Literature Seminar (M2 part)

Matthew J. Gaunt Research Group2012. 9. 24 (Mon.)
Keiichi KANEKO (M2)

0. Introduction
Biography
1995 graduated from the University of Birmingham.
1999 moved to the University of Cambridge to carry out his graduate studies, and finished.
he was awarded a prestigious GlaxoWellcome Postdoctoral Fellowship.
2001 returned to the UK to work with Professer Steven Ley as a Junior Research Fellow at Magdalene College.
2003 began his independent research career in October at the University of Cambridge.
2004 and awarded a Royal Society University Research Fellow in October.
2006 he was appointed Lecturer in Organic Chemistry, and a Philip & Patricia Brown Next Generation Fellow.

They are actively pursuing research programmes in the following areas• Enantioselective Organocatalysis• Transition Metal Catalysed C-H Activation• Cascade Reactions for Complex Natural Product Synthesis• Chemical Biology

Contents
0.
1.
2.1
2.2
3.
4.

Introduction
An Organocatalytic Cyclopropanation Reaction
Palladium-Catalyzed Intermolecular Arylation of Indoles
Arylation with Diarylindonium Salts
Meta-Selective C-H Bond Activation
Summary1/16

1.1 An Organocatalytic Cyclopropanation Reaction[Background]
The cyclopropane motif is a common feature in the synthesis of complex molecules and in medicinal chemistry owing
to a unique combination of reactivity and structural properties

1958
The formation of Simmons-Smith reagent
III ZnI

CH2I2

H H

Zn/Cu

Zn/Cu

H H

Simmons-Smith reaction

1967

E. J. Corey, JACS, 1967, 89, 3912.
O+

Ph2S

O-70 ~ -30 oC, 3 hRRsulfur ylide+SPh2

71 ~ 86%

There are comparatively few methods for synthesis of enantiomerically pure tri- and tetrasubstituted cyclopropanes.

S. Hanessian, JACS, 1995, 117, 10393.

1995MeN OPNMeMeMeN OPN
MeO+ClO

MeOH

MeHEpimerization

MeHO

1. NaBH4
2. TESCl
3. O3

HOO
DBUH

H

M. J. Gaunt's works
2003 Stoichiometric ''one-pot'' ammonium ylide based cyclopropanation

M. J. Gaunt, ACIE, 2003, 42, 828.

N
1. NO
PhCl
2.

(1 eq.)
COtBu , NaOH, MeCN, 80 oC

OOtBu

PhO

single diastereoisomer
The reaction proceeds without the formation of byproducts, and simple aqueous workup affords pure cyclopropanethat does not neessarily require further purification.

2/16

Catalytic cyclopropanationhigh diastereoselectivity
Enantioselective Organocatalytic Cyclopropanation

M. J. Gaunt, ACIE, 2004, 43, 4641.

high diastereoselectivity&
high enantioselectivity

Reversing the role of the S.M

This enantioselective catalytic cyclopropanation process via ammonium ylides has a number of advantages.
1) There are no transtion metals involved in the reaction.
2) The starting materials are readily available and conveniently handled.
This is the first general intermolecular enantioselective organocatalytic cyclopropanation reaction.

• Intramolecular CyclizationM. J. Gaunt, ACIE, 2004, 43, 2681.

[Catalytic cycle]
Finally the bicycloalkane 2 is generated
through displacement of the ammonium
group, concurrently regenerating catalyst I.

The amine catalyst I displaces the chloridein 1 to give the quaternary ammonium salt II.
Intramolecular conjugate
addition forms IV.

Deprotonation forms
the ammonium ylide III.
Small Summary
They have developed an organocatalytic inter- and intramolecular cyclopropanation reaction as single
diastereoisomers. This powerful catalytic process effects the controlled formation of stereocenters insingle transformation.

3/16

2.1

Palladium-Catalyzed Intermolecular Arylation of Indoles

Selective C-2 Arylation of (NH)-Indole
D. Sames, JACS, 2005, 127, 8050.
D. Sames, OL, 2004, 6, 2897.

i) The Key Reaction Pathway in the C-2 Arylation of 1-Methylindole
The first step proceeds to an aryl-palladium halide
intermediate, which may then undergo twocompeting pathway:

key issues: 1) the choice of base2) formation of the biphenyl side product(1) cross-coupling with the substrate to furnish
the disered productor(2) formation of byproduct biphenyl.

biphenyl formation required a bimoleculartransmetalation of the allyl-palladium species.
[Hypothesis]
Decrasing the catalyst loading should
increase the rate ratio v3/v2 and thus favor
production of the desired product.

> 0.5 mol%: biphenyl formation< 0.5 mol%: led to a sharp decline in yeild, which was accompanied by a dramatic increase in the catalyst
turnover number.
At such low concentrations, catalyst decomposition processes, including biphenyl formation weresuppressed.
Good functional group tolerance was demonstrated.
ii) Mechanistic Studya value too small for thecleavage of this bond to be
involved in the rate-limiting
step.

the large KIE value wasobtained for the 3-position
where the substitution does
not occur.
4/16

Possible Reaction Mechanisms in the Arylation of N-Alkylindole

There are three reaction mechanisms that may rationalize the strong preference for C-2 arylation.
(1) Electrophilic metalation-migration(2) δ-Bond metathesis(3) Carbometalation, that is, Heck-type reaction(2) This is primarily due to the large KIE at C-3.
(3) Carbopalladation of indole, following by isomerization and syn-β-hydride elimination, should also be considered.
A plausible mechanism for the isomerizaiton step is a reversible α-hydride elimination, proceeding via a palladium
hydride-carbene intermediate.
(1) The most likely candidate seems to be the electrophilic palladation pathway, supported by the kinetic studies.
Electrophilic Pathway for Arylation of Indole

The first step involves the formation of intermediate 6 byelectrophilic addition of an aryl-palladium(II) species to the 3position of indole. If the reverse step (k1) and the migration (k2),then the formation of 6 and the migration may become kineticallyrelevant.

In such instance, k3 must be fasterthan k2, and k4 must be slower than k2.

The driving force for this migration is related to stabilizaiton of the carbon-palladium bond by theadjacent nitrogen atom.

5/16

M. J. Gaunt's worksiii) Intermolecular Alkenylation of Indoles by Solvent-Controlled Regioselective C-H Functionalization
New swichable solvent-controlled regioselective palladium-catalyzed
indole alkenylation by C-H functionalization.

M. J. Gaunt, ACIE, 2005, 44, 3125.
The natural reactivity of indole suggested
that palladation and Heck coupling would
take place preferentially at the 3-position.

reversal of selectivity
acid effectimprove the yield

They propsed plausible pathways for the two reactions inScheme 2. Palladation at C3 is thought to occur via
intermediate I, and following rearomatization to II a Hecktype reaction forms the C3-functionalized indole 3.
Under neutral conditions, the acetate ion formed from theattack of indole on Pd(OAc)2 will readily remove a proton
from I to form the C3-palladated species II.
Under acidic condition they propose that thisdeprotonation would be slow, which could allow a
migration of the C3-PdX bond in I to the highly activated
2-position of the iminium intermediate to giveintermediate III and ultimately IV.
The effect of the cosolvent is also important since the results in Table 1 suggest that strongly coordinating solvents(DMSO, MeCN) override any effect that the presence of acid may have, thus leading to C3 selectivity.

This strategy thus allows the selective installation ofsubstituents at either position in any order and provides accessto highly functionalized indoles by catalytic methods.

6/16iv) Cu(II)-Catalyzed Direct and Site-Selective Arylation of Indoles

M. J. Gaunt, JACS, 2008, 130, 8172.

Pd(II) → d8 ≡ Cu(III)highly electrophilic aryl-Cu(III) intermediate

enable a mild arylation process
C3 Arylation
In order to improve the conversion, 10 mol% of theCu catalyst was required, prusumably because thepyridine base binds to the Cu center and reduces
its activity.

poor aryl transfer of a large groupoxidative addition
Cu(III)-arylintermideate I would react initiallythrough the C3 position before migration to C2.

reductive elimination

rearomatization

C3 attack

They reasoned that the use of an N-acetylgroup might render the intermediate iminium
ion IV more likely to accept the migrating CCu bond at the C2 position.

C2 Arylation
C2:C3 = 2.6:1 ~ 6.5:1
49 ~ 82% yield

Small Summary
Free(NH)- and N-alkylindoles → C3-arylated productN-acetylindoles→ C2-arylated product

7/16

2.2

Arylation with Diaryliodonium Saltsi) Copper-Catalyzed Alkene Arylation with Diaryliodonium Salts

W. C. MacMillan, JACS, 2011, 133, 13782.
M. J. Gaunt, JACS, 2011, 133, 13778.
A broadly expanded array of carbonyl systems
might be readily accessible using chiral copper
catalysts in the presence of iodonium salts
with silyketene acetals.

high electrophilic chiral copper(III) species

Catalytic Enantioselective Arylation

1) formed as single (Z)-isomers,2) rigidify a transition state via stabilizing interaction
with a chral copper complex,3) α-functionalized N-acyloxaxolidinones are lesssusceptible to postreaction racemization than othercarbonyl compounds,
4) the products can be transformed into usefulintermediates.

75 ~ 96% yield electron-deficient arenes
90 ~ 95% ee electron-rich arenes
meta- and para-substituted aryl rings
heteroaromatic systems

Appendix
The order for divalent ions in the first transition series indicates that Cu(II) forms the moststable ligand-metal complex and dissociation of the chelating chiral ligand in derived
complexs apparently not a complication.
Mn < Fe < Co < Ni < Cu > Znii) Copper-Catalyzed Alkene Arylation with Diaryliodonium Salts

M. J. Gaunt, JACS, 2012, 134, 10773.

This combination of a Cu catalyst and adiaryliodonium salt appears to behave as anactivated aromatic electrophile, paralleling theFriedel-Crafts type reactivity.
8/16

Exploiting the diverse reactivity of a possible carbocation intermediate♦ Pinacol rearrangements♦ Grob fragmentations♦ Cascade reactions

This new Cu-Catalyzed arylation may proceed by a reaction pathway displaying carbocation-like character,allowing the development of a number of novel tandem and cascade reactions that could expedite the synthesis ofcomplex molecules.

Small summary
They have shown that the product out comes differ significantly from these commonly obtained by the Heck reaction.
Preliminary studies have shown that a carbocation-type mechanism may be involeved in these reactions.

9/16

3.1 Meta-Selective C-H Bond Activation
Introduction

Chemical transformations of benzene derivatives have been guided by the high selectivity forelectrrophilic attack at the ortho/para positions in electron-rich substrates and at the meta
position in electron-deficient molecules.

Pioneerting WorkFriedel-Crafts Reaction
electron-donating substituents → ortho and paraelectron-withdrawing substituents → meta

Precedent & Other Works

P. Knochel, ACIE, 2008, 47, 1503.

meta and para Functionalization of Arenes
2: TMP2Mg•2 LiCl

not completely selective meta functionalization

Carboxylic Acid as Traceless Directing Groups for meta Selective Direct Arylation

I. Larrosa, ACIE, 2011, 50, 9429.

harch condition and long reaction timePd(OAc)2 were needed.

58 ~ 83% yield
Why was meta-selective C-H bond activation difficult and elusive ?
The several mechanisms that usually rationalize the majority of selective metal-catalyzed C-H bond activation.
a) oxidative addition (OA) at electron-rich low-valent transition metal centersb) σ-bond metathesis (SBM) at electrophilic early transitionmetal centersc) electrophilic activation (EA) at electron-deficient late transitionmetal centersd) concerted metalation-deprotonation (CMD)
These mechanistic pathways most commonly form the ortho-substitution product.

But there is a paucity of methods for metal-catalyzed C-H bond activation at the meta position.
10/16

Meta-Selective C-H borylationi) Meta Halogenation of 1,3-Disubstituted Arenes via Iridium-Catalyzed Arene Borylation
J. F. Hartwing, JACS, 2007, 129, 15434.

They reported the development of such a one-pot method for synthesis of bromo- and chloroarene.
but.......

1. iridium-catalyzed borylation of arenes
2. halogenation of the resulting aryl boronate esters
with copper(II) bromide or copper(II) chloride

The regiochemstry of the products results
more from steric than electroic control.
Regioselectivity was low.
Substrate scope was narrow.

M. J. Gaunt's works

M. J. Gaunt, Science, 2009, 323, 159.
M. J. Gaunt, ACIE, 2011, 50, 463.
ACIE, 2009, 48, 9052.

Circumventing the inherent ortho/para-selectivity of electron-rich aromatic systems to generate the meta productremains a largely elusive and unmet goal for chemical synthesis.

Step 1:

Step 2:

Step 3:

A possible rationalization could involve thehighly electrophilic Cu(III)-aryl species
activating the aromatic ring sufficiently topermit an anti-oxy-cupration of the carbonylgroup of an acetamide across the 2,3positions on the arene ring.

The dearomatizing
transformation would place theCu(III)-aryl species at themeta position, andrearomatizing deprotonation.

Reductive elimination

11/16ii) Meta-Selective Copper-Catalyzed C-H Bond Arylation

ortho-substituted pivanilides

meta-substituted pivanilides
poor reactivity

meta-dirylation productcontrolling the stoichiometry (2s)more complex (tri- ortetrasubstituted) anilide

Controlling the site selectivity of the C-H arylation

controllable swich
in regioselectivity
3-OTs group
3-OMe group→ 1,3,5-trisubstitute arene product→ 1,3,6-trisubstitute arene productIn certain cases the meta-selectivity can be overridden by strongly electron-donating substiruents.

12/16

iii) Concerted Metalation deprotonation (CMD)
Proposed transition states and calculated agostic intermediate

Dalton Trans, 2009, 30, 5820.

an electrophilic substitution via a Wheland intermediatewith subsequent intramolecular deprotonation bycoordianted acetate via a 6-membered transition state (5).
4-membered transition state for
intramolecular deprotonation (6).

agostic structure > Wheland intermediate
agostic interaction (weak)
ambiphilic activation electrophilic metal center&intramolecular base
The rate-determining step is computed to be formation of the agostic intermediate
via the κ2-κ1 displacement of acetate.
The agostic structure is sufficient to polarize the C-H bond and allow acetate to form an intramoleularhydrogen bond to the transferring hydrogen.
Computed reaction profiles for C-H activation[DMBA-H with (Cp*2IrCl2)]

Pathway I: via a 6-membered transition state
Pathway II: via a 4-membered transition state
Pathway III: by oxidative addition

No intermediate agostic complex was obseved.

The main activation energy barrier seems to be related
to converting a κ2-acetate to κ1.

[Small summary]
6-Membered transitionstate to give 9a was favoured overa 4-membered process via 8b to 9b or oxidative addition
to an Ir(V) species, 9c.

Transition state energy decomposition study of C-H activation
similarHydroxide can only act as an intramolecular base with a4-membered transitionstate (21).
but acetate can have a 4-membered or 6-memberedtransisiton state (22, 23).

The authors conclude the most significant contribution tothe energy difference between 23 and 22 is the energy
required to deform the reactants into their transition stategeometries.
13/16

Analysis of the Concerted Metalation-Deprotonation Mechanism

K. Fagnou, JACS, 2008, 130, 10848.
• Concerted Metalation-Deprotonation (CMD)[Feature] 1. Very little charge is present on the aromatic ring.
2. Retention of aromaticity is observed for all substrates at the CMD TS.
Free energy of activation for direct arylation via the CDM pathway

CDM TS (8)η1- and η2−C-Pd coordination compleses,
not Wheland intermediates

14 reacts preferentially over the more nucleophilic
13 in a competition reaction.

It conforms with CMD values.
Activation-Stain Analysis
distortion energy, Edist : associated with
distortion of the catalyst and arene fromground state I and II to TS geometries IIIand IV.
electronic interaction energy Eint :arising from bringing III and IV together toform TS V.

Eint = strength of the carboxylate-HAr and Pd-CAr interaction
Edist = ongoing study
thiazole N-oxides
small Edist
large Eint
electrondeficient arene
not large Eint
low Edist
π-electron-rich arenes
large negative Eintlarge Edist

benzenenot favored either value
14/16iv) Mechanistic Understanding
The three calculated reaction pathways. Relative free energies including the solvent effect (ΔGsol) are given in kcal/mol.

separated positive andnegaitve charge[Path a]Antioxycupration mechanism
1. the highly electrophilic Cu(III)-aryl
species activates the aromatic system
as Lewis acid
2. the carbonyl oxygen attacks theortho position, pushing electrons out toform a C-Cu bond at the expected metaposition.
Path a is extremely unfavorable for the following reasons;(a) the amide group is a weak π-electron donor, and the site being attacked is the unfavorable electron-rich ortho
position.
(b) copper shifts from the preferred electron-rich para position to the unfavorable meta position.
(c) the aromaticity is brocken without adequate compensation.

[Path b]Starting Z-type carbonyl
coordinated complex 2 with thecopper, a intramolecularFriedel-Crafts-type
electrophilic attack at Cortho
takes place.

The other four
ligands roughlyin a plane

The apical OTf- anion
disassociates from thecopper and abstracts
the proton from Cortho
in an intermolecularfashion.

Reductive elimination,
which is easy because of
the strong driving force forCu(III) reduction, results inthe ortho-arylated product.

[Path c]path c shares withpath b theelectrophilic-attack
step from 2 to Int0.

The phenyl group bonded to copper istransferred to the mata position via theHeck-like four-membered-ringtransition state TS1-c, leading tointermediate Int1-c.

Free OTf- anion abstracts the proton
at the meta positon, recovering thearomaticity and resulting in the metaarylated product.

indicating a weaker Cu-Cortho interaction

Aromaticity is not completely destroyed in path c.

TS1-c

Int1-c
15/16

The effects of the terminal R1 proup and the aromatic substituent R2 group

JACS, 2011, 133, 7668.

• A large R1 group pushes copper to the trans position,
facilitating the electrophilic attack at the ortho carbon.
(entry 2)• The electronic character of R1 has a small effect on thereaction. (entry 3~7)
• All of the ortho, meta, and para EDGs lower thebarrier for path c because they can increase theelectron density at either C1 or C2.
• EWGs generally raise the berriers for both pathways.

R1 → reflect the steric character of the Cu(III)-Ph species
R2 → reflect the electrophilic character of the Cu(III)-Ph speciesv) Activation of remote meta-C-H bonds

Jin-Quan Yu, Nature, 2012, 486, 518.

high meta-selectivity

4. Summary
Meta-selective C-H activation chemistry has room to improve the range of substrates so on.
but I think......

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