topic: catalytic divergent synthesis 1 selectivity ......topic: catalytic divergent synthesis 1...

Update to 2011 Bode Research Group http://www.bode.ethz.ch/

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Topic: Catalytic Divergent Synthesis

1 Selectivity definition 1.1 Diastereoselectivity: preferential formation of one diastereomer over another 1.1.1 Type A: simple diastereoselectivity

CO2Me0oC

CH2Cl2CO2Me

H

HCO2Me

endo80%

exo20%

MeO2C H

endo TS

H CO2Me

exo TS Sauer ACIE 1967, 6, 16

1.1.2 Type B: induced diastereoselectivity

Me MeO

Me OCH2OBn

LiAlH4Et2O Me Me

OH

Me OCH2OBn

chelation controlO alkene

Me

O HCH2OBn

Li

H-

Me MeO

Me OSiPh2tBu

LiAlH4THF Me Me

OH

Me OSiPh2tBu

Felkin controlO alkene

OSiR3

H MeH-

Overman Tet. Lett. 1982, 23, 2355 1.2 Enantioselectivity: preferential formation of one enantiomer over another 1.2.1 Type A: generation of new chiral center

Me OMe

O O

Me (R)(R) OMe

OH ORuCI2[(R)-binap]

H2 99% yield99% ee

Noyori JACS 1987, 109, 5856 1.2.2 Type B: enantiodiscrimination

racemic

N N

O O

tBu tBu

Co

OAc

0.55 equiv H2O

2 mol%

tButBuOCl

/ THF

42%99% ee

OCl

52%89% ee

OHCl OH

Jacobsen Science 1997, 277, 936 & JACS 2002, 124, 1307

1.3 Regioselective: A regioselective reaction is one in which one direction of bond making or breaking

occurs preferentially over all other possible directions.

Type A

R

1) Hg(OAc)2

2) NaBH4

1) BH32) H2O2

Me

R

HO

R OH

Me

cat. a

cat. b

MeX

Me

Xcat. c Me

X

Type B Type C

cat. a

cat. bNHBocHN

NO

OtBu

NHBocHN

NO

OtBu

NHBocN

NO

OtBu

Me

Me Trost Science 1983, 219, 245


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1.4 Chemoselectivity is the preferential reaction of a chemical reagent with one of two or more different functional groups.

OCO2Me

Me

MeO

3

4

NaBH4O

CO2Me

Me

MeO

3

4

NaBH4CeCl3

HOCO2Me

Me

MeO

3

4

Luche's reduction

MeH

O

ONaBH4 NaBH4CeCl3Me

OH

O

MeH

O

OH via

MeHO

HO

O

H2O Ce3+ Yudin ACIE 2010, 49, 262

1.5 Product-selectivity is the preferential formation of two (or more) distinct products that are not stereo-

or regioisomers. This area of research is currently gaining interest within the synthetic community.

HNCO2Et

CuBr•SMe2 2,2`-Bipyridine

(1.1 equiv each)

O2 (1 atm)DMSO, 60 °C

N H

CO2Et

HN

CO2Et

CHO

Cu(OAc)2 (20 mol %DABCO (50 mol %)K2CO3 (2.0 equiv)

O2 (1 atm)DMSO, 80 °C

89% yieldcyclopropanation

56 % yieldcarbooxygenation

Chiba JACS 2011, 133, 13942 2 Selective catalysis 2.1 Why selective catalysis?

- Object of selective catalysis is to use fewer protecting groups, cutting synthetic protocols, thereby contributing to atom economy, step economy, reduced time, and increased efficiency. - Biological systems have an amazing combination of stereo-, regio-, and chemoselectivity. - Chemists can use the following metrics to predict selectivity: redox potential, pKa, HSAB, and A (steric) values.

In an ideal case, we would like to have 4 distinct catalysts to perform, in this particular case, both chemo-, and enantioselective catalysis

O

O

O

O

cat a

cat b

cat c

cat d

2.2 The underlying principle The same rationale and physical organic chemistry concepts apply to asymmetric catalysis as well as catalytic divergent synthesis:

E

reaction coordinateproducta

TSa

productb

TSb

intermediate

!!G

!!G

Fig. B) A generic energy diagram for a catalytic diveregent synthesis

E

reaction coordinate

product"R"

TS"R"

product"S"

TS"S"

intermediate

!!G

Fig. A) A generic energy diagram for an enantioselective reaction

Miller ACIE 2006, 45, 5616


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2.3 Energetic factors in the selectivity

- In some cases, a partition experiment can elucidate the energetic factors behind the competing pathways. This may allow for the use of temperature to control a desired pathway by adjusting the relative energy given to the intermediate.

N

N N

O

Mes

O

ArN

N N

O

Mes

OHAr

O

O

O

O

Ar

O

O

O

Ar

O

OO

O

C from a transiton state

involving a sigmatropic rearrangement

R from a transiton state involving

a C-C bond cleavage

a kinetically importanthemiacetal (HA)

kR

kC

OH

OO

10 mol %

NNN

O

MeMe

Me

Ar

O

H

OH

OOAr = p-OMeC6H4

T(oC)2535456070

!!G -0.33-0.59-0.86-1.26-1.53

!!G = !!H - T!!S

!!H = 7.61 kcal/mol!!S = 26.62 cal/K.mol

a catalytically generated reactive intermediate

krel(R/C)1.433.384.295.629.75

E

reaction coordinatePC

TSC

PR

TSR

HA

!!G in kcal/mol

Bode ACIE 2011, 50, 1673 3 Two classes of catalytic divergent synthesis 3.1 We propose two classes of catalytic divergent synthesis; these differ in their mechanistic nuances: Class A: Divergency arising from a common intermediate:

substrate A

[A-Cat]a common intermediate

(same connectivity, but differ in ligand or metal)

pathway 1

pathway 2

product D

product E

For example:

O

OO O

OTBS

O

OO

R1TBSO

R1

N

N N

O

ArO R3

O

R1

HOR2

(R1 = p-ClC6H4)

O

O

OOH

O

OTBS

R1

H

NNNO

MeMe

Me

Cl-

10 mol %

NNNO

F FF

FF

BF4-

10 mol %

cat B

cat C

Bode Chem. Sci. 2012, 3, 192

Class B: Divergency arising from two catalyst-substrate complexes with two available pathways:

substrate A

intermediate D[substrate A + cat B]

intermediate E[substrate A + cat C]

pathway 1

pathway 2

product F

product G

Cat B

Cat C

structurally distinct


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For example:

ONNs

PhH

ClLScCl2+

TiCl410 mol%

10 mol%

N

O

N

OMe Me

Me MeMeMe

L=N

Ph

Ns

O

O PhNNs

Ns = 4-nitrobenzenesulfonyl

Ar

Ar

O NNs

PhAr

N O

PhAr

Ns

69%

80%40oC

23oC

Yoon ACIE 2010, 49, 930

4 Types of selectivity: - Innate selectivity: the selectivity comes from a substrate-controlled process. - Catalyst-controlled selectivity: the catalyst, ligand, or an additive induces the selectivity. Innate selectivity can be viewed as similar as traditional “background rate” in asymmetric catalysis. Catalytic divergent synthesis may involve overcoming this intrinsic barrier in favor of the desired pathway.

N

Me

OCH3

5 mol% Pd(OAc)21.05 equiv NCS

CH3CN or AcOH100 oC, 12 h

1.1 equiv NCS

CH3CN or AcOH100 oC, 12 h

N

Me

OCH3

N

Me

OCH3

Cl

Cl95 %

76 %catalyst-directed

chlorination

Innate selectivity:Electrophilic aromatic

substitution

N

Me

OCH3

PdAcO OAc

Sanford Org. Lett. 2006, 8, 2523

- Innate selectivity may be absolute Chemospecificity arises when a pair of functional groups react preferentially only with one another (i.e. below the ketoacid couples only with the hydroxylamine, even in the presence of 2 other amines).

H2NHN N

HOH

O

O

O

OH2N

Me

Ph

HOHN N

H

HN OH

O

O

O

Me Ph

COOH

+ H2NHN N

H

HN

O

O

O

H2N

Me

Ph

NH

HN OH

O

O

O

Me Ph

COOHaq. DMF40 oC-CO2-H2O

Bode ACIE 2006, 45, 1248 5 Methods to achieve selectivity (either regio-, chemo-, or product-selectivity) 5.1 Change of substrate (substrate control selectivity) - Circumvent the intrinsic preference of functional groups by modifying the substrate

OHO

MeH+H+

HO O

Me

favored

OO

Me

H

Hstrained

HO

OMeO

OMe

H

H

introduce structural bias

OHO

MeH+H+

HO O

Me

favored

OO

Me

H

Hstrained

HO

OMe

OH

H

OOH

H

O

H

HO

OMe

H

HO

Jamison Science 2007, 317, 1189 5.2 Change of the reaction condition such as solvent, pH, or temperature

N DMSO:H2O

46-60 %(~2.5:1)

R NaSO2CF3tBuOOH

N

R

DCM:H2O

NaSO2CF3tBuOOH

52-67 %(~2.5:1)

N

R

CF3

CF3

R = Ac or CN

Baran PNAS 2011, 108, 14411


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- Depending on the excitation energy given to the diester, chemoselective cleavage is possible.

O

O

O O

O OMe

OmeO2NOMe

MeOn

hv, 254 nmMeCN, 5 min

hv, 420 nmMeCN, 24 h

O

O

O O

OH

OMe

MeOn

HO

O O

O OMe

OMeO2Nn 78-96%

yield

70-87% yield

Bochet JOC 2002, 67, 5567 5.3 Introduction of a directing group (substrate control selectivity - Circumvent the intrinsic preference of functional groups by modifying the substrate or adding a catalyst

20% Pd(TFA)2

R= Ac

2 equiv CsOAc

61%

NR

H

H

Me NAc

H

Me 75%

NPiv

H

R = Piv

5% Pd(TFA)23 equiv AgOAc

Me

Me

Me

Me

PivOH (no oxidant)

Fagnou JACS 2007, 129, 12072 5.4 Innate vs. reagent-controlled selectivity

OAcBr

NaCH(CHO2Me)2

no catSN2

OAc(MeO2HC)2HC

Pd(PPh3)4 Br

75 %

CH(CHO2Me)2 77 %

!-allylationvia

Br[Pd]

"inniate"

reagent-controlled

Trost Science 1983, 219, 245 5.5 Reagent vs. catalyst-controlled selectivity

Me OH

Me Me

Me OH

Me Me

Me OH

Me Mereagent

A B

mCPBA A:B = 2:1VO(acac)2 + tBuO2H A:B = 0:1

O O

reagent-controlledcatalyst-controlled

Trost Science 1983, 219, 245 6 Regioselective Catalysis 6.1 Definitions and Key Principles Regioisomer: The positional isomers formed from the different directions of bond formation/cleavage Note: The term “regiospecific” to refer to a reaction that is 100% regioselective is discouraged, and has no correlation to the difference between “stereoselective” and “stereospecific”

R1R2

H X

HX

R1R2

X

HR1

R2H

X

Regioisomers IUPAC Gold Book (http://goldbook.iupac.org/)


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Controlling regioselectivity in reactions of non-aromatic pi-systems is dependent on electronic and steric factors- charged intermediates and polarized transition states dictate relative position of nucleophile and electrophile

OHH

H+

H

more stable benzylic cation

H2O HOH H

H+, H2O

-H+

M+, NuH

MNu M

Nu!+

developing+ve charge

benzylic

MNu

HNu

more stericallyhindered

exposed

Clayden, et al. Organic Chemistry, Oxford Uni. Press. 2011

The regioselectivity of aromatic substitution reactions is heavily influenced by the inherent electron distribution of the conjugated pi-system. The canonical example is the regioselectivity of the Friedel-Crafts reaction:

OMeE E

OMe OMe

E

+

+ charge most stabilized

OMeE

OMe

E

+

ortho/para selective

H

H

- H+

OMeO

E

EH

OMeO

+ charge least destabilized

- H+

OMeO

E

Electron-Donating Groups

Electron-Withdrawring Groups

meta selective

Clayden, et al. Organic Chemistry, Oxford Uni. Press. 2011

It is worth mentioning that issues of regioselectivity are normally encountered in reactions of functional groups with relatively weak dipoles. In the example below, the red attack would lead to a regioisomeric product, but this product is not formed due to the required inversion of polarity this implies.

XY

R RNu

XY

R R

Nu H+XY

R R

Nu

H

R XNu

YR

H+R X

NuR

Y Hregioisomers

Example:

O

R2R1

ONAr

NHO

R

For example, see MacMillan JACS 2003, 125, 10808 & Maruoka JACS 2006, 128, 6046

6.2 Regioselective Functionalization of Alkenes and Alkynes The design of catalytic regioselective reactions can overcome poor selectivity inherent to the substrate. For example, Tsuji-Wacker oxidation of allylic carbamates gives a nearly 1:1 ratio of aldehyde and ketone products. This is likely because the electronic bias of the bond formation is counteracted by the sterics of the neighbouring group, leading to poor selectivity in the intermolecular attack of water on the Pd-activated alkene:


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56% (6:4)NCbz

O

MeMe

Me

O

NCbzO

MeMe

O

NCbzO

MeMe

H2O, O2

10% Pd(OAc)2CuCl

NCbzO

MeMe

PdX2

OH

HElectronically favouredSterically disfavoured

Sterically favouredElectronically disfavoured

NCbzO

MeMe

OHPdX

NCbzO

MeMe

PdXOH

H2O

PdX2

+

+

!-hydride elim.then tautomerization

- Sigman has designed a new ligand/oxidant combination that renders this reaction remarkably selective and illustrates some design elements that could have general implications for Pd-catalyzed activation of alkenes. - Key elements include the use of electronically asymmetric ligands to pre-organize both reactants, a complexed nucleophile to make the addition intramolecular (migratory insertion) and a cationic metal for high reactivity and maximum electronic bias in the transition state. These factors combine to precisely control the site of attack.

N N

O

electon-poordonor

electon-richdonor

PdOO

t-Bu R

defined, pre-coordinatedNu-Pd-alkene complex

electron-richnucleophile

electron-pooralkene

coordinatively saturatedPd centre (prevents extra

substrate ligation)

single isomer

NN

O

PdCl Cl

18% AgSbF6TBHP (aq)

69%

NCbzO

MeMe NCbzO

MeMe

Me

O

(5 mol %)

2

via

Sigman, Acc. Chem. Res. 2011, doi: 10.1021/ar200236v

This catalyst system can even completely reverse the inherent selectivity of the substrate:

Me

NO O

PdCl2 (10 mol %)CuCl (1.0 equiv)

DMF/H2O (7:1)O2, 3 dMe

NO O

O

94% yield>99:1 aldehyde

NN

O

PdCl Cl

AgSbF6 (18 mol%)TBHP (aq)

CH2Cl2, 17 h

(5 mol %)

Me

NMe

O O

O91% yield

ketone only Aldehyde selective: Feringa, JACS, 2009, 131, 9473 & Ketone selective: Sigman, JACS, 2011, 133, 8317.

Regioselectivity can be altered by the appropriate choice of catalyst- Pd vs Cu-catalyzed diamination of dienes proceeds with reversal of internal/terminal selectivity based on a change in the mechanism.

R N N

O+

Pd(PPh3)4(10 mol %)

C6D6, 65 °CNN

R

OCuCl•P(OPh)3(6 mol %)

RN

NO

Reaction atterminal alkene Reaction at

internal alkene

C6D6, rt

via

N N

O

Cu(II)R+

R N

N OCu

Cu: Radical Mechanism

more stable radical

Pd: Polar Mechanism via

NPd

N

O

R+

insertion into mostelectron-rich alkene

NPd N

R

O

Pd-Catalyzed: Shi, JACS, 2007, 129, 762; Shi, JACS, 2010, 132, 3523

Cu-Catalzyed: Shi, OL, 2007, 9, 2589.


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The ligand environment around the same metal can also play an important role: Fe-catalyzed hydroboration of dienes with reversal of regioselectivity.

While the change in regioselectivity is difficult to rationalize, it should be pointed out that the reaction is chemoselective as well- only the conjugated diene reacts. This can be explained by stronger, two-point chelation to the low-valent iron catalyst.

myrcene

Me

Me

10% Mg

N FeCl2

N3,5-diMePh

3,5-diMePh

N FeCl2

N

iPr

iPr

HBPin

10% Mg

Me

Me

Me

Me

BPin

PinB

80%

78%

viaMe

Me

[Fe](4 mol %)

(5 mol %)

H

pinB

Me

Me

[Fe]Bpin

H

via

H

H

Ritter JACS 2009, 131, 12915

This kind of ligand-dependant regioselectivity has also been demonstrated in catalytic conjugate additions. In this case, the right choice of ligand can lead to preferential nucleophilic attack on the more hindered and less electropositive carbon atom of the maleimide.

N

O

OEt

Bn

[RhCl(C2H4)]2(2.5 mol %)

Ligand (2.75 mol %)N

O

O

BnEt

Ph

PhB(OH)2 (3.0 equiv)

KOH (0.5 equiv)Dioxane/H2O (10:1)

50 °C, 3h

N

O

O

BnEt

Ph+

(R)-H8-binap

C1

C2

C2 attacked C1 attacked

Ph

Ph

87 13

15 85

Hayashi JACS 2006, 128, 5628

Hydrometallation of alkynes is a very important synthetic transformation since it provides vinyl organometallics that are very useful in cross-coupling reactions. Control of regioselectivity is essential as the often-sensitive regioisomeric products can be difficult to seperate.

The regioselective hydrostannation of alkynes can be affected by Pd catalysts. Here, the selectivity between internal and terminal stannation is determined by the ligand (larger ligands lead to better terminal selectivity).

OH

Me

L2PdCl2(1 mol %)

PhCH3, rt

OH

MeBu3SnH

OH

MeHSnBu3

+

terminal internalL

PPh3

P(o-tol)3

P(Cy)3

68 32 (57% yield)

80 20 (60% yield)

95 5 (84% yield)

increasingsize

Pd HBu3Sn L

OH

MeviaBu3SnH +

Chong OL 2008, 5, 861

Selective synthesis of the internal stannane can be achieved using Mo catalysts. In this case, the presence of the bulky CNt-Bu ligands is proposed to favour placing the Mo center at the less hindered terminal position (note that this also implies that Mo-Sn migratory insertion preceeds Mo-H reductive elimination).


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OAcBu3SnH +

Mo(CO)3(CNt-Bu)3(2 mol %)

THF, 55 °C HSnBu3

OAc OH

MeBu3SnH

+

96 4 (91% yield)internal terminal

with P(Cy)3PdCl2 33 67 (61% yield)

SnBu3

[Mo]

OH

Hvia

Kazmaier OL 1999, 1, 1017; Kazmeier EJOC, 2000, 2761

Similar control of selectivity can be achieved in hydroalumination of arylalkynes- in this case the catalyst controls both the regio and chemo selectivity, as it directs the hydrometalation and suppresses competitive deprotonation of the acidic terminal proton.

Ni complex (3 mol%)

THF, 22 °C, 2 h

Al(i-Bu)2

HH

Al(i-Bu)2

Ni(PPh3)2Cl2Ni(dppb)Cl2

93 7

< 2 > 98

+

(i-Bu)2AlH (1.3 equiv) Al(i-Bu)2

+

none

0

0

25050 (+ 25% styrene)

terminal internal deprotonation

Hoveyda JACS 2010, 132, 10961

Catalytic hydration of alkynes is typically under Markovnikov control as the transition states are highly polarized and use hard nucleophiles. Recently, gold-catalysts have emerged as highly reactive catalysts for this process, however the influence of the inherent selectivity is obvious from the examples below:

NN

Au+SbF6-

Ar Ar

(50-100 ppm)

Dioxane/H2O (2:1)100 °C

R1 R2 R1R2

O

R1R2

O

+

A B

H

85% yieldonly A

81% yield4.4 A: 1 B

Me

74% yield2.1 A: 1 B

Decreasing bias, decreasing selectivityAr = 2,6-i-PrC6H3

Nolan JACS 2009, 131, 448

In order to reverse the selectivity, a new mechanism is required. Hydration of terminal alkynes catalyzed by Ru complexes leads very selectively to anti-Markovnikov products (aldehydes), especially under the influence of new ligands developed by Hintermann:

R

H CpRuCl(PPh3)2 (2-10 mol %)ISIPHOS (2-10 mol %)

acetone/H2O (4:1), 60-70 °CR

O

Haldehyde only

NPh3P

i-Pr

i-Pr i-Pr

ISIPHOSR

[Ru]

HH •

R

[Ru]

H2O

terminal carbonnow electrophilic

H[Ru]

ROH

H

tautemerization/reductive elim.

Catalyst: Hintermann JACS, 2011, 133, 8138 Mechanism: Wakatsuki ACIE 1998, 37, 2867

6.3 Regioselective Functionalization of Arenes There are three main methods for the regioselective functionalization of arenes- 1) Reagent-controlled reactions 2) Chelation-assisted directing-group controlled reactions 3) Catalyst-controlled reactions


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While by modern methods nearly any substitution pattern can be achieved on nearly any arene, these are typically achieved by applying a variety of different chemistries to the starting material at hand, exploiting the inherent reactivity of the specific arene involved. General regiocontrol in arene substitution remains an area of intense investigation. 6.3.1 Reagent-Controlled Reactions

Reactions of monosubstituted alkylbenzenes (o/p directing group) typically favour formation of the para isomer because of the steric hindrance around the ortho position. However, judicious choice of reagents can lead to reversal of regioselectivity- in this case the “naked” iodonium provided by Barluenga’s reagent is guided to the ortho position by pre-complexation with the trifluoroacetamide

HN

O

CF3

I2

H2O, AcOH, HClO4 50 to 70 °C

CH2Cl2, TFART

Barluenga'sReagent

HN

O

CF3

I

para 51% yield

single isomer

HN

O

CF3

I

ortho85% yieldo/p 25:1

IPy2BF4•2 HBF4Barluenga'sReagent

N

O

CF3

I

H

via

Ortho-selective: Barluenga ACIE 2007, 46, 1281

Para-selective: US2003/225266 A1, 2003

Especially interesting are examples where the expected regioselectivity can be overridden. Cu-catalyzed reactions of pivanilides with diaryliodonium salts are highly meta-selective, despite the nitrogen group being a strong o/p director. Note that Cu(OTf)2 is required to activate the electrophile but plays no role in the selectivity- reactions without copper at higher temperature give the same meta regioisomer

HN OI OTf

+Me

Cu(OTf)2 (10 mol %)

DCE, 70 °C

HN OMe

strong o/pdirector O

HN

EH

Mevia

Gaunt Science 2009, 323, 1593

Discussion on role of Cu(OTf)2, see footnote 14 in Gaunt ACIE 2011, 50, 463 For the mechanism, see Wu JACS, 2011, 133, 7668

6.3.2 Chelation-Assisted Directing Group-Controlled Reactions

Many reactions take advantage of the coordinating ability of the functional groups on the arene to direct functionalization of adjacent positions.

This is especially common for Pd-catalyzed reactions, where the directing group also helps stabilize high oxidation state intermediates. In the example below, the pivanilide group directs ortho-palladation of the aromatic ring. Note that consecutive alkylations/arylations are hallmarks of electrophilic substitutions where the product is more nucleophilic than the starting material. Also, contrast this example with the copper-catalyzed reation just above- this will reinforce the importance of directing groups and changes in mechanism.

HN

Me O

I PF6+

Pd(OAc)2(5 mol %)

AcOH 70 °C

HN

Me O

Ph

Ph79% yieldortho only

PdONH

OAcvia

Daugulis ACIE 2005, 44, 4046

The main drawback of using directing groups is that their presence in the molecule is often permanent, limiting the overall generality of the process. A new trend is the use of directing groups that can be converted into a range of new products:


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SiNi-Pri-Pr

Pd(OAc)2 (10 mol%)NIS (2 equiv)PhI(OAc)2 1.5 equiv

DCE, 60 °C

SiNi-Pri-Pr

I

93% yieldonly 1 ortho

isomer formed

BCl3 thenH2O2

Me Me

I

Me

OH

I

Me

BPin

80% yield

BCl3 thenpinacol

80% yield

chelatinggroup

removaltether

Gevorgyan ACIE 2010, 49, 8729

Different types of regioselectivity can work together to make for very highly selective reactions. In the example below, a chelating group puts the Pd catalyst ortho to the amide. The resulting Pd(IV) intermediate is attacked by the toluene solvent in a reagent controlled fashion- this is an electrophilic palladation that favours the para position of the nucleophile for steric reasons.

Me ONHAr

+

Me

H

H

Pd(OAc)2 (10 mol%)F+ source (1.5 equiv)DMF (2 equiv)

toluene, 100 °C

ONHAr

Me

Me

Directing groupcontrolled

Reagentcontrolled(F+ source)

NPd

OAr

AcO

F-X NPd

OAr

AcOF

X

Me

N

OAr

AcO

- HX

PdF

Me

red. elim.ONHAr

Me

Me

Me Me

MeNN

Cl

F

2BF4

p/m 8:118% yield

p/m 10:111% yield

N F BF4 N F BF4

Me

Me

Me

p/m 13:170% yield

PhO2S N SO2Ph

Fp/m 13:181% yield

Yu JACS 2011, 133, 13864

6.3.3 Catalyst-Controlled Reactions

This is an emerging area which is being hotly pursued and is a step toward ideal regioselectivity in the functionalization of arenes.

A Pd-catalyzed reaction of thiophenes with aryl iodides can be tuned to give either regioisomer simply by changing the ligand. This has been calculated to be a result of a change in mechanism- electron-rich phosphines favour CMD-based direct arylation, while electron-poor phosphites allow a Heck-type carbopalladation.

S

PdCl2 (10 mol %)Ligand (20 mol %)

AgCO3 (1 equiv)m-xylene, 130 °C

!

"

+ Ph-I S

!-product "-productS

PCy3 > 99% < 1% (99% yield)

+

P{OCH(CF3)2}3 14 86 (86% yield)

S

H

Pd OO

O!-product via CMD

"-product via Heck-type

S PdOCO2HH

HPh

Itami ACIE 2010, 49, 8946

Calculation of mechanism: Fu CEJ 2011, 17, 13866

Functionalization of indole has been of long-standing interest in the field of direct arylations. Only very recently have truly catalyst controlled reactions been found that can control the C2/C3 regiochemistry. At present the mechanism and the reason for the switch are unknown, and the selectivities are modest.


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N

O

+

Pd source (5 mol %)Ligand (5 mol %)

PhH/EtCO2H (10:1)1 atm O2, 120 °C

C2

C3

N

O

N

O

+

N N

N N

O

+ Pd(TFA)2

C2 productC3 product

14.4 (52% yield)

+ Pd(OPiv)2 4.81 (66% yield)

Stahl Chem.Commun. 2010, 47, 10257

7 Chemoselective catalysis 7.1 Chemoselective functionalization of nucleophiles 7.1.1 Selective acylation reactions: the issue of innate relative acidity, steric, or nucleophilicity

OH

OHmore acidic

more nucleophilicOH

more nucleophilic

less nucleophilic

NH2

acylate first

OH

more sterricallyhindered

less sterricallyhindered

OH

acylate first

acylate first

Me

Selective acylation strategies is about how to override this inherent preference

Melman OBC 2004, 2, 1563 7.1.2 Reagent-controlled selective acylation of phenolic OH over aliphatic OH group.

HOOH

N S

SO

tBu N S

SO

tBu

Et3N

HOO

OtBu

80%"innate pathway"

OOHO

tBu

98%

via

OOH

Yamada TL 1992, 33, 2171 7.1.3 Overriding steric preference.

O

O

O

MeHO

OH

Me

OHMe

O

O

MeMe

Me Me

O

OMeMe

OHMe

OHO

NMe2

Me

(10 mol%)Ac2O (1 equiv.)

O

O

O

MeHO

OH

Me

OHMe

O

O

MeMe

Me Me

O

OMeMe

OHMe

OHONMe2

Me

MeO C2'-monoacetate

O

O

O

MeHO

O

Me

OHMe

O

O

MeMe

Me Me

O

OMeMe

OHMe

OHONMe2

Me

MeO

C11-monoacetate

N

ON HBoc

N

N

Me HNH

O

NO

MeMe

NHO

H

NBoc

OMeO

Ph

cat

Ac2O (2 equiv.)(2) MeOH quench

N NMe

5 mol% catErythromycin A

Miller ACIE 2006, 45, 5616


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7.1.4 Another challenging issue is chemoselective monoacylation for diols. This is possible, for example, in the presence of a catalytic amount of YbCl3 due to the stability of the bidentate complex.

PhPh

OHHOYbCl3 (10 mol %)Ac2O (10 equiv)

THF PhPh

OAcHO

quantitative

YbCl3Ph Ph

OH

OH+ Ac2O

YbCl3 O

O

Ph

Ph

H

O

OO

Me

Me H

YbO O

O Ph

Ph

Me

OMe

OH

Cl3

Ph PhOH

OAc

+ AcOH

Clarke JOC 2002, 67, 5226 7.1.5 Selective O-acylation in the presence of amine - Catalytically generated acyl azoliums have been long known to prefer to acylate alcohols and water, rather than amines. This chemoselectivity may be used to acylate hydroxyl groups in the presence of amino groups. Catalytic amidation reaction may be achieved when HOAt or imidazole is used.

H

O 2 mol% NHC O

R

OH

NN

NMe

Me

3 mol% DBU100% oxidantPh

OH

H2N Ph O

NH2

R

O

NN

NMe

Me

OH

H2N

oxidation

tBu

tButBu

tBu

OOacyl azolium

Studer JACS 2010, 132, 1190 - Polymeric Zn catalyst selectively allows for acylation of the hydroxyl group and not the amine due to the enhanced oxophilicity of the Zn ions.

Zn4(OCOCF3)6O

iPr2O, reflux, 180hPh

O

OMeNH2

+ O

O PhHO

NH2

99%

Mashima JACS 2008, 130, 2944 - The anionic nature of ligand A attenuates the electrophilicity of Cu(I) and favors coordination of amine. The Cu(I) complex with B is much more electrophilic and favors binding of alcohol.

H2N

HO

IBr+

CuI (5 mol%), A (20 mol%)Cs2CO3 (2 equiv)

CuI (5 mol%), B (20 mol%)Cs2CO3 (2 equiv)

DMF, RT, 7h

toluene, 3A MS90 oC, 16h

BrHN

OH

Br O

NH2

97% yield

86% yield

O O

iPrA =

B =N N

Me

Me

Me

Me

Buchwald JACS 2007, 129, 3490 7.1.6 Selective O- vs. N-alkylation Selective Buchwald-Hartwig amination of 1,2 amino alcohol (simple amines and alcohols do not work). The selectivity arises from the relative tightness of chelation, depending on the reaction condition and additive.

RR

N(H)R1

OH

+ R2

I

CuI (2.5 mol %)K3PO4 (2 equiv)

ethylene glycol (1 equiv)iPrOH, 75oC

CuI (5 mol %)Cs2CO3 (2 equiv)

butyronitrile, 125oC

R2

NR1

RR

OH

RR

N(H)R1

OR2

66-76%47-74% yield

Buchwald OL 2002, 4, 3703


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7.2 Chemoselective oxidation and reduction Depending on the mechanism, selective oxidation reactions may reinforce or override innate steric or nucleophilic preference (similar to the cases above)

- Innate steric preference. The catalyst reinforces innate chemoselectivity to achieve complete oxidation of primary over secondary alcohol.

OHMe

OH

N N

N OO

O

Cl

ClCl

0.01 mol% TEMPO1 equiv

OMe

OH

Giacomelli OL 2001, 3, 3041 - Selective oxidation of secondary alcohol over primary may be achieved by employing Pd & benzoquinone

OHHOOH

OHHOO

N NMe MePd

AcO2

5 mol%3 equiv benzoquinone 92%

N NMe MePd

OH

HO

O

H

!-hydride elim.N N

Me MePdOH

HO

OH

!-hydride elim. N N

Me MePdO

HO

HOH

X

Waymouth ACIE 2010, 49, 9456

Ru-catalyzed chemoselective amide formation over esterification

OHR2 NH2 R1

R2NH

ORu

N P tButBu

NEt Et

COH

1 mol%R1reflux-tol

C6H13BnN

H

O96%

C5H11PhN

H

O58%

NH

O

OMe

99%

RuN P tBu

tBuNEt

EtOC H

O

R1

OR1

RuN P tBu

tBuNEt

EtOC H

H

- H2

RuN P tBu

tBuNEt

EtOC H

OR1

NHR2

+ R2NH2

OH

R1 NHR2

RuN P tBu

tBuN

Et EtCO

H R1R2N

H

O

competing pathwayR1

R1O

O

faster, better Nu+ R1OH slower

Milstein Science 2007, 317, 790 7.2.1 Chemoselective reduction reactions Hantzsch ester for selective reduction of amide in the presence ketone or ester.

Ph

O

N

NH

HH

MeMe

O

OEt

O

EtOHEH =Tf2O

HEH (2.5 equiv)Tf2O (1.1 equiv)

CH2Cl2RT, 1h

Ph N

HH

HEH

Ph

OTf

N

OTfHEH

Ph

H

N

OTf

O O86%

NaBH4Ph

O

N

OH

Charette JACS 2008, 130, 18


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Chemoselective hydrogenation of heteroaromatic systems. A proper choice of ligand (steric and/or electronic) can completely control the chemoselectivity.

N

N Ph

Ph

Me

N NAr Ar(10 mol %)

Ru(cod)(methallyl)2 (5 mol %)

KOt-Bu (15 mol %)H2 (60 bar), PhCH3

80 °C, 18 h

Ar = 2,6-(i-Pr)2C6H3

NH

HN

Ph

PhMe99% yield

N NCy Cy(10 mol %)

Ru(cod)(methallyl)2 (5 mol %)

KOt-Bu (15 mol %)H2 (65 bar), C6H14

60 °C, 18 h

Cl Cl

N

N Ph

Ph

Me99% yield

Glorius ACIE 2011, 50, 3803

8 Chemoselective α ,β-unsaturated carbonyl reactions

1,2- vs 1,4-Addition: α,β-unsaturated carbonyl compounds are ambident electrophiles- nucleophiles can attack either the C=O or C=C bonds

O

X

R

Nu1,2-

addition1,4-

addition

O

X

R NuR

XO Nu

O.59

-.39

-.48.51

O.59

.48

-.3-.58

LUMO

HOMOLUMO coefficients correspond with

increased reactivity of !-carbon

O

Frontier Orbitals: Charge Distribution:

-.41

+.23

-.34

Compare butadiene with acrolein-

-.35

+.48

Oxygen atom makes !-carbon

more positive

Significantly morepositive charge on C=O

carbon

LUMO calculations: Houk, JACS, 1973, 4094. Charges: Tidwell, JOC, 1994, 4506

8.1 Substrate-controlled chemoselective addition to α,β-unsaturated carbonyl reactions

The selectivity is determined by a combination of the nature of the leaving group and nucleophile:

O

Cl + NH3

morereactivecarbonyl

O

NH21,2-addition only

O

OMe + NH3

lessreactivecarbonyl

O

OMe 1,4-addition only

H2N Fleming, Molecular Orbitals and Organic Chemical Reactions, 2010, p 188

8.2 Catalyst-controlled chemoselective reduction or addition to α,β-unsaturated carbonyls - Ligand controlled 1,2 vs. 1,4 reductions as a result of “subtle and complex interactions between the substrate, solvent, and bulky ligands.”

O

MePh

O

Me

Me

Phcat. Cu(OAc)2.H2O

DMES

1,2-reduction 1,4-reduction!,"-unsaturated

ketone

Me cat. Cu(OAc)2.H2O

DMES

O

O

O

O

PAr2PAr2

92 %97 %ee

OH

MePh

Me

90 %99 %ee

PPh2P(tBu)2

MeH

Fe

Lipshutz Tetrahedron 2011, doi:10.1016/j.tet.2011.10.056

For selective non-metal-catalyzed 1,4-reduction, see MacMillan JACS 2005, 7, 32 & List JACS 2006, 128, 13368 - Diene ligands can provide exquisite chemo- and enantioselectivity - additions to unsaturated aldehydes proceed by 1,4-addition, not 1,2. This is in stark contrast to a Rh/phosphine catalyst, which furnishes the 1,2-additon product exclusively.


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Me

MeO Me

i-Bu

Bn

(3.3 mol %)[Rh(C2H4)2Cl]2 (1.5 mol %)

KOH (50 mol %)

Ar2B(OH)2

O

HAr1

+O

H

Ar2

Ar1

R = pOMe-Ph, 80%, 92% eeR = pF-Ph, 90%, 93% eeMeOH, H2O, 50 °C

cat. Rh(acac)(coe)2 / tBu3P

DME / H2O 3:2, rt

OH

Ar2Ar1

1,2-addition 1,4-addition!,"-unsaturated

aldehydephosphine ligand diene ligand

Carreira, JACS 2005, 10851 & Miyaura, JOC 2000, 65, 4450

- Changing counterion can change the preference for selective 1,2- vs 1,4-conjugate addition

Ph

O

CO2Me

+

NMe

OO P

O

OH

Ph

Ph(10 mol )

InX3 (10 mol %)

CH2Cl2, 4Å MS, -80 °CPh

O

CO2Me

NMe

Ph CO2MeHO

NMe

X = Br 31 1X = F 1 30

+

::

Luo ACIE 2011, 50, 6610 9 Chemoselective arene functionalization

Bond Bond Strenth (in kcal/mol)

C-C 90 C-O 92 C-N 85 C-F 115 C-Cl 84 C-Br 72 C-I 58

Blanksby and Ellison Acc. Chem. Res. 2003, 36, 255 9.1 C-X substitution - Chemoselective Suzuki-Miyaura cross-coupling. It was found that monoligated Pd (favored with PtBu) favors C-Cl insertion and bisligated Pd (the active species with PCy3) favors C-OTf insertion.

Me

(HO)2B

OTf

Cl+

Pd(OAc)2 (3 mol %)PCy3 (6 mol %)

KF (3.0 equiv)THF, RT

Pd2(dba)3 (1.5 mol %)P(t-Bu)3 (3 mol %)

KF (3.0 equiv)THF, RT

Me

Cl

Me

TfO

95% yield 87% yieldBDE = 90.6

kcal/mol

BDE = 101.5kcal/mol

Fu JACS 2000, 122, 4020

For rationale: Houk and Schoenebeck JACS 2010, 132, 2496 & Schoenebeck ACIE 2011, 50, 8192 - Changing the ligand and Pd sources can affect the chemoselectivity of cross-coupling reaction. A working hypothesis postulates that the more bulky ligand directs an oxidative addition at the less hindered para position while oxidative addition is irreversible at the ortho position for a system with less bulky ligand.

COOHBr

Br

B(OH)2 Pd2(dba)3NMP-H2OLiOH

NMP-H2OLiOH

COOHBr

p-MePh

COOHp-MePh

Br

p-MePh

99%92%

OPPh2 PPh2 0.5%Pd(OAc)2

Houpis (Johnson and Johnson) OL 2008, 10, 5601

[M]

Y

X+

Me

XX and Y maybe Cl, Br, I, OTf, etc

Me

vs.

YMe

If oxidative addition is RDS, then selectivity depends on the Lv (i.e. Cl slower than Br)

If reductive elimination or transmetallation is RDS, then selectivity may depend on other factor such as choice of metal, ligand, etc

substrate control

reagent control


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9.2 C-H functionalization Parameter: kinetics (rate) vs.

thermodynamic (bond strength or pKa)

Rates of C-H oxidation normally follow tertiary C-H> ethereal C-H ≈ benzylic C-H > secondary C-H >

primary C-H. These are general rules dependent upon electronic factors and not steric bias.

Bond BDE (kcal/mol) pKa CMethyl-H 105 48

CIsopropyl-H 99 51 Ctertbutyl-H 97 53

Callyl-H 89 43 Cphenyl-H 113 43 Cvinyl-H 111 50

HCC-H (ethyne) 133 25

Blanksby and Ellison Acc. Chem. Res. 2003, 36, 255 & Bordwell Acc. Chem. Res. 1988, 21, 456 9.2.1 Aryl C-H functionalization: depending on the mechanism, formal classification of C-H bond

functionalization may change

[Metal] HSEAr

oxidativeaddition

MH

X-

MX H

ConcertedMetalation

Deprotonation

Heck-typereaction

MX

HB

XMH

chemoselectivereactions

regioselectivereactions

Ackermann ACIE 2009, 48, 9792 - Changing the base, along with the Pd source, may allow for selectively C-H bond activation by selective deprotonation at a different site.

Br

Me

Pd2(dba)3

NaOtBuK2CO3

iPrCy2P

Pd(OAc)2

N+

N

HHO-

HBF4PtBu3

iPriPr

X-PhosN+

N

O-

MeMe

89%sp2 arylation

N+

N

MeO-

Me

Me

79%sp3 arylation

Me

N+

N

HHO-

Mesp2 C-H

LPdAr

X

sp3 C-H

K2CO3

NaOtBu

N+

N

LPdHO-

Me

Ar

N+

N

HPdLO

Me

Ar

PdLO

NN MeMe

HO

MeN+

N

O-

Me Me

N+

N

MeO-

Me

Me

concerted metallation-deprotonation (CMD)

O-

Fagnou JACS 2008, 130, 3266 & Tetrahedron 2009, 65, 3155 & Chem. Lett. 2010, 39, 1118

- Pd catalyst mediates standard cross-coupling reaction. Switching to iron leads to a directed C-H activation/ortho arylation in the presence of a leaving group.

+

10% Fe(acac)3Me

N p-OMePh

XX = Br or TfO

H

ZnCl2-TMEDA

4,4ʼ-di-tert-butyl-2,2'-bipyridine

10% PdCl2(dppf)

0oC60oC

Me

O

X Ph

Me

O

Ph H

C-H activationcross-coupling 83-92%96-97%

PhMgBr

(H+ workup)

(H+ workup)

Nakamura ACIE 2009, 48, 2925 - Ortho iodination can be achieved with an acidic directing group. In order to achieve mono-iodination, it was necessary to use a tetra-alkyl ammonium salt as an additive. Mono-iodination normally occurs on less hindered side.

O

OHX

Pd(OAc)2 (5 mol%)IOAc (2-4 equiv)

R4NICH2ClCH2Cl

O

OHXI

Pd(OAc)2 (5 mol%)IOAc (3equiv)

DMF

O

OHXI

I

65-89% yield 62-75% yield

Yu ACIE 2008, 47, 5215


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9.3 Chemoselective alkane functionalization - Rh-catalyzed C-H acitivation/annulation Du Bois and co-workers observed that product formation could be catalyst dependent slightly in favor of steric factors when comparing a secondary C-H to a benzylic C-H.

Ph

O

nPr

SH2N

OO RhII catalystPhI(OAc)2

MgO, CH2Cl2Ph

O

nPr

SHN

OO

+

Ph

O

nPr

NHSOO

Catalyst = [Rh2(OAc)4] 8 : 1 = [Rh2(O2CCPh3)4] 1 : 1.5

Du Bois ACIE 2004, 43, 4349 - Depending on the choice of ligand, an aziridine or a product obtained from an allylic C-H oxidation can be obtained. Carboxylate ligands tend to give aziridine adducts and carboximidates give the product arising from allylic C-H oxidation.

Et O

OH2N RhII catalystPhIOC6H6

N O

O

EtEt

OHN

O

+

Catalyst = [Rh2(oct)4] 71% 6% = [Rh2(S-meox)4] 1 40%

NHO

O

OMeO

S-meox =

oct = O

OH

Hayes Chem. Comm. 2006, 4501 - N-arylation is favored for Cu due to a large energy difference (14 kcal/mol) between M-C vs M-N complex. - C-arylation is favored for Pd due to the equilibrium between the M-C and M-N complexes. The outcome then follows Curtin-Hammett situation – red. eim. from M-C complex is lower in energy by 2.4 kcal/mol.

NH

O

H

pKa = 18.5

pKa = 18.5

+

Ar-X

[Pd2(dba)3] (1 mol %)XPhos (5 mol %)K2CO3 (2 equiv)

CuI(1-5 mol %)CyDMEDA (4-10 mol %)

K2CO3 (2 equiv)

NH

O

Ar

NO

Ar

55-94% yield

61-94% yield

solvent, 80-100oC, 24 h

dioxane, 40-100oC, 8-24h

iPriPr

iPr

P MNO

iPriPr

iPr

P MNH

O

iPriPr iPr

P M N

OiPriPr iPr

P M NH

O

!!E = 4.8 kcal mol-1 for Pd = 14 kcal mol-1 for Cu

!!E = 2.4 kcal mol-1 for Pd

Buchwald JACS 2008, 130, 9613 10 Chemoselective olefin metathesis reaction

Cross Metathesis (CM)R + R' R

R' RR'

+ +[M]

Ring-Closing Metathesis (RCM)

Ring-Opening Metathesis+

( )nAcyclic DieneMetathesis (ADMET)

Ring-Opening MetathesisPolymerization (ROMP)

Some general metathesis catalysts

PCy3

RuPh

PCy3Cl

Cl

Grubbs I

i-Pr i-PrN

Mo PhOO

F3C

CF3

CF3F3CSchrock

N N

RuPh

N N

Ru

PCy3Cl

Cl

Oi-PrCl

Cl

Grubbs II

Hoveryda-Grubbs

Classes of metathesis reaction

For a general review of olefin metathesis reaction: Hoveyda Nature 2007, 450, 243


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- Olefin metathesis reaction has emerged as one of the most powerful synthetic tools. Many class of reactions (CM, RCM, ROMP) have been investigated; several reports have demonstrated that catalyst structure or type can influence the distribution of metathesis products, i.e. the chemoselectivity.

For a review in chemoselective metathesis reaction: Nolan Chem. Soc. Rev. 2010, 39, 3305

10.1 Innate reactivity of olefins in metathesis reactions - Grubbs and co-workers developed an empirical system for categorizing olefins in metathesis. For example, terminal olefins and allylic alcohols fall under the type I. Type IV olefins are spectators (no catalyst deactivation) and are slow cross-metathesis.

OAc

+ Grubbs I (5 mol%)

78%E/Z 4.5:1

Type I olefin

Type I olefin

Type IV olefinPCy3

RuPhCl

PCy3

ClO

OAcMe

O

MeOAc

Grubbs JACS 2003, 125, 11360 10.2 Catalyst controlled chemoselective metathesis reaction - Large phosphine ligand in Grubb I catalyst is too sterically hindered for RCM.

PCy3

RuPhCl

PCy3

ClO

O Me

10 mol%

O

O Me

RuPhCl

PCy3

Cl

10 mol%

O

O

Me

65%RCM favored

2

79%dimerization

favored

NN MesMes

Furstner CEJ 2001, 7, 3236 - NHC ligand prefers the thermodynamic product vs. the phosphine ligand prefers the kinetic (RCM) product

PCy3

RuPhCl

PCy3

Cl

10 mol%

RuPhCl

PCy3

Cl

10 mol%

85% (12:1)Ring-rearrangmentmetathesis favored

75% (5:1)RCM favored

N

O

NN MesMes

N ON

O

Ma CEJ 2004, 10, 3286 11 Product-selective catalysis

This is a recent area of research that deals with catalyst-controlled reactions with the preferential formation of two (or more) unrelated products that are not stereo- or regioisomers. Many of these reactions were discovered serendipitously, and rational design of this kind of selectivity is not easy. However, advances in understanding this type of selectivity and development of this mode of catalysis is especially relevant in modern synthesis, in which increased efficiency and selective functionalization of complex targets is highly desirable. We highlight here some notable examples, whose explanation illustrate the case.

- By adjusting the strength of the base (pKa), selective generation of a reactive species may be achieved.

H

O

Ph

+

EtO2C

10 mol% cat15 mol% NMM

O

O

EtO2C Me MeOH

Me

OH

Me10 mol% cat

25 mol% DBUO

OEtO2C

Me MeOH

Ph

Ph

via

NNN

O

Mes

N

N N Mes

O-

Ph

enolate(DA reaction)

viaN

N N Mes

OH

Ph

homoenolateaddition/cyclization

O

Bode PNAS 2010, 107, 20661


20

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- Selectivity arises from different affinity of each metal to the alkyne and allene. Pt(II) and Pt(IV) activate the alkyne and Au(I) activates the allene towards nucleophilic attack by the hydroxyl

HOR

MeMe

MeMe

PtCl2 or PtCl4 (5 mol%)toluene, reflux 36 h

[AuCl(PPh3)] (2 mol %)AgSbF6 (2 mol %)

CH2Cl2, reflux, 1h

HOR

MeMe

MeMe

M

MeMe

MeMe

RH

O

MeMe

MeMe

RH

MHO H

H+

HOR

MeMe

MeMe

M

O

R

HMe

Me Me

MeM O

R

Me

Me Me

Me

M

M

R = CH2iPr

85% yield

72% yield-H+

Fensterbank and Malacria CEJ 2008, 14, 1482 - Selectivity arises from tuning of the electronic nature of the ligands for Au catalysis

[(t-Bu)2P(o-biphenyl)P-AuCl] (5 mol %)

AgSbF6 (5 mol %)electron-rich

83% yield(8:1)

TESO Me

[(C6F5)3]PAuCl] (5 mol %)AgSbF6 (5 mol %)electron-poor

H

OTES

Me[Au]

pinacol

[3,3]

H

OTES

Me

H

TESO

Me

[Au]

[Au]

Me

O

81% yield(19:1)

Me

H

O

Duschek and Kirsch OL 2008, 10, 2605 For a brief review on electronic tuning of ligand in Au catalysis, see Kirsch ChemCatChem 2011, 3, 649

- Direct olefination of 1,4-dien-3-ones remains a synthetic challenge. Competing catalytic Meyer−Schuster rearrangement versus Nazarov-type electrocyclization may be selectively promoted by V vs Au catalysts.

5% VO(acac)284%

Meyer-Schusterrearrganement

dehydrativecyclization

93%

Me

Ph

Me

Ph

HOOEt PhMe, 80oC

5% AuCl3THF rt

Ph

Me

Ph

OEt

Me

Ph

Me

Ph

CO2Et

Me

Ph

Me

Ph

OEt

4!-electro-cyclization

hydrationtautomerization

West JOC 2011, 76, 50 - Changing the metal catalyst from Pd to Rh allows for acceleration of decarbonylation over reductive elimination, although only with moderate selectivity. As an improvement to the previous system, changing the metal catalyst from Pd to Cu allows for acceleration of decarboxylation over reductive elimination, with better selectivity.

120oC

O

arylation

esterification

32-98%

46-95%

R

R

R20% Pd(TFA)2O

OH

RRB(OH)2

R

fast red. elim

slow red. elimCu

O

Ar1Ar2-CO2

Ag2CO3

120oC

20% Cu(OTf)2Ag2CO3

O

O

PdO

Ar1Ar2 O

Liu Chem. Comm. 2011, 47, 677

topic: catalytic divergent synthesis 1 selectivity ......topic: catalytic divergent synthesis 1...

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