topic: n-heterocyclic carbene catalysis not covered here · 2011, 3, 880 see also: zeitler and...

Update to 2013 Bode Research Group http://www.bode.ethz.ch/

1

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

Topic: N-Heterocyclic carbene catalysis

N-heterocyclic carbenes (NHC’s) are neutral species that possesses a divalent carbon atom with an electron sextet. They were recognized and isolated as stable molecules at the end of 1980’s and beginning of 1990’s but the first evidence of their existence as reactive intermediates was presented almost hundred years earlier. NHC’s have broad field of application in organometallic chemistry (ligands for metathesis, hydrogenation not covered here) and in organocatalysis as nucleophilic catalysts. 1 NHC catalysis NHC’s can be generated from the parent imidazolium, triazolium or thiazolium salts by treatment with a base and can be represented both as ylides or carbenes.

General Structures of nucleophilic carbenes

S N R'

thiazolylidene

N NR R'

imidazolylidene

NN NR R'

triazolylidene

XY N R

XY N R

H

XY N R

Base

carbene ylide

Nolan ACIE 2007, 46, 2988

- pKa values of precatalysts and 13C shifts NHC’s

NN MeMe

H

pKa in DMSO

NN MeMe

H

NN MeMe

H

NN PhMe

H

NN PhPh

H

SNMe

H

22.3 21.1-22.0 19.7 16.1 21.6 14.5

NN MesMes

13C ! (ppm) 243.8 219.7 254.3 214.6

NN MesMes SN

Me MeiPr

iPr

NNN PhPh

Ph

Glorius ACIE 2010, 49, 6940

- NHC nucleophilicity: The observed reactivity of NHC originates from their high Lewis basicity, not nucleophilicty. The attack of NHCs to the carbonyl group of aldehydes occurs under kinetic control and has a lower degree of reversibility.

NN MesMes NN MesMesNNN PhPh

PhN

NPh3P

Higher nucleophilicity (kinetics data)

NNN MeMe

NNN tButBu

NNN PhPh

NNN MesMes

Higher Lewis basicity (calculation) Mayr ACIE 2011, 50, 6915

- The effect of the N-substitution is also of important consequence in both the properties of the NHC and in the catalytic pathway.


2

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

DBU

DBU-H+

NN N

BF4-

F

FF

F

FH

NN N

F

FF

F

Ftriazolium salt fully deprotonated

with 1 equiv DBU

NN N

Cl-

Me

MeMeH

NN N

Me

MeMe

DBU

DBU-H+

triazolium salt not fully deprotonated with 1 equiv DBU

O

RNN

N

ArH

initial adductirreversible

reversible

H

O

R

H

O

R

more Lewis acidic

less Lewis acidic

Bode Chem. Sci. 2012, 3, 192 See also Rovis Chem. Lett. 2008, 37, 2

NHC intermediates: - While the initial NHC-aldehyde adducts have been isolated and reported by many groups, the enaminol Breslow intermediate (see Thiamine catalyzed Benzoin reaction mechanism) remains elusive.

N N

N

Ph

PhPh

OH

ClO4-

N N

N

Ph

PhPh

OH

ClO4-

Me

Teles and Enders Helv. Chim. Acta., 1996, 79, 61

N

N

Bu

Me

OH

Cl-

Ph

AggarwalChem. Commun. 2002, 1612

N

NN

Ph

Ph

O

Me

H

Breslow intermediate (keto form) and a dimeric speciesBerkessel ACIE, 2010, 49, 7120

N

NN

Ph

Ph

OO

Me

MePhPh

2 Cyanide ion catalyzed benzoin condensation

Ph H

OKCN

Ph CN

OH

Ph CN

OHPh H

O

Ph CN

HOO

Ph

Ph CN

OOH

PhPh

OOH

PhThe benzoin condensation was the first organic reaction with its mechanism fully elucidated.

Liebig Annalen der Pharmacie, 1833, 3, 249

For mechanism: Lapworth, J. Chem. Soc., Trans. 1903, 83, 995 & 1904, 85, 1206 In the benzoin reaction (and many other NHC-catalyzed reactions), the aldehyde carbon undergoes a reversed polarity from an electrophilic center to being a nucleophilic center. This concept is termed “umpolung.”

Corey JOC 1975, 40, 231 & Seebach ACIE 1979, 18, 239 3 Thiamine catalyzed benzoin reaction Thiamine or vitamin B1 is the first water soluble vitamin described and an important coenzyme in a number of biochemical reactions. In the beginning of 1940’s Ugai found that thiamine in the presence of a base catalyzed the benzoin reaction. Recognizing the similarities in reactivity of the cyanide anion and thiamine, Breslow proposed that a stabilized carbene is responsible for the reactivity of thiamine. This work of Breslow in 1950’s constitute first mechanistic description of NHC’s.


3

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

OH

H2NN S

H3CNH3C

N base

HCl

thiamine

OH

R N S

H3C

OH

R N S

H3C

ylide

carbene

O

Ph H

OH

R N S

H3C

Ph OH

OH

R N S

H3C

Ph OH

OH

R N S

H3C

PhOHO

Ph

OH

R N S

H3C

PhOOH

Ph

PhPh

O

OH

O

Ph H

R2 N S

R3R1

HCl

A general struture of thiazolium salt precatalyst

for benzoin reaction(R = alkyl or aryl)

Breslow intermediate

NHC-aldehydeadduct

reversible

rate-limiting

Proton shift

Ugai J. Pharm. Soc. Jpn. 1943, 63, 296 & Breslow JACS 1958, 80, 3719

The mechanism of the benzoin reaction is complicated, see Breslow Tet. Lett., 1994, 35, 699 & Leeper, JOC, 2001, 66, 5124.

4 Acyl anion As mentioned above upon NHC addition to a carbonyl, the latter undergoes a reversed polarity and this newly generated acyl anion has been used in many transformations.

O–

CatR H

O

HRCat HO

CatR

HO

RO–

RH

Cat

O

ROH

RHO

H R

OH

R H O

R1O

RHN

R1H O

R S R1

O

R

NO2

O

R' NO2

FS R'

SR'

Benzoin Product

Stetter Reaction Aldehyde–ImineCouping

AromaticAcylation

ThioesterSynthesis

R2

R1H

N R2

For a review of catalyzed reactions of acyl anion equivalents, see Johnson ACIE 2004, 43, 1326

4.1 Enantioselective 1,2 additions – Benzoin reaction

Ph

O

H2

S N

Me!!O

Ph

OBr

(10 mol %)

Et3N (10 mol %)MeOH, rt

Ph!! Ph

O

OH50%

optical purity: 0.77%

Ph

O

H2 (10 mol %)

KOtBu (10 mol %)THF, 18 °C

Ph!! Ph

O

OH

NN N

O

PhtBu

BF4

83%90% ee

N

N

N

O

Ph

tBu

Ph

HO

Ph

OH

Early attempt by Sheehan: Enders:

Sheehan JACS 1966, 88, 3666 & Enders ACIE 2002, 41, 1743

For computation investigation, see Houk PNAS 2004, 101, 5770


4

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

- A catalytic enantioselective intramolecular benzoin reaction:

N

O

OMeO

O

10 mol% cat10 mol% Et3N

THF, RT

N OOMe

OOH

86% yield, 99%ee

NN N

O

Cl-

OMe

OMe

CF3

CF3

MeOMeO

O HOOH

OMeO

O

O

Me

OHOMeOMe

O OH

MeMe OH

HO

(-)-seragakinone A

N

O

OO

O

O

40 mol% cat40 mol% DBU

THF, RT

N OOO

OOH

73% yield, 99%ee

cat=N

N

N

O

Ph

Cl

An application in natural product synthesis:

Suzuki ACIE 2006, 45, 3492 & ACIE 2011, 50, 2297

- A cross-benzoin between aldehydes and ketone has also been achieved using very electron poor ketone substrate.

O

O

O

F3C Ph

NN

NF

F F

F

F

OTBDPSBF4-

10 mol%

1.0 equiv i-Pr2NEt

OHCF3

PhO

O86 %78 %ee

Enders Chem. Commun. 2010, 46, 6282

- A more challenging problem is the chemoselective cross-benzoin reaction between two aldehydes, due to the self condensation

OO

H Me

NN

NF

F F

F

F

BF4-

10 mol%

10 mol% Cs2CO3

Cl

10 mol% Cs2CO3

HO

S N EtBr-

10 mol%

Me

H

OH

ClO

Me

82 %

O

ClOH

Me

84 %

Ryu and Yang Org. Lett. 2011, 3, 880

See also: Zeitler and Connon JOC, 2011, 76, 347 & Synthesis 2011, 2, 190 - Aza-benzoin variant - Aldehyde-imine coupling via acyl anion chemistry

O

H +R4 N R5

O

R1NH

HN R2

O

OS

NEt

HN R5

O

R4 Obase(15 mol %)

I

up to 90%up to 87% eeR R

Miller JACS 2005, 127, 1654


5

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

4.2 1,4 additions – Stetter reaction

- Mechanism and early example

Ph

O

H

PhO H

N

S

R1R3

R2

Ph

OH

N

S

R1 R2

R3

O

PhAr

O

PhAr

OHPh

NS

R1R3

R2

Ph

OPh

OAr

SN Me

MeHO

I

S

NMe

Me

HO

I

O

O

H20 mol% catK2CO3, THFCO2Me

O

O

CO2MeMeO

56% yiel, 61% ee

NN N

O

OMeMe Ph

PhClO4

MeO

Enders Helv. Chim. Acta. 1996, 79, 1899

- The research program of Prof. Tom Rovis (Colorado State University) has established the current state of the art for enantioselective Stetter reactions.

X

O CO2R2

R1

20 mol% cat20 mol% KHMDS

xylenes, 25 oC, 24 hX

O CO2R2

R1

O

O CO2Et

94% yield, 94% ee

O

O CO2Et

OMe95% yield, 87% ee

S

O CO2Me

63% yield, 96% ee

NMe

O CO2Me

64% yield, 82% ee

N NN

OMe

O

BF4-

Rovis JACS 2002, 124, 10298

- Stetter reaction is not as well studied mechanistically as benzoin reaction:

O

O CO2Et

O

O CO2EtN N

NPh

Bn

PhMe20 mol%

O

HO RN

RN N

H/D

O

OH/DRN

RN N

rate-limitingrate = k[ald]1[cat]1

KIE = kH/kD = 2.62

Rovis OL 2011, 13, 1742

4.2.1 Intermolecular variants Many aldehydes can be used in Stetter reaction unfortunately formaldehyde undergoes benzoin condensation too fast and can not be used as a C1 source. However recently group of prof. Chi reported use of biomass-based carbohydrates as formal formaldehyde (C1) source for intermolecular Stetter reaction:


6

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

OHO

HOOH

OH

OHOH

HOHO

OHO

OH

OHHO

HOOH

O

OHN S

MeMe

Me

OHHO

HOOH

O

OH

N

S

Me

Me

Me

OHHO

HOO

OH

OH

N

S

Me

Me

Me

retro-benzoin

HO

N

S

Me

Me

Me

Ph Ph

O

Ph Ph

OCHO

Stetterreaction

Ring-chain tautomeric forms

OHO

HOHO

OH

OH

R1

O

Ar

NMeS

MeMe

I(20 mol%) K2CO3µW 130°C

R1

O

Ar

CHO

Chi JACS, 2013, 135, 8113

- Enantioselective variants

R2

O

R3R1

O+

10 mol% cat10 mol% Cs2CO3

THF, 0 oC, 6h R1

O

R2

R3

O

Ph

O

Ph

Ph

O65% yield, 66% ee

O

Ph

Ph

OMe43% yield, 78% ee

O

Ph

Ph

OS

98% yield, 56% ee

N

N

N

OTBDPS

BF4

cat=

Enders Chem Commun 2008, 3989

- The effect of the catalyst conformation in an intermolecular Stetter reaction

H

O

N NO2

+

10 mol% cat100 mol% DIPEA

O

NNO2

N NN

F F

FFF

BF4MeMe

90 %88 %ee

N NN

F F

FFF

BF4MeMe

95 %95 %ee

N NN

F F

FFF

BF4MeMe

22 %88 %ee

F F

Rovis JACS 2009, 131, 10872 & Rovis and Houk JACS 2011, 133, 11249

- A bifunctional additive (catechol) was found to accelerate the reaction’s rate


7

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

H

O

NO2

+10 mol% cat

100 mol% DIPEA

O

NO2

N NN

iPr F F

FFF

BF4

F

Ph Ph

80 %; 93 % ee(5 % w/o cathecol)

OH

OH

N

N

NAr

H

O R

O

OH

Rovis JACS 2011, 133, 10402

5 Summary: reactive intermediates generated from α-functionalized aldehyde

H

O

R1

NN N

R2 R3

NN N

R2 R3

H

NN N

R2 R3

Base

carbene ylide

OH

R1N N

NR2

R3


OH

R1N N

NR2

R3

acyl anion

OH

R1N N

NR2

R3

homoenolate

O

R1N N

NR2

R3

protonationH

O

R1N N

NR2

R3

enolate

O

R1N N

NR2

R3

!," unsaturatedacyl azolium

H

H+

transfer

H

oxidationacyl azolium

azolium

Recently group of Prof. Chi reported generation and reactions of the homoenolates from saturated esters.

R O

ONO2

R1 R2

O

N NN

Ph

t-Bu BF4

DBU, MeCN4A MS, rt, 24h

(20 mol%)

R2

RR1

R

O

N N

N

ArO

R

O

N N

N

H

H

R

O

N N

N

Homoenolate!-deprotonation proton shift

Homoenolate generation

Chi Nat. Chem. 2013, 5, 835 For a full mechanism of cyclopentene formation see 6.4 or the reference above

6 Homoenolate reactions 6.1 γ-lactone synthesis

For a review of NHC-homoenolate chemistry, see Nair Chem. Soc. Rev. 2011, 40, 5336


8

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

R1 H

O

H

O

R2

+DBU (7 mol %)

THF/t-BuOHrt, 3!15 h

O

R2

R1

ON N MesMesCl

(8 mol %)

R1 H

O

R1

O

N

NMes

Mes

H

R1

OH

N

NMes

Mes

R1

OH

N

NMes

Mes


homoenolate

H

O

R2

R1

OH

N

NMes

Mes

R2 O

activated carboxylate

R1

O

N

NMes

Mes

R2 O

N

NMes

MesOR2

R1O

Bode JACS 2004, 126, 8126 and Glorius ACIE 2004, 43, 6205

- Rendering γ-lactone formation enantioselective however remains challenging

R2

O

R3

O+

5 mol% cat10 mol% Cs2CO3THF, 0 oC, 6h

Ph

N NN

O

Me

Me

MeCl-

O

EtO

O

O

PhPh

CO2EtO

O

PhPh

CO2Et

18%25% ee

82%23% ee

You Adv. Synth. Catal. 2008, 350, 1885 6.2 γ-lactam synthesis

R1 H

O

R2 H

NS

O O

OMe (15 mol %)+

N

NMes

Mes

OH

R1

N

O

R1 R2

SO2Ar

61!75%

N N MesMesCl

DBU (10 mol %) R2

NS

Ar

O O

Bode OL 2005, 7, 3131 & Bode JACS 2008, 130, 17266

OHS

N

OON

ONN

Me

Me

MeCl

NS

O O O

R2

R3

R1

R3

via

SNH

OO

R3

O

R2

R1

N

N NMes

SN

OO

R3

catO

R1

R2

up to 94% yieldhigh dr and ee

R1

R2

!,"-unsaturatedacyl azolium

O O

t-Bu

t-Bu t-Bu

t-Bu

10-20 mol %

Bode ACIE, 2012, 51, 9433

- A Lewis acid can also be used for preorganization; however, an uncommon protecting group was needed.


9

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

R1

O

H+

5 mol% NO

R2OC

R1

N

O

NN

BF4- Et

Et

5 mol% Mg(OtBu)2

60-85 %88-98 %ee

TBD (10 mol%)N

COR2

NH

O

ArHN

O

Ar

ON

NNN

NH

R1R2OC

OMg

Ar

LL

OHN

NN

NNH

R1

R2OC

OMg

Ar

LL

Scheidt Nature Chem. 2010, 2, 766

- A Bronsted acid was found to improve the selectivity of a γ-lactam formation reaction

R

ArN

H

O

H

N20 mol %+ N

O

EtO2C

Ph

NN N C6F5

BF4

MS; acrylonitrileO

OEt

Ph

ONa

O

Cl 20 mol %

PhPh

92%92% ee

dr = 14:1

NN N

O

EtO2HCO

O

ClH

H

CyC6F5

Rovis JACS 2011, 133, 12466

6.3 Other electrophilic acceptors

R1 H

O

R2 H

N (20 mol %)+

NN N Me

62!80%81!93% ee

Et3N (20 mol %)R3O

OPh

Ph

BF4

NO

O

R1

R2R3

MeOHNOH

R1

R2R3

O

MeO

Scheidt JACS 2008, 130, 2416

R H

O+

NO (10 mol %)

N N ArArCl

Ar = 2,6-(iPr)2C6H3

KOtBu (10 mol %)H+, CH3OH

OMe

ONH

MeOO

NR

O

R

Zhang and Ying OL 2008, 10, 953

6.4 Cyclopentene synthesis

Ar

OHN

N

Mes

Meshomoenolate equivalent

Ph Ph

O

O

PhO

Ph

ArN

N

Mes

Mes

ON

N

Mes

Mes

O Ph

Ar Ph

Ph

Ph

OO

Ar

R1 H

O

Ar' Ar

O+ (6 mol %)

DBU (12 mol %)

Ar

R1 Ar'

N NMes MesCl

55!88%

Nair JACS 2006, 128, 8736

- Alternatively the mechanism of cyclopentene formation reaction maybe considered as Benzoin oxy−Cope rearrangement, rather than homoenolate chemistry.


10

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

R1

O

H

+

R2

O

CO2Me

10 mol%

N

N N

O

Mes

Cl

15 mol% DBU

ClCH2CH2Cl, 0!23 oC, 40 h

R2

R1

MeO2C

R1

Ph

Ph

p-CF3C6H4

n-Pr

R2

Ph

p-MeOC6H4

Ph

Ph

%yield

78

58

68

25

cis:trans

11:1

5:1

4:1

14:1

% ee

99

99

98

96

Ph

CO2Me

O

Cat

O

Ph

H

Boat-like oxy-Cope TS

Ph

CO2Me

OH

Ph

Cat

O

Ph

CO2Me

O

tautomerization

intramolecularaldol

Cat

O

Ph acyl addition

decarboxylation

Ph

CO2MePh

Bode JACS 2007, 129, 3520

- Recently Scheidt has revisited cyclopentene formation and applied the use of a Lewis acid

R1

O

R1

O

H+

R3

O

R2

10 mol% R3R1

R2

N

O

NN

BF4- Et

Et

20 mol% Ti(OiPr)4

50-82 %98-99 %ee

RN

N N R2

O

R3

R

[Ti]

R1

ORN

N N R2

O

R3

R

[Ti]

Scheidt JACS 2010, 132, 5345

For a review on NHC-Lewis acid cooperativity, see Scheidt Chem. Sci. 2012,3, 53 6.5 Cyclopentane synthesis The nature of the precatalyst used controls the stereochemical outcome that results in two complex pathways with absolute control of product selectivity

Ph H

O

+

EtO2C

O

OH

Me Me

N

O

N

N

MesCl-

(10 mol %)DBU

OPh

EtO2C

O

OH

Me Me

PhCH3

N

O

NMes

ClO4-

(10 mol %)DBUPhCH3

Me

OH

Ph

EtO2C

O

O

Me

Me

Bode OL 2009, 11, 677

7 Enolate 7.1 Catalytic generation of NHC-bound enolate

R1N

YN

O– R

R

R2

enolate

R1

O

HCl

R2 CO

R1

R2R2=H

R1

O

H

R2R2=H

R1

OH

SO3NaCl

R2

R2=H

7.2 Hetero Diels-Alder reaction from aldehydes and related compounds


11

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

H

O

ClR1 +

R2

O

CO2Me 0.5 mol% cat1.5 equiv NEt3

0.2 M EtOAc, rt

O

O

R1

MeO2C R2

R1

PhPhPh

n-C9H19OTBS

R2

MePhc-Hex

MePh

d.r.

>20:115:1

>20:1>20:1

3:1

% ee

9999869997

% yield

8898767180

NNN

O

MesCl

O

H

Ph

O–

NN

N

Ph

O–

NN

N

MesH

NN

N

Mes (Z)-enolate

O

Ph O

MeO2C

MeMe

Me

MeO2C

O

Me

Elimination

Diels-Alder

nuc. addition

O

MeO2C

Ph

O N

NNMes

Ph

Cl

Cl

MeMe

Bode JACS 2006, 128, 15008

7.2.1 Hetero Diels-Alder reaction, a bisulfite salt variant - The issue of handing and storage of chloroaldehyde was addressed by its in situ generation via a masked bisulfite salt adduct.

+R2

O

R3

1 mol% cat1.0 M aq K2CO3

(3.2 equiv)

0.16 M Toluene, rtO

OR1

R3R2

SO3Na

OHR1

Cl

O

O

CO2EtPh

84% yield, 90% ee

O

O

n-PrEtO2C

80% yield, >99% ee

O

O

n-PrEtO2C

Ph

78% yield, >99 %ee

O

O

CO2EtMe

Ph

65% yield, 99% ee Bode OL 2008, 10, 3817

- Recently our group has demonstrated the use of enal in hetero Diels-Alder reactions

H

O

R1+

R2

O

R3

10 mol% cat15 mol% base

0.1 M CH2Cl240 oC, 6!16 h

O

O

R3 R2

R1

O

O

EtO2C

PhNHCbz

Me Me

98% yield, >20:1 d.r., 99% ee

O

O

EtO2C

Me

Me MeOH

89% yield, >20:1 d.r., 99% ee

O

O

MeO2C p-MeOC6H4

60% yield, >20:1 d.r., 99% ee

n-C3H7

Bode PNAS 2010, 107, 20661

- A generation of enolate via formylcyclopropanes

H

O+

NN N Mes

BF4-

(12 mol %)

10 mol% DBUAr Ar'

O

O

R

O

NHC+

OR

O

ArAr'

OOO Ar'

Ar

O

R

39 - 95%99 %ee

Chi OL 2011, 13, 5366

- An aza-Diels-Alder reaction has also been achieved


12

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

H

O+

NN N Mes

Cl

(10 mol %)iPr2NEt (10 mol %)

Toluene/THF, rt, 23 h

R H

N

O

EtO

O

SO2Ar

Ar = p-C6H4OMe

N

OSO2Ar

R

EtO2C

90% yield, 99% ee

N

OSO2Ar

Ph

EtO2C

58% yield, 99% ee

N

OSO2Ar

Pr

EtO2C

71% yield, 99% ee

N

OSO2ArEtO2C

O

Bode JACS 2006, 128, 8418 - A Mannich reaction has also been reported for the synthesis of β-amino acid derivatives

ArOH

O

Ar = 4-NO2C6H4

+

R H

NTs

NN N

OMe

Me

Ph

Mes

BF4

(10 mol %)

4-NO2-C6H4ONa (2 euqiv)2) BnNH2

1)

R NHBn

NH OTs

56!75%88!95% ee

Scheidt JACS 2009, 131, 18028 7.3 Generation of NHC-bound enolate via ketene - Many formal [2+2] and [3+2] cycloadditions have been reported for the synthesis of β -lactones and lactams

O

Ar R H COR'

O+

OO

RAr COR'

NN N Ph

BF4

PhOTBSPh

O

Ph Ph R H

N+

NO

Ph RPh

Ts TsN

N N PhBF4

5-10 mol%KHMDS

59-94%

73-99%78-99 %ee

12 mol%Cs2CO3

Smith OBC 2008, 6, 1108

Ye JOC 2008, 73, 8101

NN NO

Ph Et

+NHC (10 mol %)

Cs2CO3 (10 mol %)toluene, rt

71%91% ee

ArOHAr

CF3

CF3N

OCl N

O

O

EtPh

H

TsCl

Ts

Ar = 2-iPrC6H4

BF4

OPh

Et

NHCAr

NO

Ts

Ye ACIE 2010, 49, 8412

- Ye has demonstrated this strategy also in many [4+2] cycloaddition reactions


13

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

NN N

BF4O

Ph Et

+ 10 mol % NHC

Cs2CO3 (10 mol %)THF, rt

95%90% ee

NBz

O

CO2Et

O NO

PhEt

CO2Et

Bz

PhOHPh

CF3

CF3

NN N Ph

OO

Ph Et

+PhN

Ts

CO2Et

NO

EtPh

CO2Et

TsPh

Cs2CO3 (40 mol %)benzene, rt, 12 h2) DME, rt, 24 h

1)87%

91% ee

BF4

NN N Ph

BF4O

Ph Et

+Cs2CO3 (10 mol %)

THF, rt

93%94% ee

N N

OO

ArOTBSAr

N

PhO

NPh

Ar = 2-naphthyl

Ph

PhEt

Ph

20 mol % NHC

10 mol % NHC

Ye JOC 2010, 75, 6973, ACIE 2009, 121, 198, & Chem. Commun. 2011, 2381

7.4 Generation of NHC-bound enolate for enantioselective protonation - Rovis has demonstrated the proof of this principle

R1H

O

Cl Cl

+OH

NN N

O

C6F5

BF4

(5–10 mol %)

KH/18-crown-6toluene, 23 °C

R1O

O

Cl62–85%

76–93% ee

R2R2

H

O+

NN N

O

BF4

(10 mol %)

1M K2CO310 mol% Bu4NItoluene, 23 °C 65-96%

90-96% ee

H2O orD2O

F

F

FR OH

O

FR

O

XR

N

N

N

O

Ar

H+

Rovis JACS 2005, 127, 16406 & JACS 2010, 132, 2860

- Ketenes have also been used. Impressive results can be obtained with some substrates. This works best when the two substituents on the ketene differ greatly in size.

O

Ar R

+ NHC cat.R'OH R OR'

O

ArH

NN N Ph

BF4

PhOTBSPh

BF4NN N Ph

OMeMe

iPr

Ye: Smith:

24-77 %11 - 95%ee

65-91 %33-84 %ee

- 40oC

Ye OBC 2009, 7, 346 & Smith Adv. Synth. Catal. 2009, 351, 3001

8 Acyl azoliums “Acyl azoliums are fascinating reactive intermediates with chemistry quite distinct from that of other activated carboxylic acid derivates…. These species have long been studied for their unusual reactivity and role in biochemical pathways. Unlike other acylating agents, acyl azoliums display a high preference for ester formation or hydrolysis rather than amide formation. This is attributed to the rapid formation of kinetically important hydrates or hemiacetals that undergo general base catalyzed C-C bond cleavage in the acid or ester forming step.”

Bode JACS 2010, 132, 8810

R

ON

YX

ON

YX

R

I II


14

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

8.1 Internal redox esterification Epoxy aldehyde

R1R2

O O

H R3OH R1R2

O

OR3

OH

10 mol % NHC8 mol % DIPEA

30 °C, 3–15 h

+

S

NBn

Me

Me

Cl–

redox-neutral

oxidized

reduced

Bode JACS, 2004, 126, 8126

- Mechanism:

O

R1HO

S

NBn

Me

Me

OH

R1O

S

NBn

Me

Me

OH

R1O

S

NBn

Me

Me

S

NBn

Me

Me

R2

R2

R2

O

R1

O

S

NBn

Me

Me

R2

H

O

R1

HO

S

NBn

Me

Me

O

R1

OH

S

NBn

Me

Me

R2

R2

23

O

R1

OH

OR3R2

O

R1O

HR2

+

H

or

S

NBn

Me

Me

H

DIPEA

R3OHR3O–

- Redox esterification from α-bromoaldehyde was concurrently reported:

R1H

O

Br

R3OH(20 mol %) R1

OR3

O

R2R2

NN N Ph

BF4

Et3N (1 eq)

55!91% Rovis, JACS, 2004, 126, 9518

- Other redox reaction of other α-functionalized aldehydes

EWG

R1

H

O

+

NN N Mes

(5 mol %)DBU (20 mol %)

EWGOR2

OR1

84!98%

Cl

R2OHBode ACIE, 2006, 45, 6021

NaN3/ TMSN3

Bu NH

O

N320 mol % NHC16 mol % Et3N

+BuH

O

ClEt

NN N

O

C6F5

BF4

Et

50%55% ee

Rovis JOC 2008, 73, 9727

R1

H O

NN N Mes

BF4

(20 mol %)Et3N (1.5 equiv)

THF

R1

R2O O

22-95%

R2OHSmith Chem. Commun 2011, 47, 373O

O

O2N


15

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

- Protonation of homoenolate

R1 H

O

NN N Mes

BF4

(5 mol %)DIPEA (10 mol %)

THF, 60 °CR1 OR2

O

63–97%

R2OH+

OH

R1N N

NR2

R3


OH

R1N N

NR2

R3

homoenolate

O

R1N N

NR2

R3

HO

R1N N

NR2

R3

enolate

H

H+

transferH

acyl azolium

H+

Bode OL 2005, 7, 3873

8.2 Catalytic amidation reactions - Amidation reactions are difficult to achieve due to acyl azolium’s reluctance to acylate amines. This property has been utilized in chemoselective amidation by intramolecular O to N transfer.

OMe

O

+(5 mol %)

N N MesMesPh

OHH2NTHF

OPh N

NMes

Mes

HONH2

OPh

O NH2

OPh

HN OH

Movassaghi OL 2005, 7, 2453 & TL 2008, 49, 4316

- The use of cocatalyst (i.e. HOAt or imidazole) solves the chemoselectivity issue

R1 H

O

(20 mol %)HOAt (20 mol %)DIPEA (1.2 eq)

HNR3

R2

+ R1 N

O

Cl Cl Cl R3

R2

72!89%

NN N C6F5

BF4

EWG

R1

O

H(5 mol %)

imidazole (1.1 eq)DBU (20 mol %)

HNR3

R2

N

O

R3

R2

53!99%

+R1

EWG

NN N Mes

Cl

OPh

N

RN

RN

N NH OPh

N

N

react slowly with amine

react readilywith amine

(A)

(B)

(A) Rovis JACS 2007, 129, 13796 & (B) Bode JACS 2007, 129, 13798

8.3 Oxidative esterification

- Although the reaction outcomes are the same (net oxidation of aldehyde), the mechanism for each oxidant may differ (i.e. electron transfer, hydride transfer, or benzoin type addition).


16

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

Ph+

S N Bn(5 mol %)

H

O

1.0 equiv [O]MeOH

Br-

Et3N (7.5 mol %)

Ph OMe

ON

NPh

NN

Ph

71 % 84 %

Azo compounds; Inoue, J.C.S. Chem. Commun. 1980, 549 & Connon TL 2008, 49, 4003

+

NN N Me

(2 mol %)

DBU (1.1 equiv)

Me

H

O

Ph tBu

tBu

tBu

tBu

OO

(1.0 equiv)

Ph OR

O

(A) Quinone as oxidant

ROH

71!93%

I

R1

OH

N N

NR2

R3


R1

O

N N

NR2

R3

acyl azolium

[O]

+

Cs2CO3 (0.5 equiv)

H

O

R

tBu

tBu

tBu

tBu

OO

(1.0 equiv)

R O

O

(B) Quinone as oxidant

53-93% yield70-94% ee

R3

O OH

R2

O

N NN+

MesBF4-

(10 mol %)

R2R3OC

", #-unsaturatedaldehydes

saturatedaldehydes

+

DBU (1.0 equiv)

H

O

Ph

(5.0 equiv)

(C) MnO2 as oxidant

24-57% yield64-95% ee

O

N NN+

C6F5BF4-

(10 mol %)

", #-unsaturatedaldehydes

NPG

R1 OH

O

NPG

R1 O

O

O

Ph

+ recovered alcohols

MnO2

S factor up to 70

O

NN

N+C6F5O

Ph

chiral acylating agent

(A) Studer JACS, 2010, 132, 1190 & (B) Chi ACIE 2013, 132 8750 and related work, Chi Nature Chem. 2013, 5, 835 &

(C) Zhao ACIE, 2013, 52, 1731 & for other KR, see Maruoka OL 2005, 7, 1347; Suzuki Tetrahedron 2006, 62, 302; Studer Synthesis 2011, 12, 1974 & Yashima CEJ 2011, 17, 8009

9 α-Hydroxyenone as aldehyde surrogate

Bode and co-workers have previously acknowledged the relative difficulty of preparing cinnamaldehyde derivatives and introduced α-hydroxyenones as easily prepared (one step from commercial materials via aldol condensation) and stored surrogates.

R1 OHO

Me Me

NN N Mes

R1 OH

Me Me

ON

N

NMes

R1 O

Me Me

OHN

N

NMes

retro-benzoin

Me

O

Me

R1R1 H

OR1

O

N N

NH

MesBreslow intermediate

OH

N N

N

Mes

Surrogate concept: retro-benzoin reaction


17

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

MeO2C Ar

O

DBU (50 mol %)

Ar

R1 CO2Me35!76%

2:1!10:1 drDBU (15 mol %)

SN

O O

R2

SN

O OO

R1R2

43!99%2:1!12:1 dr

R1 OHO

Me Me

+Ph Ph

N

N

R1

PhPh

OSO2Ar

SO2Ar

77%3.5:1 dr

DBU (50 mol %)

NN N Mes

ClH

O

Br

O

O

R1 p-BrC6H458%

3:1 dr DIPEA (20 mol %)1,2,4-triazole (10 mol %)

HNR4

R3

R1 NR3

O

R421!99%

(5!20 mol %)

DBU (50 mol %)

Bode JACS 2009, 131, 8714 & Chem. Commun. 2009, 4566

10 NHC promoted sigma-tropic rearrangement - Bicyclo-β-lactam formation

R1

O

H Ph

N

Ph

SO2Ar

+10 mol%

N

N N

O

MesCl

15 mol% DBU

0.1 M EtOAc, rt, 15 h

NO SO2Ar

PhH

R1

Ph

%yield

94

81

45

80

% ee

>99

99

99

99

R1

Me

n-Pr

H

Ph

Ph

Ph

O

Cat

N

Ph

H

Boat-like oxy-Cope TS

SO2Ar

Ph

CO2Me

NH

Ph

Cat

O

Ph

CO2Me

N

tautomerization

Mannich

reaction

Cat

O

Ph

ArO2S SO2Ar

!-lactamformation N

O SO2Ar

PhH

R1

Ph Bode JACS 2008, 130, 418

- Claisen rearrangement via α,β-unsaturated acyl azolium. A competing plausible conjugate addition between the enol and the unsaturated acyl azolium was ruled out by a detailed kinetics analysis.

!H‡ = +15.30 kcal/mol

!S‡ = – 25.50 cal/K.mol

kobs = – 3.41x10-4 s-1

rate = -kobs [cat]1[ald]0.5[Nu]-0.5

O

H

R3

O

HO N

NN

R3

R2

R1

Mes

O

R3

R2

R1

O

10 mol % 1PhCH3, 40 °C

no added base

R3

O

N N

N

Mes

N

O

N

NCl!"#

Mes

1

azolium catalyzedinternal redox reaction

I ",#-unsaturated acyl azolium

OH

R2

R1

O

HO N

NN

R3

R2

R1

Mes

+

Claisen rearrangement

tautomerization and lactonization

H

activated carboxylateII III

OH

R2

R1

O

O

HO

p-ClC6H4

MeO2C

OTBS

O

O

HO

Bu

MeO2C

OTBS

90% yield96% ee

78% yield99% ee

For Examples:

O

Ph

O

CO2Me

O

O

Me

CO2Et

74% yield99% ee

73% yield88% ee

O

O

Ph

79% yield68% ee

MeO

Bode JACS 2010,132, 8810 - An aza-Claisen variant of the above reaction has also been achieved. Here, the key α,β-unsaturated acyl azolium was catalytically generated via an oxidation of the Breslow intermediate instead of an internal redox reaction. α-hydroxyenones can also be used as aldehyde surrogate in this reaction.


18

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

O

HR1 NH

R1

R3R2

O

NH2

R3R2 N

N NMesHN R3

OHR1R2

oxidant (1.2 equiv)

24 examples58-99%

(ee = up to 96%)

O

R1

or

OH

Me Me

via

NHC-catalyzedaza-Claisen

NNN

O

MeMe

Me

Cl–

(10 mol %)

OO

tBu

tBu tBu

tBu

NH

CNMe

O

NH

MeCN

Me

O

NH

PhNO2

Ph

O

NH

CO2tBuMe

O

F

F

60 %96 %ee

99 %90 %ee

91 %79 %ee

67 %88 %ee

Me

MeNH

CO2MeMe

O

91 %

N

NH

O

58 %

O

Bode Org. Lett. 2011, 13, 5378

11 α ,β-Unsaturated acyl azolium

RH

O

R

O

N X

NR1

R2

R3

catalytically generated unsaturated acyl azolium

NucR

O

Nuc

R H

O oxidant

or

or

R X

O

X= OR or F

NHCR

OOH

MeMeor

- Redox esterification

RH

O N

N

Mes

MesCl

5 mol%

3 equiv R1OHToluene, 60 oC, 2 h

R

O

OR1E/Z ratio in all cases >95:5

O

OMe

63% yield

O

OEt48% yield

O

OEtMe

MeMe

90% yield

O

OEt

O

H 66% yield

Zeitler OL 2006, 8, 637

- α,β-unsaturated acyl azolium: observation and mechanistic investigation

!H‡ = + 23.60 kcal/mol!S‡ = – 2.93 cal/K.molkobs = – 5.41x10-5 s-1

rate = -kobs [cat]0.5[ynal]1[MeOH]-0.5

Hammett " = -0.69MeOH

10 mol%

NNN

O

MeMe

Me

Cl-

O

N

RN

RNAr

O

HAr

MeOH

OH

N

RN

RNAr MeO

RDS O

Ar OMe


19

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

acyl azolium 1!max = 355 nm

Chemical Formula: C30H27ClN3O2+

m/z: 496.1793 (found by LC-HRMS) m/z: 496.1792 (calculated)

react rapidly with MeOH, H2Obut not piperidine

N

N NC2

O

Mes

C1O

Cl

Hc

Hdn

o

m

2D NMR correlations

Bode ACIE 2011, 50, 1673

- Rearrangement reaction in conjunction with electrocyclic ring opening reaction

OO

O

Ph

N N

10 mol%Toluene,

130 oC, 14 h

iPr

iPr

iPr

iPr OO

O

Ph

OO

OPh

OO

OPh Claisen

cascade

OO

OPh

+ NHC

Lupton Chem. Sci. 2012, 3, 380

- Alternative approaches to dihydropyranone synthesis

R1H

O 10 mol%

Toluene, 40 oC 4 A MS

NNN

O

MeMe

Me

Cl-

O

R3

OH

R2

O

O

R1 R2R3

52-81 %85-98 %ee

R1 H

O O

R3

OH

R2

O

O

R1 R2R3

34 - 89%

NN N Me

(2 mol %)

DBU (0.1 equiv)

Me

tBu

tBu

tBu

tBu

OO

(1.0 equiv)

I

(A)

(B)

(A) redox approach: Xiao Adv. Synth. Catal. 2010, 352, 2455 & Chem. Commun. 2011, 47, 8670,

(B) oxidative approach: Studer ACIE, 2010, 49, 9266 & You OL, 2011, 13, 4080 - A [4+2] cycloadditions via α,β-unsaturated acyl azolium

N N

10 mol%THF

-78 to -10 oC

iPr

iPr

iPr

iPrMe Me

O

Ph

OTMSPh

F

OPh

ON

RN

RNAr

- TMSFO

Ph

O

NNRRN

Ar

OPh

OAr

-NHC -CO2 Ph

Ar56-94 %

Lupton JACS, 2011, 133, 4694 12 NHC catalyzed hydroacylation reactions - Recently the group of Glorius (Uni. Munster) has contributed to many advances in this area of research. For reviews see: Glorius Chem. Lett. 2011, 40, 786 & Acc. Chem. Res. 2011, 44, 1182


20

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

X

O

R20 mol% cat

20 mol% DBU80 oC, 20 h X

OMe

R1

N NN

BnMes

OCl-

X = S or O

Ar Ar

28-99 %99 %ee

O HRN

N NR RconcertedConia-ene

DMSO (0.25 M)40 oC, 16 h

N NN

Cl-

linear16-78 %

O

R Ar

5 mol% catK3PO4 (1.5 equiv)

O

RAr

intramolecular:

MeO

MeO

branched8-47 %

O

RAr

intermolecular:

Glorius ACIE, 2011, 50, 4983 & ACIE, 2013, 52, 2585

- Other variations

O

R15 mol% cat

15 mol% tBuOK

S N MesClO4-

42-93 %

O HS

NR

TMS

TfO

O

R2 equiv KF

0 oC

N NN

Bn

O

up to 96 %> 20:1 dr

up to 96 %ee

O

R R2

R1R2

R1O

R

MeO

MeO

MeMe

O HRN

N NR R2

R1

Cl-

O

R5 mol% cat

1.1 equiv Cs2CO3

S N MesClO4-

40-93 %

O HS

NR

Br

O

RBr R1

R2

R1

R2 R1 R2

20 mol% cat1.5 equiv K3PO4

Glorius ACIE, 2010, 49, 9761 & OL, 2011, 13, 98 & ACIE, 2011, 52, 12626

13 Dual catalysis using NHC - Iminium-NHC catalysis

R1 H

O O

Me

OH

Me

32-93%80-95 %ee

NN N C6F5

(20 mol %)

BF4-

10 mol %NaOAc (10 mol%)

NH

Ar

OTMSAr

OMeOC

R1

OHMe

NAr

OTMSAr

R1

O

Me

OH

Me NHC

benzoin

R1

O

Me

RN

NHO

C6F5

MeOCMeOC

R1 O

O

Me

Rovis JACS, 2009, 131, 13628


21

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

- Photoredox-NHC catalysis

51-90%62-92% ee

20 mol%

NN N

OR1 H

O

[Ru(bpy)3]Cl2

:

Br

BrBr

10 mol%

PhN

H+

m-DNA (1.2 equiv)blue LEDs

PhN

O

R1

NN N

O

Br

Br

BrR1HO

Ru3+

N

NN

NN

*

Ox

Ox. _

N

Ru2+

N

NN

NN

N

Ru2+

N

NN

NN

N

blue LED

R

NR'

H

:

R

NR'+

-H.

NN N

O

Br

Br

BrR1HONR'R

Breslow's intermediateR

NR2

O

R1

productNHC catalysis Photoredox catalysis

Rovis JACS 2012, 134, 8094

14 Chiral triazolium and imidazolium catalysts synthesis 14.1 Chiral thiazolium salts

S N

OO

HO

MeMeKOtBu S N

Cl O

(R)(R)

O

O

Me

MeH

1) HCl, MeOH, H2O2) TBSCl, Et3N, DMAP S N

O OH

OTBS

H

Tf2O, pyr S N

O

OTBS

TfO

Leeper, TL, 1997, 38, 3611

14.2 Imidazolium salts

H

OO

H

R NH2

nPrOH(2 equiv)

H

NN

H

R R ClCH2OEtTHF N N RR

Cl Arduengo Tetrahedron 1999, 55, 14523

14.3 chiral aminoindanol-derived imidazolium salts


22

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

NH2

OH

Br CH3

NaH, THF

NH2

O

CH3HCO2Et

AcOH

NH

O

CH3H

O

OxoneacetoneNaHCO3

NH

O

CH3H

O

O

O

NH

OCH3

HO

O

NH

OCH3

O

NaHAc2OHClO4

O

N

O CH3

OAcClO4

RNH2

O

N

N CH3

OAcClO4

R

Ac2Ocat. HClO4

O

N

NClO4

R

CH3

(COCl)2DMSOEt3N

Bode Tetrahedron 2008, 64, 6961

14.4 Chiral pyrrolidinone-derived triazolium salts

ROH

O

NH

Meldrum's acidDMAPDCC

CH2Cl2

R

O

NHO

O

BocBoc

O

OMe

Me

NaBH4

AcOHCH2Cl2

R

NHO

O

Boc

O

OMe

Me

toluene

110 oC;

TFA

CH2Cl2

NH

O

R

Me3O+BF4-

CH2Cl2

Ar-NHNH2

CH2Cl2N

OMe

R

NH

N

R

NH

Ar

BF4-

HC(OEt)3 PhClN N

N

ArR

BF4-

Rovis JOC, 2005, 70, 5725

14.5 Chiral aminoindanol-derived triazolium salt

OH

NH2 Cl

O

EtO

NaH O

HN

OMe3O+BF4

-

CH2Cl2;NaHCO3 (sat.)

Mes-NHNH3+Cl-

MeOH

HC(OEt)3 PhCl

HCl/dioxane

O

N

OMe

O

HN

NH

HN

Mes

cat. HCl

Cl

O

NN

N

Mes

Cl

NH2

Me

HN

Me

NH2HCl

1) HCl (aq)2) NaNO2

3) SnCl2.H2O

MeMe MeMe

Bode Org. Synth. 2010, 87, 362

14.6 Chiral triazolium and imidazolium precatalyst reactivity comparison


23

This

wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

N N

NO

Me

Me

MeClO4

N N

O

Me

Me

Me

Me

ClO4

imidazoluim (cat.1) triazolium (cat.2)

Cyclopentene forming benzoin oxy!Cope reactions

Ph H

OMeO

O

O

Ph+


0.1 M ClCH2CH2Cl

0 oC, rt, 18 hMeO2C

Ph

Phcat.1: 10% yield, 1.6:1.0 d.r., 99% eecat.2: 85% yield, 7:1 d.r., 99% ee

Butyrolactone forming annulations

Ph H

OO

H

Br


10:1 THF:t-BuOH

40 oC, 15 h

+ O

O

p-BrC6H4

Ph cat.1: 55% yield, 1.4:1.0 d.r.cat.2: 14% yield, 1.3:1.0 d.r.

Intramolecular Stetter reactions

O

H

O CO2Et

20 mol% cat20 mol% KHMDS

0.02 M xylene

25 oC, 24 h O

CO2Et

O cat.1: no reactioncat.2: 94% yield, 98% ee

Intermolecular benzoin dimerization

H

O 10 mol% cat

10 mol% KOtBu

0.7 M THF

25 oC, 16 h

O

OH

cat.1: 11% yieldcat.2: 83% yield

Bode OL 2008, 10, 957

topic: n-heterocyclic carbene catalysis not covered here · 2011, 3, 880 see also: zeitler and...

Documents