Complex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C-H Bond

AminationElisabeth T. Hennessy & Theodore A.

Betley*Science 2013, 340, 591

Also featured in Driver, T. Nat. Chem. 2013, 5, 736

Literature Meeting 11/13/2013Daniela Sustac

Hoffmann-Löffler-Freytag Reaction

NBr

i. H2SO4, 140 C

ii. -OH N

N XR1

R2

H+

N XR1

R2

H

- X

NR1

R2

HH

1,5-H atom

abstraction N HR1

R2

HN H

R1

R2

HX

Initiation: heat, hvradical initiator

Propagation

N XR1

R2

Termination/Work-up

N HR1

R2

HX

B-

N HR1

R2

X

- X-

NR1

H

R2- H+

NR1

R2

NR1

R2

HH

a. Hoffmann, A.W. Berichte 1885, 18, 109. b. Wolff, M.W. Chem. Rev. 1963, 63, 55.

Intramolecular C(sp3)-H Amination Strategies

Perspective: Leffrey, J.L.; Sarpong, R. Chem. Sci. 2013, 4, 4092.

Nitrene Examples: Aliphatic C-H Amination

Ph

OS

H2N

OO Fe-por (10 mol %)AgSbF6 (10 mol %)

PhI(OPiv)2 (2 equiv)PhMe/MeCN, rt

Ph

OS

HN

OO

70%

White JACS 2012, 134, 2036

NS

N3

O O [Co(Por)] (2 mol %)

PhCF3, molec sieves, 40 C, 20 hN NH

SO O

95%Zhang ACIE, 2010, 49, 10192

• White: Iron porphyrin –based catalyst , allylic position favouredWhite: Iron porphyrin –based catalyst , allylic position favoured

• Zhang: Cobalt porphyrin catalystZhang: Cobalt porphyrin catalyst

ONH

O OTs Rh2(TPA)4 (6 mol %)

K2CO3, DCM, rtO

HN O

84%Lebel JACS 2005, 127, 14198

• Lebel: avoids the use of an oxidant Lebel: avoids the use of an oxidant (TPA = triphenylacetate)

Nitrenes from Azides

O

O

N3 FeCl2 (10 mol %)TMSCl (1.5 equiv)

EtOH, 0 C to rt

ONH

O

Cl

72% dr 9:1

Bach Chem. Commun. 2000, 287Bach Chem. - Eur. J. 2001, 7, 2581

HN3

Rh2(esp)2 (5 mol %)

Boc2O, PhMe, 120 C NBoc

84%Driver JACS 2012, 134, 7262

• Bach: AminochlorinationBach: Aminochlorination

• Driver: Rhodium catalysis, azidesDriver: Rhodium catalysis, azides

N3

[Cu] (2.5 mol %)

NHAd

80%

110 C

ACIE 2008, 47, 9961

N N

tButBu

Cu

PhH

Cl

Cl

Cl

Cl

[Cu]

• Cundari&Warren: copper nitrene Cundari&Warren: copper nitrene complexcomplex

Review of N-atom transfer from azides: Driver, T. Org. Biomol. Chem. 2010, 8, 3809

Aliphatic C-H Amination

HHN

N

OAcO

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

AcOH, PhMe, 110 CN

AcO

ON

Chen JACS, 134, 134, 3

• Chen: Picolinamide directing group, Pd (II)-Pd(IV) cat. cycle, oxidantChen: Picolinamide directing group, Pd (II)-Pd(IV) cat. cycle, oxidant

O O

NH

Cl PhI(OPiv)2 (3 equiv)CH3CH2CO2H (15 equiv)

MeNO2, 110 CCl

N O

O

Zhang JOC, 2013, 78, 733

• Li&Zhang: via dianion formationLi&Zhang: via dianion formation

“How To” Design Your Own Amination Reaction

• C-H Amination as an C-H Amination as an Inverse Correlation Inverse Correlation of C-H bond strengthof C-H bond strength

• N-Atom sourceN-Atom sourceN-Atom Sources RS

NH2

O O

RO NH2

O

RO NH

O

OTs

+ oxidant eg PhI(OAc)2

AzidesRO

PN3

O OR

RO N3

O

RS

N3

O O

- no need of oxidant- by-product: N2

Ar N3

• Catalyst: Rh, Fe, Co etc. (nitrene formation), Pd (directing group)Catalyst: Rh, Fe, Co etc. (nitrene formation), Pd (directing group)• Other requirements: ligand (porphyrin type), oxidant (hypervalent iodine)Other requirements: ligand (porphyrin type), oxidant (hypervalent iodine)

HH

O

H

H

H

C-H bond strength

C-H Amination

Ted Betley

• 1999 – B.S.E. Chemical Engineering at University of Michigan1999 – B.S.E. Chemical Engineering at University of Michigan

• 2000-2005 – PhD at Caltech (Prof. Jonas Peters)2000-2005 – PhD at Caltech (Prof. Jonas Peters) - Coordination chemistry at trigonally coordinated iron platforms: - Coordination chemistry at trigonally coordinated iron platforms:

chemistry related to dinitrogen reductionchemistry related to dinitrogen reduction

• 2005-2007 – NIH Postdoctoral fellow at MIT (Prof. Daniel Nocera)2005-2007 – NIH Postdoctoral fellow at MIT (Prof. Daniel Nocera)

• 2007-2011 – Harvard, Assistant Professor2007-2011 – Harvard, Assistant Professor• 2011-now – Harvard, Associate Professor2011-now – Harvard, Associate Professor• Research interests:Research interests:

- - Polynuclear complexes for cooperative redox chemistryPolynuclear complexes for cooperative redox chemistry - - Iron-mediated, catalytic C-H bond functionalizationIron-mediated, catalytic C-H bond functionalization

Inspiration: Cytochrome P450

• Synthesis of Fe imido complexes as surrogates of Fe oxo complexes to achieve Synthesis of Fe imido complexes as surrogates of Fe oxo complexes to achieve effective nitrene transfereffective nitrene transfer

N

N N

N

Fe

O

Heme IronHeme IronIVIV-oxo-oxo

Proposed Catalytic Cycle of Cytochrome P450Proposed Catalytic Cycle of Cytochrome P450

Oxidation mechanism of cytochrome P450: Chem. Rev. 2004, 104, 3947.

Initial communication & article (Initial communication & article (Inorg. Chem. Inorg. Chem. 2009, 2009, 4848, 2361; , 2361; JACSJACS 2011, 2011, 133133, 4917), 4917)•Iron dipyrromethene complexes as heme surrogatesIron dipyrromethene complexes as heme surrogates•Application: intermolecular aziridination and aminationApplication: intermolecular aziridination and amination

• High-spin FeHigh-spin FeIII III antiferromagnetically antiferromagnetically coupled to an imido radicalcoupled to an imido radical

Proposed Mechanism• Key features: high spin Fe(III) (S = 2) featuring an imido radical putative Key features: high spin Fe(III) (S = 2) featuring an imido radical putative

group transfer reagentgroup transfer reagent• KIE studies: C-H bond-breaking rate-limiting (12 for pre-catalyst)KIE studies: C-H bond-breaking rate-limiting (12 for pre-catalyst)

Betley JACS 2011, 133, 4917

ChallengesChallenges•Saturated hydrocarbons chemically inert due to large C-H bond dissociation Saturated hydrocarbons chemically inert due to large C-H bond dissociation energies (93 to 105 kcal/mol), C-H bond non polarizedenergies (93 to 105 kcal/mol), C-H bond non polarized•Aliphatic C-H bond harder to preferentially react in presence of other Aliphatic C-H bond harder to preferentially react in presence of other functionalitiesfunctionalities•Avoid the synthetic requirement for an EWG on N or an oxidantAvoid the synthetic requirement for an EWG on N or an oxidant

SolutionSolution•Non-heme iron complex, sterically hindered, high spin ground state, akin Non-heme iron complex, sterically hindered, high spin ground state, akin to iron-oxoto iron-oxo•Extension of their previous Fe complex to linear, aliphatic azides to Extension of their previous Fe complex to linear, aliphatic azides to synthesize complex N-heterocycles in one stepsynthesize complex N-heterocycles in one step

Synthesis of Iron Complexes

NH

CO2Et

1. Ad-Cl, AlCl3 (67%)

2. NaOH, glycol, 200 C 88%

NH

Ad

1. MesCH(OMe)2, 5% PPTS (97%)

2. DDQ (50%) NH N

Ad Ad

Mes1/2

or

1. 10% PPTS

2. DDQ (71%)

Cl

Cl

O88%

NH N

Ad Ad

1/2Cl Cl

NH N

Ad Ad

ArPhLi

thawing PhH N N

Ad Ad

Ar

Li

FeCl2, Et2O

Ar

N NFe

OEt2ClAd Ad

Ar = Mes (53%)

Ar = 2,6-diClPh (26%)

Proof of Concept: Stoichiometric Reaction

Ar

N NFe

LClAd Ad

PhN3

PhH, RT- N2

Ar

N NFe

ClAd Ad

NPh

H

Ad =

H H

Other azides

N3

Ar

N NFe

ClAd Ad

NH

HN3

Ar

N NFe

ClAd Ad

NH

Ar

N NFe

ClAd Ad

NEt

H

Ar

N NFe

ClAd Ad

NH

EtN3

H H

N3

H H

H

N3

Fe complexNH2 NH

Limitation

Towards a Catalytic Version• No catalyst turnover due to product inhibition: formation of a tight Lewis No catalyst turnover due to product inhibition: formation of a tight Lewis

acid/base pairacid/base pair

• Solution: perform cyclization in presence of a Nitrogen protecting groupSolution: perform cyclization in presence of a Nitrogen protecting group

N

O

O O

Fmoc

O

O

Fmoc

O O O

O O

tBu tBu

Boc2OFmoc-OSuc

N

OH

O O

catalyst inhibition!

tBuOH, CO2

No inhibition!

Catalytic ScopeR1 N3

R3

R4

R6

R2H

R5 Complex 2 (10 or 20 mol %)Boc2O (1 equiv)

PhH, 60 C, 12 h

BocNR1 R5

R2 R6

R3 R4

N N

Ad Ad

Cl Cl

FeCl L

Complex 2

Azide Pyrrolidine

PhN3

HH

BocNPh 57%

Yield

N3HH

BocN

72%

HN3

MeMe

BocN 49%

EtN3

HH

BocNEt 19%

HN3

HH

BocN 17%

linear by-products

unreacted azide

benzylic

allylic

3

2

1

EtO2CN3

HH

BocNEtO2C 11%

Azide Pyrrolidine Yield

Ph ON3

HH

BocN

O

Ph 47%

N3HH OTMS

BocN

OTMS

68%

N3HH

Ph BocN Ph

60%(dr 3.9:1)

N3HH Ph

BocN

Ph

66%(dr 1.5:1)

Catalytic Scope - Continued

Azide Pyrrolidine Yield

MeN3

MeH Ph

BocN

Ph

98%

PhN3

MeH

BocNPh 75%

93% ee

N3HH

Me BocN Me

84% (dr 1.1:1)

N3HBocN 67%

95% ee

Azide Pyrrolidine Yield

N3HH Me

Me BocN Me

Me

73%(dr 2.1:1)

N3HH Me

MeEt BocN Me

MeEt

58%(dr 5.5:1.5:1:0.08)

N3

MeMe BocN 14%

78% (Fmoc, stoich.)Me

MeMe

R1 N3

R3

R4

R6

R2H

R5 Complex 2 (10 or 20 mol %)Boc2O (1 equiv)

PhH, 60 C, 12 h

BocNR1 R5

R2 R6

R3 R4

N N

Ad Ad

Cl Cl

FeCl L

Complex 2

Varying Ring Size

Azide Product Yield

N3

H HBocN

45%

BocN 82%

Ph N3

BocNPh

BocNBn

52%

1 : 0.9

N3

3

2

BocN Boc

NiPr

1 : 1.5

47%

N3

BocN Boc

NtBu

47%

1 : 1.5

N3

R1 N3

R4

R2H

R3 Complex 2 (1 equiv)Boc2O (1 equiv)

PhH, RT, 12 h N N

Ad Ad

Cl Cl

FeCl L

Complex 2

n

BocN

R4

R3R2

R1

n

Proposed Mechanisms

Mechanistic Studies

• Retention of stereochemical information: spatial constraints imposed Retention of stereochemical information: spatial constraints imposed by bulky adamantyl ligand to inhibit racemization of intermediate by bulky adamantyl ligand to inhibit racemization of intermediate carboradicalcarboradicalPh

N3MeH

BocNPh 75%

93% ee

95% ee

• Intramolecular KIE StudyIntramolecular KIE Study

DN3

H Ph

Complex 2 (20 mol %)Boc2O (1 equiv)

PhH, temp, 12 h

BocNPh

H/D

(+/-)

kH/kD = 5.3 (rt) 5.1 (60 C)

• Radical Clock ExperimentRadical Clock ExperimentN3

PhHH

Complex 2 (20 mol %)Boc2O (1 equiv)

PhH, 65 C, 12 h

BocN

Ph

73%

Mechanism?• Stepwise mechanism for benzylic Stepwise mechanism for benzylic

substrates;substrates;• If a stepwise mechanism is If a stepwise mechanism is

operative, then the radical operative, then the radical intermediate following H-intermediate following H-abstraction must be short-lived;abstraction must be short-lived;

• Direct C-H insertion when stronger Direct C-H insertion when stronger C-H bonds are functionalizedC-H bonds are functionalized

HH

O

H

H

H

C-H bond strength

[Fe]

[Fe]N

RH

H

[Fe]

N

RH

HN

[Fe]N

RH

[Fe] H

R

concerted

stepwise

RN3

H H

BocN R

fast if benzyl, allyl, tertiary

H

Conclusion

• Have demonstrated the utility of Fe imido high-spin radical for the intramolecular functionalization of activated and unactivated aliphatic C-H bonds;

• Nitrene formation from azide (N2 only by-product);

• Synthesis of complex N-heterocycles from readily available starting materials;

• These products cannot be easily obtained by HLF or photolysis (usually require EWG, oxidant);