1𝟑𝐬𝐩 C-H insertion byα-Oxo Gold Carbene
B4 Kei Ito
2016. 1. 30

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1. Introduction

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About Carbene
Carbene ・・・ Neutral compounds featuring adivalent carbon atom with only
six electrons in its valence shell
Brief history of carbene (～2000)

Chem. Rev. 2000, 100, 39

1835 Dumans firstly proposed to prepare carbene CH2：

1925 Chugaev firstly synthesized carbene metal complex
1954 Discovery of cyclopropanation reaction
1957 Appearance of NHC catalysts

1988 Bertland firstly reported isolable carbene
1999 2nd generation Grubbs catalyst (Nobel Prize 2005)
etc.

Chem.Rev., 2015, 115, 11503

4Singlet carbene and Triplet carbene

Chem. Rev., 2000, 100, 39

Triplet carbene

Singlet carbene

ウォーレン有機化学

Representative reactions of carbene

5・ Triplet carbene reacts radically
Biradical
intermediate

Acta.Chem.Scand., 1992, 46, 680

Dimerization

JACS, 1995, 117, 11355

Cyclopropanation with loss of stereochemistry6Carbene metal complex

1925 Firstly synthesized by Chugaev
Anorg. Allg. Chem., 1925, 148, 37

・ Fischer carbene and Schrock carbene

Fishcer carbene

Schrock carbene

Carbocation-like(electrophilic)

Carbonion-like(nucleophilic)weak π back-donaton

strong π back-donationadjacent to heteroatom(stabilization by π donation)

adjacent to C or H atom
(no stabilization)

Generation of carbene from diazo compound

7

Thermally or photochemically generatedcarbenes
Unselective

Metal carbene from α-diazo carbonyl compound
M (Rh, Ru, Cu, Au etc.) and L control
the reactivity and selectivity of carbene
centerReactivity (electrophilicity) is depend on
the metal(+ligand) and substituent ofcarbene center
Chem. Rev. 2010, 110, 704

Ligands affect the reactivity and selectivity(1)ex.1 Chemoselectivity

R=C3F7 Rh2(pfb)4Rh2(cap)4JACS. 1993. 115, 8669

8

Ligands affect the reactivity and selectivity(2)ex.2 Stereoselectivity

JACS. 1994. 116, 4507

9102. Gold carbene

Characteristics of Gold79Au

Group 11, 6th period
Electron configuration [Xe], 4f𝟏𝟒 , 5d𝟏𝟎 , 6s𝟏
Oxidation state 5 ,4, 3, 2. 1. -1
especially Au(Ⅲ) and Au(Ⅰ) are stable(work as soft Lewis acid)
Most electronegative transition metal in the Pauling`s scaleGold carbene exhibits special characteristics

1112Gold catalysts can activate alkyne(1)Soft Lewis acidities→ Activate alkyne,allene,alkene for attack of nuicleophile

J. Chem. Soc. Perkin. Trans.1., 1976, 29, 123Gold coordinated intermediates are trapped by various types of nucleophile
・Alkyne + amine

Heterocycles, 1987, 25, 297

Gold catalysts can activate alkyne(2)13・Alkyne+Carboxylic acid

JACS, 2006, 128, 3112

・Allene+Thiol

Angew. Chem. Int. Ed., 2006, 45, 1897

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Gold is less effective in π-back donation than Rh(1)π-back donation ability depends on the electronegativity

Most electronegative transition metal⇒ weak π-back donation
π-back donation from metal stabilizes the carbene center⇒ weak π-back donation makes more reactive (electrophilic)Gold-coordinatedcarbocation
Electrophilicity

Gold carbene

Gold-stabilized
singlet carbene

15Gold is less effective in π-back donation than Rh(2)・ Gold carbene is so electrophilic that it can abstract Cl from solvent

Org. Biomol. Chem., 2012, 10, 3168

16Gold is less effective in π-back donation than Rh(3)・ In the case of Rh carbene

J. Org. Chem., 1995, 60, 2112

Tetrahedron, 2003, 59, 9333

Rh carbene intermediates are flanked by two electro-withdrawing carbonyl groups
Electrophilicity

Au carben intermediates with one electro-withdrawing carbonyl groups17Gold is less effective in π-back donation than Rh(4)・ Diazo compound and gold catalysts give azine compound

Inorganica. Chimica. Acta.,1994, 222, 267

So electrophilic to be attacked by diazo compoundcf.
Stable enough forcharacterization by UV, IR, NMR

Angew. Chem.Int. Ed., 2015, 54, 15452

18Gold is less effective in π-back donation than Rh(5)Intermediates as gold carbene

Tetrahedron. Let., 2003, 44, 2019

Chem. Commun., 2015, 51, 13937

Gold carbene and Gold stabilized carbocation(1)19What decides the character of carbene center?
・ Computational and experimental analysis → Focusing on ligand and substituent(By Toste`s group)① Substituent
Structural and electronic comparison of cationic metal-free and [AuPMe3] + substituted substratesNat. Chem., 2009, 1, 482

Gold carbene and Gold stabilized carbocation(2)Bond length

Natural atomic charge

A = (𝑪𝟏 − 𝑪𝟐 )/(𝑪𝟐 − 𝑪𝟑 )

+0.28

+0.38

+0.46

Lower A ・・・ Positive charge isstabilized by C𝟑 substituent

Higher A・・・ Positive charge isstabilized by C𝟏 substituent(AuL)A increases with less-donating C𝟑 substituent (O→Me→ester)

A increases by the stabilization of positive charge at C𝟏 from AuL
Au→ C𝟏 stabilization grows with increasing electrophilicity of the allyl cation
Effect on natural atomic charge at C𝟑 grows with increasing electrophilicityof the allyl cation (0.86→0.83, 0.43→0.34, 0.21→0.10)

20Gold carbene and Gold stabilized carbocation(3)21The effect of AuL on rotational barrier with different substituentsNat. Chem., 2009, 1, 482+1.4 kcal mol−𝟏+8.1 kcal mol−𝟏

C𝟐 −C𝟑 bond of carbene resonance extreme has
double bond character＊M06, B3LYP, BP86 ・・・ Functional
Expt. ・・・ experimentHigh rotation barrier indicatescharacter of carbene intermediate

AuL→C stabilization (carbene character) is dependent on carbene substituent!!

Gold carbene and Gold stabilized carbocation(4)22Experiment analysis

Experimental analysis also shows electron-donating substituent
Ligand effect is important?
decrease carbene character!!

Gold carbene and Gold stabilized carbocation(5)② Ligand23

Short bond length = Double bondcharacter= carbene-like reactivityCalculated bond length

Polymerized product ・・・ carbocation-like reactivity
IPr ≡Cyclopropanation ・・・ carbene-like reactivity
Computational and experimental analyses are
consistent with each other !!

What difference is deciding
ligand effect?

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Representative bond of metal carbene
Representative bond of carbene

L→M σ donation
・HighM←：C σ donation C：←M π donation
・Low

・High

(weak σ bonding)(strong π bonding)M→L π donation
・Lowπ-acidic
weakCarbene-like reactivity

strongLigandstrongCarbocation-like reactivity
weakσ-donating

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NHC ligand
NHC・・・ N- Heterocyclic Carbene

Stable singlet carbene

N→C π donation stabilize carbene center≡
Strongly σ-donating andweakly π-acidic ligand

Increase Au→C π-donation

18Gold is less effective in π-back donation than Rh(5`)
Intermediates as gold carbene

Tetrahedron. Let., 2003, 44, 2019

Less donating catalysts give allene(Reaction time is very short)

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3. α-oxo gold carbene

α-oxo gold carbene (By Zhang`s group)
Nucleophile/Electrophile

Angew. Chem. Int. Ed., 2007, 46,5156

α-carbrene gold carbene≡
O− − Y + + alkyne is equivalent ofdiazo carbonyl compounds

Hazardous / Potentiallyexplosive2728

Intramolecular oxidation (1)Intramolecular oxidation ・・・ Using sulfoxide as oxidant

Aromatic substitution of α-goldcarbene route was ruled out
by mechanistic studies
5-exo-dig
cyclization

Facile 3,3-sigmatropic rearrangement is favorable

α-oxo gold carbene can`t
be generated?
Angew. Chem.Int.Ed., 2007, 46, 5156

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Intramolecular oxidation (2)Evidence of α-oxo gold carbene formation
Pinacol-type rearrangement

α-oxo gold carbene

4 ・・・ IPr(NHC) ligand is suitable
8 ・・・ o-chlorinated benzene ring is good substrate
to inhibit competitive 3,3-sigmatropic rearrangement
Angew. Chem.Int.Ed., 2007, 46, 5156

30Intermolecular oxidation (1)Intermolecular oxidation
Aryl sulfoxide as oxidant

Reaction at the position adjacent to C-S=O
was only observed

More activated C5
position didn`t occur
aromatic substitution
Apparently goodresult

Org. Lett., 2009, 11, 4906

Formation of α-oxo gold carbene< 3,3-sigmatropic rearrangement

Sulfoxide isn`t suitable for intermolecular oxidation

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Intermolecular oxidation (2)Pyridine N-oxide as oxidant→ Avoid 3,3-sigmatropic rearrangement

Acidic condition is needed(Pyridine deactivate catalyst?)
Phosphine ligand is better
than NHC ligand

JACS, 2010, 132, 3258

32Intermolecular oxidation (3)The condition is so mild MOM and Boc can tolerate

Highly reactive intermediate

Less stable trans-fused ring

Reaction efficiency depends on
kinetics of OH trapping
JACS, 2010, 132, 3258

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Other type of Ligand (1)P,N-bidentate ligand

JACS, 2012, 134, 17412

Other type of Ligand (2)34

The role of ligand① Steric shield on carbene center by rigid conformation② N→Au donation increase Au→：C donation(Carbene like
Carbocation like)①,②

Decrease electrophilicity (= Increase selectivity)

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α-oxo gold carbene to C-H insertion (1)sp3 C-H insertion (→cyclopentanone)①Conformation control byThorpe-Ingold effect②β-diketone-α-gold carbene(more electrophilic =more reactive to C-H insertion)③Bulky acyl group to hinderintermolecular side reactions
Outset substrate

Intermediate

JACS, 2015, 137, 5316

α-oxo gold carbene to C-H insertion (2)36⑨ L4 ligand (Most bulky P,N-bidentate ligand)is the most favorable for reactivity and selectivity⑬ More hindered oxidant and NTf2 as counteranion are the most suitableα-oxo gold carbene to C-H insertion (3)Proposed mechanism of the reaction37

α-oxo gold carbene to C-H insertion (4)Substrate scope with YnonesAB38α-oxo gold carbene to C-H insertion (5)39Key points for control of reactivity①

Thorpe-Ingold effectis important !
Higher yield and selectivity

Lower yield and selectivity (3j)②

Masking of competing
nucleophile is important !

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Summary・More electrophilic

Reactivity・Less electrophilic・Less donating ligand(Phosphine ligand)

Ligand・More donating ligand(NHC, P,N bidentate ligand)α-oxo gold carbene

・Prepared from alkyne + AuL + pyridine N-oxide( Safe method without hazardous α-diazo carbonyl compounds)
・For C-H insertion
NHC or P,N bidentate ligand is suitable
Thorpe-Ingold effect is important (cyclization)
Blocking of competing nucleophile is required