Recent Developments in Rhodium Carbene and Nitrene Chemistry

Home , Carbene, Diazo, Nitrene

R1 C H N2 1 LnM R H R2 N2 C R1 R2 2 Metal carbenoid R C-H functionalization

LnM LnM

"Traditional' C-H activation H C X C H H X C MLn

MacMillan Group Meeting

February 3, 2010

Brian Ngo Laforteza Rhodium Carbene and Nitrene Chemistry Catalysts

■ Rhodium(II) acetate – prototypical structure of dirhodium carbene/nitrene catalysts

O O Me

O O

Rh Rh

O O Me O O open coordination site

Rh2(OAc)4 . “Paddle wheel” catalyst

■ Only one rhodium center functions as carbene binding site . Second acts as electron sink to increase electrophilicity of carbene moiety – additional stabilization

R N2 . Catalyst binds carbene through strong σ-acceptor R R M M interactions and weak π-back-donation R

N2 Rhodium Carbene and Nitrene Chemistry Catalysts

■ Two widely utilized classes of catalysts

R . Symmetry may vary depending X Y R on orientation of ligand binding X Y

Rh Rh

Y X R Y X

Rhodium(II) carboxylates R Rhodium(II) carboxamidates

O Rh O Rh X N Rh N O Rh SO2Ar R 4 4 X = O, NCOR

. Very active at decomposing diazo compounds . Generally much more rigid than rhodium carboxylates . Optimal for intermolecular C–H insertion reactions . Optimal for enantioselective intramolecular C–H insertion . Later generations possess rigid bridged structure Rhodium Carbene Chemistry The Metal Carbene

■ Control carbene reactivity through substituents - “acceptors” and “donors”

Acceptor Acceptor/Acceptor Acceptor/Donor

O O O O H Y X X Y X

N2 N2 N2

X = R, OR, NR2 X, Y = R, OR, NR2 X = R, OR, NR2

Y = vinyl, aryl

. Acceptor/acceptor and acceptor/donor groups stabilize diazo compound – more active catalyst needed for decomposition

. Carbenoids formed from acceptor/acceptor diazo compounds very electrophilic

. Donor substituent stabilizes carbenoid through resonance Rhodium Carbene Chemistry Trends in C–H Activation

■ Generally believed to occur through concerted (though asynchronous), three-centered transition state

A A A H R B C H + B H Rh2L4 D B R + Rh2L4 R C Rh2L4 D R D R R

. Build-up of positive charge at carbon undergoing C-H cleavage

. C–H activation occurs preferentially at sites that can stabilize δ+

α-hetero C–H, allylic C–H, benzylic C–H preferred sites of activation

Reactivity of C–H bonds undergoing insertion

methine > methyelene >> methyl

. Steric factors, however, can sometimes override this selectivity Rhodium Carbene Chemistry Rh2(DOSP)4

■ Rhodium(II) carboxylate developed and heavily utilized by Huw M. L. Davies (Emory)

SO2Ar H H N O O N Rh O O SO2Ar O Rh O SO2Ar O O N N H H SO2Ar

Ar = p-(C12H25)C6H4

■ Stereochemical model

L L H M S S M L MeO2C R L MeO2C R

MeO2C R S M S M Rh H

. Esther considered sterically demanding group Davies et al. Chem. Rev. 2003, 103, 2861. Davies et al. J. Org. Chem. 2009, 74, 6555. Combined C–H Insertion/Cope Rearrangement Synthesis of 4-Substituted Indoles

■ C–H insertion into 4-methyl-1,2-dihydronaphthalene proceeded with high diastereoselectivity

Me Me Ph 95% yield Rh (S-DOSP) (0.5 mol%) Ph N 2 4 + 2 >98% de 2,2-dimethylbutane, 0 °C CO2Me H >99% ee CO2Me

. Selectivity unusually high compared to what is known for C–H insertion into cycloalkenes

. Mechanism more complex than appears?

■ Proposed combined C–H activation/Cope rearrangement, followed by retro-Cope rearrangement

Ph Ph Ph Me CO2Me Me CO2Me Me CO2Me H C-H/Cope Cope H H

. Fully conjugated product favored

Davies et al. J. Am. Chem. Soc. 2004, 126, 10862. Combined C–H Insertion/Cope Rearrangement Retro-Cope

■ Mechanistic analysis

Me Et Me

Rh2(S-DOSP)4 (2 mol%) Et N + 2 // 2,2-dimethylbutane, 23 °C CO2Me H CO2Me

Et CO Me C-H/Cope 2 110 °C Me >98% de 92%, 98% ee

98% ee

■ Preliminary scope

R2 X = CH2, O R1 = H, m-/p-OMe R1 2 X R = OAc, OSiR3

Davies et al. J. Am. Chem. Soc. 2004, 126, 10862. Combined C–H Insertion/Cope Rearrangement Synthesis of 4-Substituted Indoles

■ C–H insertion into dihydroindoles followed by Cope rearrangement and aromatization

OAc R CO2Me N2 Rh2(S-DOSP)4 + R CO2Me N DMB, rt Boc N Boc

OAc R R R AcO Cope

N H Boc N Boc CO2Me

Davies et al. J. Am. Chem. Soc. 2006, 128, 1060. Combined C–H Insertion/Cope Rearrangement Synthesis of 4-Substituted Indoles

■ C–H insertion into dihydroindoles followed by Cope rearrangement and aromatization

OAc R CO2Me N2 Rh2(S-DOSP)4 + R CO2Me N DMB, rt Boc N Boc

MeO Br Cl

65%, 98% ee 52%, 98% ee 53%, 99% ee 45%, 98% ee

H3C N Boc

56%, 98% ee 64%, 98% ee 65%, 99% ee 61%, 99% ee

Davies et al. J. Am. Chem. Soc. 2006, 128, 1060. Combined C–H Insertion/Cope Rearrangement Application Towards Natural Product Synthesis

■ (+)-erogorgiaene: kinetic enantiodifferentiation

Me Me Me

(±) H 2 mol% Me Me 2 mol% Me H H Rh (R-DOSP) 2 4 + Rh2(R-DOSP)4 MeO2C Me N Me 2 MeO2C Me Me 48% 48%, 90% ee

Me H Me

Me Me

(+)-erogorgiaene

Davies et al. Angew. Chem. Int. Ed. 2005, 44, 1733. Combined C–H Insertion/Cope Rearrangement Application Towards Natural Product Synthesis

■ Similar enantiodifferentiating step used in analogous syntheses

O Me O Me O Me OH Me HO HO HO HO

Me Me Me O H Me H H H O O Me O Me Me H Me Me H Me Me Me

Me Me OH

(–)-colombiasin A (–)-elisapterosin B (+)-elisabethadione (+)-p-benzoquinone

Davies et al. J. Am. Chem. Soc. 2006, 128, 2485. Davies et al. Tetrahedron 2006, 62, 10477. Tandem Cyclopropanation/Cope Rearrangement Formal [4+3] Cycloadditions

■ General idea

R3 MeO C R3 2 R4 4 4 N2 MeO2C R MeO2C R R5 Rh(II) 2 5 Cope R2 + R R 2 5 R3 R R 7 6 R1 R R R1 R7 R6 1 R7 R R6

■ Stereochemical model for cyclopropanation: based on “end-on” approach of oleﬁn

H R1

H H R1 2 1 MeO2C R 2 R MeO2C R

H H R2 H H Rh Rh MeO2C

Davies et al. J. Am. Chem. Soc. 2003, 125, 15902. Tandem Cyclopropanation/Cope Rearrangement Formal [4+3] Cycloadditions

■ Scope of dienes

R4 CO Me CO2Me 2 4 R N 1 mol% Rh2(S-PTAD)4 + 2 R2 OTBS R3 OTBS R3 hexanes, –26 °C R1 R1 R2

CO2Me CO2Me TBSO CO2Me

OTBS OTBS OTBS

Me Ph Me

80% yield 82% yield 70% yield O N O Rh 87% ee 95% ee 99% ee O

H O Rh

TBSO CO2Me CO2Me 4 CO2Me Rh (S-PTAD) OTBS OTBS 2 4 OTBS Me MeO Me

63% yield 86% yield 57% yield 95% ee 92% ee Davies et al. J. Am. Chem. Soc. 2009, 131, 8329. Tandem Cyclopropanation/Cope Rearrangement Formal [4+3] Cycloadditions

■ Total synthesis of (–)-5-epi-vibsanin E

R4 CO Me CO2Me 2 4 R N 1 mol% Rh2(S-PTAD)4 + 2 R2 OTBS R3 OTBS R3 hexanes, –26 °C R1 R1 R2

CO2Me

OTBS 65% yield Me Me CO2Me 0.5 mol% Me + N2 90% ee Me OTBS Rh (S-PTAD) 2 4 Me

O Me O Me O Me

Me O Me

(–)-5-epi-vibsanin E Davies et al. J. Am. Chem. Soc. 2009, 131, 8329. Nucleophilic Attack on Rhodium Carbenes Formal [3+2] Annulation of Indoles

■ Two isomers of annulated product initially observed

CO2Me Ph H H N2 Rh2(R-DOSP)4 + +

N MeO2C Ph CH2Cl2, –45 °C Ph CO2Me Me N H N H Me Me

exo endo 72% yield 17% 80% ee >99% ee

■ Competition between C2- and C3-nucleophilic attack?

N2 N2

CO2Me Ph MeO2C Ph Me MeO2C Ph H Me Rh2(S-DOSP)4 Rh2(S-DOSP)4 Me N toluene, –45 °C Ph N toluene, –45 °C CO2Me Me N Me Me N H Me Me

exo endo 68% yield 74% yield 97% ee 99% ee

Davies et al. J. Am. Chem. Soc. 2010, 132, 440. Nucleophilic Attack on Rhodium Carbenes Formal [3+2] Annulation of Indoles

■ Proposed mechanism

MeO2C Ph CO Me CO2Me 2 Rh L 2 4 L4Rh2 H Ph

Ph N H N N Me Me Me

. Zwitterionic intermediate

■ Stereochemical rationale: conﬁguration of carbene and oleﬁn govern diastereoselectivity

NMe MeN Ph Me Me MeO2C Ph exo MeO2C endo

Rh Rh

s-cis s-trans

Davies et al. J. Am. Chem. Soc. 2010, 132, 440. Nucleophilic Attack on Rhodium Carbenes Imines As Nucleophiles

■ Bicyclic pyrrolidines are formed when excess diazo compound is used

Ph NO2

N Ar CO2Me N 2 1 mol% Rh2(OAc)4 N 47-66% yield + MeO C Ph up to 98:2 dr 2 CH2Cl2, reflux R

NO2 R = H, Cl, Me, OMe

■ Proposed mechanism

Ph CO2Me CO2Me Ph CO2Me Rh2L4 Ar N Ar N R N Ar Ph R R

Doyle et al. J. Am. Chem. Soc. 2003, 125, 4692. Nucleophilic Attack on Rhodium Carbenes Imines As Nucleophiles

■ Bicyclic pyrrolidines are formed when excess diazo compound is used

Y Ph H CO2Me

N X N 2 1 mol% Rh2(OAc)4 up to 84% yield + N MeO C Ph Ph ~ 1:1 dr 2 CH2Cl2, reflux CO2Me

X 2 eq

Y X = H, Cl, Me, NO2

Y = H, OMe, NO2

■ Proposed mechanism

Ar2 Ar2 2 CO Me E Ph Ar Ph CO2Me 2 N Ph N N CHO2Me Ar1 Rh2L4 1 Ar CO2Me Ar1 Ph H Ph Rh2L4 CO2Me Ph

Doyle et al. J. Am. Chem. Soc. 2003, 125, 4692. Rhodium(II) Carbenoid Cyclization/Cycloaddition Cascade Cycloadditions with Carbonyl Ylides

■ Carbonyl oxygen can also act as nucleophile

O N2 1 2 A B Rh(II) R O R A B R1 R2 1 2 R ( )n R O n( ) O n( ) O O

. Carbonyl ylide

■ Albert Padwa (Emory) – amide cyclization followed by [3+2] cycloaddition

A B N Me Rh (OAc) N Me N 2 4 N O A N2 O O benzene O O O reflux B

CO2Me CO2Me

O O O CO Me 2 H O OMe

O 75% 77% 78% 85% Padwa et al. Tetrahedron 2008, 64, 988. Rhodium(II) Carbenoid Cyclization/Cycloaddition Cascade Cycloadditions with Carbonyl Ylides

■ Reactions highly regio- and stereoselective

A B N Me Rh (OAc) N Me N 2 4 N O A N2 O O benzene O O O reflux B

CO2Me CO2Me

. Regioselectivity governed by FMO interactions – HOMO of carbonyl ylide, LUMO of dipolarophile

. Predominant exo-selectivity result of steric interactions

O N Me N !" OMe O O O !+

CO2Me

Padwa et al. Tetrahedron 2008, 64, 988. Carbonyl Ylides Three-Component Cycloaddition

■ Joe Fox (Delaware): Coupling between aldehydes, diazo compounds, and dipolarophiles

O R2 CO R3 3 2 O CO2R Rh2(Piv)4 (0.5 mol%) R1 up to 99% yield + + A B 2 R1 H N R 2 CH2Cl2, –78 °C A B up to >95:5 dr

R1 = aryl, alkynyl R2 = alkyl, benzyl R3 = Et, t-Bu

O O Me CO2Me R CO2Et Me

O O EtO2C N CN O N Me CO2Me CO2Et O

Fox et al. J. Am. Chem. Soc. 2009, 131, 1101. Carbonyl Ylides Three-Component Cycloaddition

■ Joe Fox (Delaware): Coupling between aldehydes, diazo compounds, and dipolarophiles

O R2 CO R3 3 2 O CO2R Rh2(Piv)4 (0.5 mol%) R1 up to 99% yield + + A B 2 R1 H N R 2 CH2Cl2, –78 °C A B up to >95:5 dr

R1 = aryl, alkynyl R2 = alkyl, benzyl R3 = Et, t-Bu

■ High diastereoselectivity result of endo approach of dipolarophile

R1 R1 O O O O R1 CO R3 R1 CO R3 R4 endo 2 exo 2 CHO R3 CHO R3 H 2 R2 H 2 R2 R5 2 2 R R4 R5 R R4 R5 R4

Fox et al. J. Am. Chem. Soc. 2009, 131, 1101. Carbonyl Ylides Three-Component Cycloaddition

■ Joe Fox (Delaware): Coupling between aldehydes, diazo compounds, and dipolarophiles

O R2 CO R3 3 2 O CO2R Rh2(Piv)4 (0.5 mol%) R1 up to 99% yield + + A B 2 R1 H N R 2 CH2Cl2, –78 °C A B up to >95:5 dr

R1 = aryl, alkynyl R2 = alkyl, benzyl R3 = Et, t-Bu

■ Suppression of β-hydride elimination of alkyldiazoacetates has been a continuing challenge

O O CO2t-Bu Me Rh2(OAc)4 + + CO2Me Me Me Ph N2

Fox et al. J. Am. Chem. Soc. 2009, 131, 1101. Carbonyl Ylides Three-Component Cycloaddition

■ Joe Fox (Delaware): Coupling between aldehydes, diazo compounds, and dipolarophiles

O R2 CO R3 3 2 O CO2R Rh2(Piv)4 (0.5 mol%) R1 up to 99% yield + + A B 2 R1 H N R 2 CH2Cl2, –78 °C A B up to >95:5 dr

R1 = aryl, alkynyl R2 = alkyl, benzyl R3 = Et, t-Bu

■ β-hydride elimination can be completely suppressed through appropriate conditions

Ph O CO t-Bu O 2 O CO2t-Bu Rh2(Piv)4 + + Me O Me -78 C Me Ph N2 ° Me 77% Sterically encumbering catalysts and low temperatures are critical!

Fox et al. J. Am. Chem. Soc. 2009, 131, 1101. Rhodium(II) Nitrene-Mediated C–H Insertion Azide Precursors to Nitrenes

■ Carbazole synthesis via bisaryl azides

1 2 R R Rh2(O2CC3F7)4 R1 R2 41-98% yield toluene, 60 °C N H N3

1 2 R -R = H, Me, Et, t-Bu, Cl, F, OMe, CF3, NO2, vinyl, CO2Et

. m-substituted pendant arenes lead to mixtures of regioisomers

■ Intermediacy of free nitrene, or completely catalyst-mediated?

OMe OMe toluene + N N H H N3 OMe

heat (250 °C) 31 : 69

Rh2(O2CC7H15)4 94 : 6

. reversal in thermal selectivity argues against presence of free nitrene Stokes et al. J. Org. Chem. 2009, 74, 3225. Rhodium(II) Nitrene-Mediated C–H Insertion Azide Precursors to Nitrenes

■ Proposed mechanism

R R

N Mechanistic Evidence H N3 [Rh] . Primary KIE 1.01 R

R . Nonlinear correlation with σm Hammet values (not electrophilic N [Rh] H N aromatic substitution on nitrene) [Rh] N2

. Linear correleation with σp 4-electron-5-atom electrocyclization Hammet values (negative ρ values) R R

N N [Rh] [Rh]

Stokes et al. J. Org. Chem. 2009, 74, 6442. Rhodium(II) Nitrene-Mediated C–H Insertion Azide Precursors to Nitrenes

■ Proposed mechanism

R R

N H N3 [Rh]

R Rh(II) // N H [Rh] N N N [Rh] 3 H N2 . Contiguous array of π-orbitals necessary

4-electron-5-atom electrocyclization

R R

N N [Rh] [Rh]

Stokes et al. J. Org. Chem. 2009, 74, 6442. Rhodium(II) Nitrene-Mediated C–H Insertion Azide Precursors to Nitrenes

■ Synthesis of indoles and N-heteroarenes via vinyl azides

1 R R1 2 R CO2Me 2 Rh2(O2CC3F7)4 R 71-98% yield CO2Me N3 R3 toluene 3 N R H

1 3 R -R = H, Me, i-Pr, t-Bu, l, Br, OMe, CF3

CO2Me CO2Me

N3 N3

E CO2Me O CO2Me E = O, S, N(PG)

Stokes et al. J. Am. Chem. Soc. 2007, 129, 7500. Rhodium(II)-Catalyzed C–H Amination Iminoiodanes

■ Traditionally, iminoidanes were treated with metal complexes to generate nitrenes

SO2Ar

I SO2Ar SO Ar N N LnM 2 R R LnM N R R . Isolated material

I(OAc) 2 O O + S H2N Ar

Dauban et al. Synlett 2003, 1571. Rhodium(II)-Catalyzed C–H Amination Iminoiodanes

■ Traditionally, iminoidanes were treated with metal complexes to generate nitrenes

SO2Ar

I SO2Ar SO Ar N N LnM 2 R R LnM N R R

■ Du Bois (Stanford): generation of iminoiodanes in situ

O O O O O O O O PhI L Rh S PhI(OAc)2 S Rh2L4 4 2 S "C-H" S H2N X N X N X HN X

R R R R

Du Bois et al. J. Am. Chem. Soc. 2001, 123, 6935. Rhodium(II)-Catalyzed C–H Amination Understanding the Mechanism

■ General reactivity trends parallel those of rhodium(II) carbenes

Reactivity of C–H bonds undergoing insertion

methine > ethereal ~ benzylic > methyelene >> methyl

■ Six-membered oxathiazinanes favored ■ Concerted C–H insertion

O O O O O O S O NH . KIE of 1.9 ± 0.2 L4Rh2 S "C-H" S H D 2 N X HN X Ph R R

O O S . Elongated S–X, S–N bonds HN X . No opening of radical clock (not C–H abstraction/radical-rebound . Obtuse N–S–X bond angle Ph H

Du Bois et al. Tetrahedron 2009, 65, 3042. Rhodium(II)-Catalyzed C–H Amination Understanding the Mechanism

■ Proposed mechanism of rhodium-nitrene formation

OAc O O O O PhI(OAc)2 O O –AcOH S S I S I RO NH2 RO N Ph RO N Ph H

Rh2L4 fast

O O S O O HN O "C–H" O O –IPh S Rh2L4 S RO N RO N!Rh2L4 R IPh

. First-order dependence on sulfamate and oxidant

. Zero-order dependence on catalyst (during initial reaction burst)

Du Bois et al. Tetrahedron 2009, 65, 3042. Rhodium(II)-Catalyzed C–H Amination Rh2(esp)2

■ Very efﬁcient catalyst for C–H aminations

Me Me Me Me O O Rh O O O O Rh O O

Me Me Me Me

Rh2(esp)2

■ Dinuclear rhodium catalysts known to undergo structural changes within minutes of initiating the reaction

. Catalyst degradation believed to proceed through ligand exchange

. Appropriately spaced linker in (esp) ligand adds stability to dirhodium complex

Du Bois et al. J. Am. Chem. Soc. 2004,126, 15378. Rhodium(II)-Catalyzed C–H Amination Rh2(esp)2

■ Interesting results obtained in intermolecular C–H amination experiments

NHTces Tces 2 mol % Rh2(esp)2 Me N Me + Me PhI(CO2t-Bu)2

TcesNH2, benzene Me

72% 15% O O Tces = S . From oxidant? Cl3C O

■ If C–H bond is slow to intercept reactive Rh-nitrene intermediate, catalyst degradation occurs

. Formation mixed-valence Rh2+/Rh3+ species observed by UV/vis spectroscopy

. Could this mixed-valence dimer interact with oxidant in reaction mixture?

Du Bois et al. J. Am. Chem. Soc. 2007,129, 562. Du Bois et al. J. Am. Chem. Soc. 2009, 131, 7558. Rhodium(II)-Catalyzed C–H Amination Rh2(esp)2

■ Interesting results obtained in intermolecular C–H amination experiments

NHTces Tces 2 mol % Rh2(esp)2 Me N Me + Me PhI(CO2t-Bu)2

TcesNH2, benzene Me

72% 15%

t-BuCO H O Me + 2 [Rh2(esp)2] t-Bu O Me

Rh2(esp)2 CO2, H• . Radical decarboxylation

R = Me 12% 1 mol% Rh(II) NHTces . More reducing carboxylic acid – higher yields n-Pr 17% Ph Me TcesNH2 Ph Me t-Bu 27% . Evidence that Rh2(esp)2 is active catalyst PhI(CO2R)2 CMe2Ph 62%

Du Bois et al. J. Am. Chem. Soc. 2007,129, 562. Du Bois et al. J. Am. Chem. Soc. 2009, 131, 7558. Rhodium(II)-Catalyzed C–H Amination Justin Du Bois

■ Rich variety of rhodium-catalyzed aminations

NHTces O O O O O O S S S R2 HN O HN NBoc HN O R1 1 2 N R R R1 R2 R1 R2 intermolecular amination oxathiazinanes 1,3-diamines 1,2-diamines

■ Amines are readily deprotected

O O S DMAP TcesHN NHBoc HN NBoc 89% Cl3CCH2OH Ph Ph dioxane, 80 °C

J. Am. Chem. Soc. 2001,123, 6935. J. Am. Chem. Soc. 2007, 129, 562. J. Am. Chem. Soc. 2008, 130, 11248. Angew. Chem. Int. Ed. 2009, 48, 2777. Rhodium(II)-Catalyzed C–H Amination Justin Du Bois

■ Products can act as iminium ion equivalents

O O O O O O S –LG S Nu- S HN O HN O HN O

2 2 LG R R Nu R2 1 1 R R R1

Li OSiR3 Nu = SiMe3 R R

■ Diastereoselectivity governed by combination of twist Felkin-Ahn transition state model

no destabilizing interactions

1 R1 O O H R 1 S O R O O O N H HN O S N O O N H S H S O H Nu O O Nu Nu R1 Felkin-Ahn T.S.

J. Am. Chem. Soc. 2003,125, 2028. Angew. Chem. Int. Ed. 2004, 43, 4349. Rhodium(II)-Catalyzed C–H Amination Justin Du Bois

■ Products can act as iminium ion equivalents

O O O O O O S –LG S Nu- S HN O HN O HN O

2 2 LG R R Nu R2 1 1 R R R1

Li OSiR3 Nu = SiMe3 R R

■ Diastereoselectivity governed by combination of twist Felkin-Ahn transition state model

. Introduction of R2 can have a dramatic impact on selectivity!

O R1 O H 1 O R 2 S N R H S N . Erosion of diastereoselectivity O O O R2 Leads to Felkin-Ahn-disfavored T.S. destabilizing

J. Am. Chem. Soc. 2003,125, 2028. Angew. Chem. Int. Ed. 2004, 43, 4349. Rhodium(II)-Catalyzed C–H Amination Justin Du Bois

■ Application towards natural product synthesis

O Me H N HO Br 2 N O NH O NH2 HN N Br HO HN NH O HO N N CO2H H Me N NH NH O

NH2 O manzacidin A (+)-saxitoxin (–)-agelastatin A

J. Am. Chem. Soc. 2002,124, 12950. J. Am. Chem. Soc. 2006,128, 3926. Angew. Chem. Int. Ed. 2009, 48, 3802. C–H Amination with N-Tosyloxycarbamates Rhodium Nitrene Formation without Iminoiodanes

■ Substitute in situ-generated iminoiodanes with alternative leaving group?

O + O K O NHCO R1 Rh2L4 OTs R2 R3 2 OTs 1 –KOTs 1 R O N R O N R1O N Rh L 2 3 H K2CO3 ! 2 4 R R Rh2L4

■ Lebel (Montréal) utilized the tosyl leaving group

O R1 H Rh2(tpa)4 (6 mol%) O Rh O N HN O R2 OTs Rh2(tpa)4 = Ph3C K2CO3, CH2Cl2, 25 °C O Rh O R1 R2 4 41-92% yield (R1-R3 = alkyl, Ar)

O Rh(II) NHTroc R1 R2 + OTs Cl C O N . Up to 15 eq of alkane required 3 R1 R2 H (Du Bois requires only 1 eq) 50-87% yield Lebel et al. Chem. Eur. J. 2008, 14, 6222. Amination of Alkynes and Allenes π-Nucleophilic Attack onto Rhodium Nitrenes

■ Electrophilic rhodium(II) nitrene analogous to rhodium carbenes

Nu- N R Nu N R LnM N Nu N R L M R LnM n MLn

■ Blakey (Emory) utilized oxygen for nucleophilic attack onto carbocation

O O L Rh O O 4 2 S L4Rh2 O O O O OSO NH S 2 2 N O N O S S N O HN O NaBH4 Rh2L4 O O O O O

Blakey et al. J. Am. Chem. Soc. 2008, 130, 5020. Amination of Alkynes and Allenes π-Nucleophilic Attack onto Rhodium Nitrenes

■ Scope

O O 2 mol % Rh2(esp)2 RO ( )n S PhI(OAc)2 HN O OSO NH 2 2 CH2Cl2, RT ( )n

then NaBH4 O R

O O O O O O O O S S S S HN O HN O HN O HN O

O O O O Ph Ph

85% 71% 56% 76%

O O O O O O S S S HN O HN O O NH R

O O O Ph

81% 98% R = H, 55% (quenched with allyl-MgBr) Me, 48% Blakey et al. J. Am. Chem. Soc. 2008, 130, 5020. Amination of Alkynes and Allenes π-Nucleophilic Attack onto Rhodium Nitrenes

■ Scope

O O 2 mol % Rh2(esp)2 RO ( )n S PhI(OAc)2 HN O OSO NH 2 2 CH2Cl2, RT ( )n

then NaBH4 O R

■ Other nucleophilic traps – arenes and oleﬁns

O O S HN O O O R' S HN O R = Ph R R =

OSO2NH2

Friedel-Crafts termination cyclopropanation

Blakey et al. J. Am. Chem. Soc. 2009, 131, 2434. Amination of Alkynes and Allenes π-Nucleophilic Attack onto Rhodium Nitrenes

■ Mechanistic insight – what is the active intermediate?

O O O O L4Rh2 S S N O 1,3-shift N O

R R

L4Rh2 vinyl cation iminocarbenoid ■ Control experiment O O O O L4Rh2 S S N O N O OSO2NH2

Rh(II) Rh(II)

L4Rh2

O O O O Friedel-Crafts benzylic "C–H" S S HN O N O

72% Not observed

Blakey et al. J. Am. Chem. Soc. 2009, 131, 2434. Amination of Alkynes and Allenes π-Nucleophilic Attack onto Rhodium Nitrenes

■ Allene amination - amidoallylcations

R • R N LnM N LnM R' R'

■ Aminocyclopropanes

O O OSO NH 5 mol% Rh (esp) O O O 2 2 2 2 O O t-Bu S L4Rh2 S S HN O PhI(CO2t-Bu)2 N O N O t-BuCO2H O

t-BuCO2H • Me Me C6H5CF3, 45 °C Me 73%

Blakey et al. J. Am. Chem. Soc. 2010, ASAP. Amination of Alkynes and Allenes π-Nucleophilic Attack onto Rhodium Nitrenes

■ Allene amination - amidoallylcations

OSO NH O O 2 2 5 mol% Rh (esp) 2 2 S PhI(CO t-Bu) HN O 52-85% yield 2 2 R' single isomers • R then R'MgX R R = Me, allyl, benzyl R' = Me, i-Pr, Ar, vinyl

. Chirality transfer . Cycloadditions

OSO2NH2 O O O O O O O S L4Rh2 S HN S HN O N O Ph O Ar H • R Ph O Me Me 40% 96% ee 53%, 82% ee

Blakey et al. J. Am. Chem. Soc. 2010, ASAP.