Source of Metal Nitrenes:  Rhodium-Catalyzed C−H Insertion and Aziridination Reactions. J. Am. Chem. Soc. 2005, 127, 14198-14199. 7. (a) Lu, H.; Zhang, X. P. Catalytic C–H Functionalization by Metalloporphyrins: Recent Developments and Future Directions. Chem. Soc. Rev. 2011, 40, 1899-1909. (b) Che, C.-M.; Huang, J.-S. Metalloporphyrin-Based Oxidation Systems: From Biomimetic Reactions to Application in Organic Synthesis. Chem. Commun. 2009, 21, 39964015. (c) Che, C.-M.; Lo, V. K.-Y.; Zhou, C.-Y.; Huang, J.-S. Selective

Functionalisation of Saturated C–H Bonds with Metalloporphyrin Catalysts. Chem. Soc. Rev. 2011, 40, 1950-1975. 8. Groves, J. T.; Kruper, W. J.; Haushalter, R. C. Hydrocarbon Oxidations with Oxometalloporphinates. Isolation and Reactions of a (Porphinato)manganese(V) Complex. J. Am. Chem. Soc. 1980, 102, 63756377. 9. Breslow, R.; Gellman, S. H. Tosylamidation of Cyclohexane by a Cytochrome P-450 Model. J. Chem. Soc., Chem. Comm. 1982, 1400-1401. 10. Yorinobu, Y.; Tamotsu, Y.; Makoto, O. Synthesis and Reaction of New type I–N ylide, n-Tosyliminoiodinane. Chem. Lett. 1975, 4, 361-362. 11. Mahy, J. P.; Bedi, G.; Battioni, P.; Mansuy, D. Allylic Amination of Alkenes by Tosyliminoiodobenzene: Manganese Porphyrins as Suitable Catalysts. Tetrahedron Lett. 1988, 29, 1927-1930. 12. Au, S.-M.; Huang, J.-S.; Yu, W.-Y.; Fung, W.-H.; Che, C.-M. Aziridination of Alkenes and Amidation of Alkanes by Bis(tosylimido)Ruthenium(VI) Porphyrins. A Mechanistic Study. J. Am. Chem. Soc. 1999, 121, 9120-9132. 13. Zhou, X.-G.; Yu, X.-Q.; Huang, J.-S.; Che, C.-M. Asymmetric Amidation of Saturated C–H Bonds Catalysed by Chiral Ruthenium and Manganese porphyrins. Chem. Commun. 1999, 2377-2378. 14. Cenini, S.; Tollari, S.; Penoni, A.; Cereda, C. Catalytic Amination of Unsaturated Hydrocarbons: Reactions of p-Nitrophenylazide with Alkenes Catalysed by Metallo-Porphyrins. Journal of Molecular Catalysis A: Chemical 1999, 137, 135-146. 15. Yang, J.; Weinberg, R.; Breslow, R. The Hydroxylation and Amidation of Equilenin Acetate Catalyzed by Chloro[5,10,15,20Tetrakis(pentafluorophenyl)Porphyrinato]Manganese(III). Chem. Commun. 2000, 531-532. 16. Yu, X.-Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Amidation of Saturated C−H Bonds Catalyzed by Electron-Deficient Ruthenium and Manganese Porphyrins. A Highly Catalytic Nitrogen Atom Transfer Process. Org. Lett. 2000, 2, 2233-2236. 17. Cenini, S.; Gallo, E.; Penoni, A.; Ragaini, F.; Tollari, S. Amination of Benzylic C–H Bonds by Aryl Azides Catalysed by Co(Porphyrin) Complexes. A New Reaction Leading to Secondary Amines and Imines. Chem. Commun. 2000, 22, 2265-2266. 18. Liang, J.-L.; Huang, J.-S.; Yu, X.-Q.; Zhu, N.; Che, C.-M. Metalloporphyrin-Mediated Asymmetric Nitrogen-Atom Transfer to Hydrocarbons: Aziridination of Alkenes and Amidation of Saturated C−H Bonds Catalyzed by Chiral Ruthenium and Manganese Porphyrins. Chem. – Eur. J. 2002, 8, 1563-1572. 19. Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-M. Highly Diastereo- and Enantioselective Intramolecular Amidation of Saturated C– H Bonds Catalyzed by Ruthenium Porphyrins. Angew. Chem., Int. Ed. 2002, 41, 3465-3468. 20. Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Che, C.-M. Intramolecular C−N Bond Formation Reactions Catalyzed by Ruthenium Porphyrins:  Amidation of Sulfamate Esters and Aziridination of Unsaturated Sulfonamides. J. Org. Chem. 2004, 69, 3610-3619. 21. Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.; Gotti, C.- L.; Lapadula, M.; Mangioni, E.; Cenini, S. Amination of Benzylic C–H Bonds by Arylazides Catalyzed by CoII–Porphyrin Complexes: A Synthetic and Mechanistic Study. Chem. –Eur. J. 2002, 9, 249-259. 22. Leung, S. K.-Y.; Huang, J.-S.; Liang, J.-L.; Che, C.-M.; Zhou, Z.-Y. Nitrido Ruthenium Porphyrins: Synthesis, Characterization, and Amination Reactions with Hydrocarbon or Silyl Enol Ethers. Angew. Chem., Int. Ed. 2003, 42, 340-343.

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

23. Fantauzzi, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Casati, N.; Macchi, P.; Cenini, S. The key Intermediate in the Amination of Saturated C–H Bonds: Synthesis, X-ray Characterization and Catalytic Activity of Ru(TPP)(NAr)2 (Ar = 3,5-(CF3)2C6H3). Chem. Commun. 2009, 39523954. 24. Harden, J. D.; Ruppel, J. V.; Gao, G.-Y.; Zhang, X. P. CobaltCatalyzed Intermolecular C–H Amination with Bromamine-T as Nitrene Source. Chem. Commun. 2007, 4644-4646. 25. Lu, H.; Subbarayan, V.; Tao, J.; Zhang, X. P. Cobalt(II)-Catalyzed Intermolecular Benzylic C−H Amination with 2,2,2Trichloroethoxycarbonyl Azide (TrocN3). Organometallics 2010, 29, 389393. 26. Lu, H.; Tao, J.; Jones, J. E.; Wojtas, L.; Zhang, X. P. Cobalt(II)Catalyzed Intramolecular C−H Amination with Phosphoryl Azides: Formation of 6- and 7-Membered Cyclophosphoramidates. Org. Lett. 2010, 12, 1248-1251. 27. Liu, Y.; Che, C.-M. [FeIII(F20-tpp)Cl] is an Effective Catalyst for Nitrene Transfer Reactions and Amination of Saturated Hydrocarbons with Sulfonyl and Aryl Azides as Nitrogen Source under Thermal and Microwave-Assisted Conditions. Chem.–Eur. J. 2010, 16, 10494-10501. 28. Lyaskovskyy, V.; Suarez, A. I. O.; Lu, H.; Jiang, H.; Zhang, X. P.; de Bruin, B. Mechanism of Cobalt(II) Porphyrin-Catalyzed C–H Amination with Organic Azides: Radical Nature and H-Atom Abstraction Ability of the Key Cobalt(III)–Nitrene Intermediates. J. Am. Chem. Soc. 2011, 133, 12264-12273.

Page 14 of 15

39. Zhang, J.-L.; Huang, J.-S.; Che, C.-M. Oxidation Chemistry of Poly(ethylene glycol)-Supported Carbonylruthenium(II) and Dioxoruthenium(VI) meso-Tetrakis(pentafluorophenyl)Porphyrin. Chem. –Eur. J. 2006, 12, 3020-3031. 40. Ruppel, J. V.; Kamble, R. M.; Zhang, X. P. Cobalt-Catalyzed Intramolecular C−H Amination with Arylsulfonyl Azides. Org. Lett. 2007, 9, 4889-4892. 41. Lin, X.; Che, C.-M. Phillips, D. L. Reaction Mechanism and Stereoselectivity of Ruthenium−Porphyrin-Catalyzed Intramolecular Amidation of Sulfamate Ester:  A DFT Computational Study. J. Org. Chem. 2008, 73, 529-537. 42. Lu, H.; Jiang, H.; Wojtas, L.; Zhang, X. P. Selective Intramolecular C–H Amination through the Metalloradical Activation of Azides: Synthesis of 1,3-Diamines under Neutral and Nonoxidative Conditions. Angew. Chem., Int. Ed. 2010, 49, 10192-10196. 43. Lu, H.; Hu, Y.; Jiang, H.; Wojtas, L.; Zhang, X. P. Stereoselective Radical Amination of Electron-Deficient C(sp3)–H Bonds by Co(II)-Based Metalloradical Catalysis: Direct Synthesis of α-Amino Acid Derivatives via α-C–H Amination. Org. Lett. 2012, 14, 5158-5161. 44. Paradine, S. M.; White, M. C. Iron-Catalyzed Intramolecular Allylic C–H Amination. J. Am. Chem. Soc. 2012, 134, 2036-2039. 45. Lu, H.; Li, C.; Jiang, H.; Lizardi, C. L.; Zhang, X. P. Chemoselective Amination of Propargylic C(sp3)–H Bonds by Cobalt(II)-Based Metalloradical Catalysis. Angew. Chem., Int. Ed. 2014, 53, 7028-7032.

29. Intrieri, D.; Caselli, A.; Ragaini, F.; Macchi, P.; Casati, N.; Gallo, E. Insights into the Mechanism of the Ruthenium–Porphyrin-Catalysed Allylic Amination of Olefins by Aryl Azides. Eur. J. Inorg. Chem. 2012, 2012, 569-580.

46. Paradine, S. M.; Griffin, J. R.; Zhao, J.; Petronico, A. L.; Miller, S. M.; Christina White, M. A Manganese Catalyst for Highly Reactive yet Chemoselective Intramolecular C(sp3)–H Amination. Nature Chemistry 2015, 7, 987-994.

30. Chan, K.-H.; Guan, X.; Lo, V. K.-Y.; Che, C.-M., Elevated Catalytic Activity of Ruthenium(II)–Porphyrin-Catalyzed Carbene/Nitrene Transfer and Insertion Reactions with N-Heterocyclic Carbene Ligands. Angew. Chem., Int. Ed. 2014, 53, 2982-2987.

47. Lu, H.; Lang, K.; Jiang, H.; Wojtas, L.; Zhang, X. P. Intramolecular 1,5-C(sp3)–H Radical Amination via Co(II)-Based Metalloradical Catalysis for Five-Membered Cyclic Sulfamides. Chemical Science 2016, 7, 6934-6939.

31. King, E. R.; Hennessy, E. T.; Betley, T. A. Catalytic C−H Bond Amination from High-Spin Iron Imido Complexes. J. Am. Chem. Soc. 2011, 133, 4917-4923.

48. Li, C.; Lang, K.; Lu, H.; Hu, Y.; Cui, X.; Wojtas, L.; Zhang, X. P. Catalytic Radical Process for Enantioselective Amination of C(sp3)–H Bonds. Angew. Chem., Int. Ed. 2018, 57, 16837–16841.

32. Huang, X.; Bergsten, T. M.; Groves, J. T. Manganese-Catalyzed LateStage Aliphatic C–H Azidation. J. Am. Chem. Soc. 2015, 137, 5300-5303.

49. Hennessy, E. T.; Betley, T. A. Complex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C–H Bond Amination. Science 2013, 340, 591-595.

33. Clark, J. R.; Feng, K.; Sookezian, A.; White, M. C. ManganeseCatalysed Benzylic C(sp3)–H Amination for Late-Stage Functionalization. Nature Chemistry 2018, 10, 583-591.

50. Shing, K.-P.; Liu, Y.; Cao, B.; Chang, X.-Y.; You, T.; Che, C.-M. NHeterocyclic Carbene Iron(III) Porphyrin-Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides. Angew. Chem., Int. Ed. 2018, 57 (37), 11947-11951.

34. Du, Y.-D.; Xu, Z.-J.; Zhou, C.-Y.; Che, C.-M. An Effective [FeIII(TF4DMAP)Cl] Catalyst for C–H Bond Amination with Aryl and Alkyl Azides. Org. Lett. 2019, DOI:10.1021/acs.orglett.8b03765. 35. He, L.; Chan, P. W. H.; Tsui, W.-M.; Yu, W.-Y.; Che, C.-M. Ruthenium(II) Porphyrin-Catalyzed Amidation of Aromatic Heterocycles. Org. Lett. 2004, 6, 2405-2408. 36. Wei, J.; Xiao, W.; Zhou, C.-Y.; Che, C.-M. Ruthenium Porphyrin Catalyzed Diimination of Indoles with Aryl Azides as the Nitrene Source. Chem. Commun. 2014, 50, 3373-3376. 37. Breslow, R.; Gellman, S. H. Intramolecular Nitrene Carbon-Hydrogen Insertions Mediated by Transition-Metal Complexes as Nitrogen Analogs of Cytochrome P-450 Reactions. J. Am. Chem. Soc. 1983, 105, 67286729. 38. Groves, J. T.; Takahashi, T. Activation and Transfer of Nitrogen from a Nitridomanganese(V) porphyrin Complex. Aza Analog of Epoxidation. J. Am. Chem. Soc. 1983, 105, 2073-2074.

51. Liu, Y.; Wei, J.; Che, C.-M. [Fe(F20TPP)Cl] Catalyzed Intramolecular C–N Bond Formation for Alkaloid Synthesis using Aryl Azides as Nitrogen Source. Chem. Commun. 2010, 46, 6926-6928. 52. Prasanthi, A. V. G.; Begum, S.; Srivastava, H. K.; Tiwari, S. K.; Singh, R. Iron-Catalyzed Arene C–H Amidation Using Functionalized Hydroxyl Amines at Room Temperature. ACS Catal. 2018, 8, 8369-8375. 53. Zhang, Q.; Wu, C.; Zhou, L.; Li, J. Theoretical Studies on Intramolecular C–H Amination of Biaryl Azides Catalyzed by Four Different Late Transition Metals. Organometallics 2013, 32, 415-426. 54. Li, J.; Wu, C.; Zhang, Q.; Yan, B. Theoretical Studies of Iron(III)Catalyzed Intramolecular C–H Amination of Azides. Dalton Trans. 2013, 42, 14369-14373. 55. Svastits, E. W.; Dawson, J. H.; Breslow, R.; Gellman, S. H. Functionalized Nitrogen Atom Transfer Catalyzed by Cytochrome P-450. J. Am. Chem. Soc. 1985, 107, 6427-6428.

ACS Paragon Plus Environment

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

ACS Catalysis 61. Singh, R.; Kolev, J. N.; Sutera, P. A.; Fasan, R. Enzymatic C(sp3)–H Amination: P450-Catalyzed Conversion of Carbonazidates into Oxazolidinones. ACS Catal. 2015, 5, 1685-1691.

56. McIntosh, J. A.; Coelho, P. S.; Farwell, C. C.; Wang, Z. J.; Lewis, J. C.; Brown, T. R.; Arnold, F. H., Enantioselective Intramolecular C–H Amination Catalyzed by Engineered Cytochrome P450 Enzymes In Vitro and In Vivo. Angew. Chem., Int. Ed. 2013, 52, 9309-9312. 57. Singh, R.; Bordeaux, M.; Fasan, R. P450-Catalyzed Intramolecular sp3 C–H Amination with Arylsulfonyl Azide Substrates. ACS Catal. 2014, 4, 546-552.

62. Dydio, P.; Key, H. M.; Hayashi, H.; Clark, D. S.; Hartwig, J. F. Chemoselective, Enzymatic C–H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor. J. Am. Chem. Soc. 2017, 139, 1750-1753.

58. Bordeaux, M.; Singh, R.; Fasan, R. Intramolecular C(sp3)–H Amination of Arylsulfonyl Azides with Engineered and Artificial Myoglobin-based Catalysts. Bioorg. Med. Chem. 2014, 22, 5697-5704.

63. Prier, C. K.; Zhang, R. K.; Buller, A. R.; Brinkmann-Chen, S.; Arnold, F. H. Enantioselective, Intermolecular Benzylic C–H Amination Catalysed by an Engineered Iron-haem Enzyme. Nature Chemistry 2017, 9, 629-634.

59. Otten, L. G.; Quax, W. J. Directed evolution: Selecting Today's Biocatalysts. Biomolecular Engineering 2005, 22, 1-9. 60. Hyster, T. K.; Farwell, C. C.; Buller, A. R.; McIntosh, J. A.; Arnold, F. H. Enzyme-Controlled Nitrogen-Atom Transfer Enables Regiodivergent C–H Amination. J. Am. Chem. Soc. 2014, 136, 15505-15508.

Insert Table of Contents artwork here R

R1 R2 H R3 Substrate

NX R

M

R

R1 X R2 N R3 H N-scaffolds

R Metal-nitrenoid

KEYWORDS: C–H amination, metalloporphyrin, nitrene insertion, metalloradical catalysis, N-scaffolds

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