Mechanistic Manifold and New Developments of the Julia-Kocienski Reaction Angelique Fortier A. B....

Mechanistic Manifold and New Mechanistic Manifold and New Developments Developments

of the of the Julia-Kocienski ReactionJulia-Kocienski Reaction

Angelique FortierAngelique FortierA. B. Charette’s Research GroupA. B. Charette’s Research Group

Literature Meeting Literature Meeting

April 29th 2009April 29th 2009

____________________________________________________________________________________

____________________________________________________________________________________OutlineOutlineIntroductionIntroduction

The Classical Julia OlefinationThe Classical Julia Olefination

The Modified Julia OlefinationThe Modified Julia Olefination

Heterocyclic SulfonesHeterocyclic Sulfones

Mechanistic ManifoldMechanistic Manifold

Stereochemical TrendsStereochemical Trends

Irreversible Addition of Aliphatic SulfonesIrreversible Addition of Aliphatic Sulfones

Reversible Addition of Allylic and Benzylic SulfonesReversible Addition of Allylic and Benzylic Sulfones

Zwitterionic IntermediatesZwitterionic Intermediates

Electron-Poor Aryl SulfonesElectron-Poor Aryl Sulfones

α-Halogenated Sulfonesα-Halogenated Sulfones

Sulfonylacetamide & -acetatesSulfonylacetamide & -acetates

MethylenationMethylenation

Tri- & TetrasubstitutionTri- & Tetrasubstitution

Allylic Ethers & AlcoholsAllylic Ethers & Alcohols

ConclusionConclusion

SummarySummary

The most efficient and generally applicable methods The most efficient and generally applicable methods for alkene synthesis remain those involving direct for alkene synthesis remain those involving direct olefination of carbonyl compounds.olefination of carbonyl compounds.

Wittig ReactionWittig Reaction

Horner-WittigHorner-Wittig

____________________________________________________________________________________IntroductionIntroduction

P

O

R1R1

R2 R3 R4

O

R3 R4

H R2base / solvent

0-110 °CP

O

R1R1

R2

R1 = aryl, alkyl; R2 = alkyl, aryl, COR, CO2R, CN, SO2R; R3, R4 = H, alkyl, aryl

R3X

R2

(R1)3P R3(R1)3P

R2

base R3(R1)3P

R2

R4 R5

O

R4 R5

R2 R3

X = Cl, Br, I, OTs; R4, R5 = alkyl,aryl, alkynyl, H

if R1 = aryl and R2, R3 = alkyl, H ⇒ "nonstab" ylideif R1 = aryl and R2, R3 = aryl, alkenyl, benzyl, allyl, H ⇒ "semi-stab" ylideif R1 = aryl and R2, R3 = CO2R, SO2R, CN, COR ⇒ "stab" ylide

____________________________________________________________________________________IntroductionIntroduction

Horner-Wadsworth-EmmonsHorner-Wadsworth-Emmons

Peterson OlefinationPeterson Olefination

P

O

R1R1

R2 R3 R4

O

R3 R4

H R2base / solvent

0-110 °CP

O

R1R1

R2

R1 = O-aryl, O-alkyl, NR2; R2 = aryl, alkenyl, COR, CO2R, CN, SO2R; R3, R4 = H, alkyl, aryl

SiR3

MR2H

R3 R4

OR3

R4

H

R2

R1 = aryl, alkyl; R3, R4 = H, alkyl, arylR2 = alkyl, aryl, CO2R, CN, CONR2, CH=NR, SR, SOR, SO2R, SeR, SiR3, OR, BO2R2

OH

R3Si R4

H

R3

R2

OH

R3Si R3

H

R4

R2

R4

R3

H

R2

acid

base

base

H2O

____________________________________________________________________________________The Classical Julia OlefinationThe Classical Julia Olefination

Requires four distinct synthetic operationsRequires four distinct synthetic operations

metallation of a phenylsulfonemetallation of a phenylsulfone

addition of the metallate to an aldehydeaddition of the metallate to an aldehyde

acylation of the resulting β-alkoxysulfoneacylation of the resulting β-alkoxysulfone

reductive elimination of the β-acyloxysulfonereductive elimination of the β-acyloxysulfone

Can be carried out in a single vessel, although overall Can be carried out in a single vessel, although overall yield is improved if β-alkoxysulfone is isolated prior to yield is improved if β-alkoxysulfone is isolated prior to functionalizationfunctionalization

SO2

R1

H

PhSO2

R1

Li

Phn-BuLi R2CHOSO2

R1Ph

LiO R2

Na(Hg)

EtOHR2R1

SO2

R1Ph

AcO R2

AcCl

____________________________________________________________________________________The Modified Julia OlefinationThe Modified Julia Olefination

Replacement of the phenylsulfones with certain Replacement of the phenylsulfones with certain heteroarylsulfones alters the reaction manifoldheteroarylsulfones alters the reaction manifold

due to the presence of an electrophilic imine-like moitydue to the presence of an electrophilic imine-like moity

S

NSO2

R1H

S

NSO2

R1Li

LDA R2CHO

S

NSO2

R1

R2

OLi

S

N

SO2

O R2

R1

Li

S

NO

R2

SR1

OO

Li

R1 R2

BT sulfoneSmilesRearrangement

unstable

spirocyclic intermediatesulfinate salt

spontaneous eliminationof sulfur dioxide

____________________________________________________________________________________Heterocyclic Sulfones for Alkene Synthesis Heterocyclic Sulfones for Alkene Synthesis

Used for modified Julia olefinationsUsed for modified Julia olefinations

SO2R

N

NSO2R

aryl sulfonesM. Julia, 1973

1-methylimidazol-2-yl sulfonesA. S. Kende, 1990

S

NSO2R

benzothiazol-2-yl sulfones(BT)

S. Julia, 1991

N

SO2R

pyridin-2-yl sulfones(PYR)

S. Julia, 1993

N

N SO2R

pyrimidin-2-yl sulfonesS. Julia, 1993

N

N N

NPh

SO2R

1-phenyl-1H-tetrazol-5-yl sulfones(PT)

P. J. Kocienski, 1998

N

N N

NtBu

SO2R

1-tert-butyl-1H-tetrazol-5-yl sulfones(TBT)

P. J. Kocienski, 2000

____________________________________________________________________________________Benzothiazol-2-yl Benzothiazol-2-yl (BT)(BT) Sulfones Sulfones

BT sulfones are particularly suseptible to nucleophilic BT sulfones are particularly suseptible to nucleophilic attack at C2attack at C2

Deprotonation must be effected with non-nucleophilic Deprotonation must be effected with non-nucleophilic bases -ie. LDAbases -ie. LDA

The donor-acceptor nature of metallated BT-sulfones The donor-acceptor nature of metallated BT-sulfones leads to self-condensationleads to self-condensation

Can be avoided by using Barbier conditionsCan be avoided by using Barbier conditions

Barbier cond.: addition of base to a mixture of sulfone and Barbier cond.: addition of base to a mixture of sulfone and aldehyde. In situ metallation of the sulfone and subsequent aldehyde. In situ metallation of the sulfone and subsequent addition to carbonyl competes against self-condensationaddition to carbonyl competes against self-condensation

S

NSO2

S

N

S

NSO2R

____________________________________________________________________________________Pyridin-2-yl Pyridin-2-yl (PYR)(PYR) Sulfones Sulfones

PYR sulfones are less susceptible to PYR sulfones are less susceptible to ipsoipso substitution substitution reactions than BT-sulfonesreactions than BT-sulfones

Simple derivatives can be cleanly metallated with Simple derivatives can be cleanly metallated with nn--butyllithium at low temperaturesbutyllithium at low temperatures

Smiles rearrangement is not facileSmiles rearrangement is not facile

Comparative lack of electrophilicity leads to excellent Comparative lack of electrophilicity leads to excellent stability, thus self-condensation is avoidedstability, thus self-condensation is avoided

PYR-sulfones give lower yields of olefin product than PYR-sulfones give lower yields of olefin product than BT-sulfones, however, can give higher levels of BT-sulfones, however, can give higher levels of ciscis selectivityselectivity

N

SO2R

____________________________________________________________________________________1-Phenyl-11-Phenyl-1HH-tetrazol-5-yl -tetrazol-5-yl (PT)(PT) Sulfones Sulfones

Introduced by Kocienski in 1998Introduced by Kocienski in 1998

PT-variant is distinguished by it’s ability to provide PT-variant is distinguished by it’s ability to provide high levels of high levels of transtrans selectivity in the absence of biasing selectivity in the absence of biasing electronic and/or steric factorselectronic and/or steric factors

The carbanions of PT-sulfones show reduced The carbanions of PT-sulfones show reduced propensity to self-condense than their analogous BT-propensity to self-condense than their analogous BT-sulfonessulfones

Trans Trans selectivity increases with both solvent polarity selectivity increases with both solvent polarity and electropositivity of the base counter-cationand electropositivity of the base counter-cation

N

N N

NPh

SO2R

____________________________________________________________________________________1-1-terttert-Butyl-1-Butyl-1HH-tetrazol-5-yl -tetrazol-5-yl (TBT)(TBT) Sulfones Sulfones

The increased stability of metallated PT-sulfones as The increased stability of metallated PT-sulfones as compared to metallated BT-sulfones is presumably compared to metallated BT-sulfones is presumably due to the ability of the phenyl ring sterically shielding due to the ability of the phenyl ring sterically shielding the electrophilic sulfone-bearing carbon from the electrophilic sulfone-bearing carbon from intermolecular nucleophilic attackintermolecular nucleophilic attack

Hence substitution of this phenyl with a Hence substitution of this phenyl with a terttert-butyl group -butyl group further improves sulfone metallate stability further improves sulfone metallate stability

The three types of sulfones were metallated and The three types of sulfones were metallated and following protonolysis the following was observed:following protonolysis the following was observed:

BT-sulfone: 0%BT-sulfone: 0%

PT-sulfone: 20%PT-sulfone: 20%

TBT-sulfone: 91%TBT-sulfone: 91%

Self-condensation accounted for the mass balanceSelf-condensation accounted for the mass balance

N

N N

NtBu

SO2R

____________________________________________________________________________________Commonly Accepted Mechanistic Manifold Commonly Accepted Mechanistic Manifold

R1 R2

SO2BT

OM

A1 anti

ka

k-a

Metallatedsulfone

(M = Li, Na, K) O

R2

R1 R2

SO2BT

OM

A2 syn

S N

SO O

H

R1

OM

HR2

k1 S N M

O SO2

R2 HH

R1R1 O

SO2M

R2

D1C1B1

BT

R1 R2

SO2M

OBT

S

NMOSO2

R1 R2

E-olefin

S N

SO O

H

R1

OM

R2

H

B2

k2

S N M

O SO2

H R2H

R1

C2

R1 O

SO2M

R2

D2

BT

R1 R2

SO2M

OBT

R1

Z-olefin

R2

R1 R2

SO2F1

R1

SO2F2

R2

E1

E2

____________________________________________________________________________________Stereochemical Trends for Heteroaryl SulfonesStereochemical Trends for Heteroaryl Sulfones

The diastereocontrol of E : Z ratio of the product The diastereocontrol of E : Z ratio of the product olefins accurately reflects the olefins accurately reflects the antianti : : synsyn ratio of the ratio of the intermediate β-alkoxysulfones for irreversible intermediate β-alkoxysulfones for irreversible reactions...reactions...

In order to undergo the Smiles rearrangement, In order to undergo the Smiles rearrangement, A1A1 and and A2A2 fold into conformations fold into conformations B1B1 and and B2B2

Less likely for tetrazoyl sulfones due to undesirable steric Less likely for tetrazoyl sulfones due to undesirable steric interactionsinteractions

N

N NN

SO OO M

R2HH

R1

N

N NN

SO OO M

R2HH

R1

TBTPT

S N

SO O

H

R1

OM

HR2

B1

S N

SO O

H

R1

OM

R2

H

B2

R1 R2

SO2BT

OM

A1 anti

ka

k-a

Metallatedsulfone

(M = Li, Na, K) O

R2

k-s

ksR1 R2

SO2BT

OM

A2 syn

____________________________________________________________________________________Stereochemical Trends for Heteroaryl SulfonesStereochemical Trends for Heteroaryl SulfonesIrreversible Smiles rearrangement through spirocyclic Irreversible Smiles rearrangement through spirocyclic intermediates intermediates C1C1 and and C2C2 would lead to would lead to D1D1 and and D2D2 respectivelyrespectively

The The gauchegauche interaction in interaction in B1B1 and the eclipsed and the eclipsed interaction in interaction in C1C1 between R between R11 and R and R22 will lead to a will lead to a slower Smiles rearrangement in slower Smiles rearrangement in A1A1 than than A2A2 ( (kk11 < < kk22))

S N

SO O

H

R1

OM

HR2

k1 S N M

O SO2

R2 HH

R1

C1B1

S N

SO O

H

R1

OM

R2

H

B2k2

S N M

O SO2

H R2H

R1

C2

S N M

O SO2

R2 HH

R1

R1 O

SO2M

R2

D1C1

BT S N M

O SO2

H R2H

R1

C2

R1 O

SO2M

R2

D2

BT


Intermediates Intermediates D1D1 and and D2D2 must be in an antiperiplanar must be in an antiperiplanar conformation (conformation (E1E1 and and E2E2) to undergo β-elimination of ) to undergo β-elimination of the heterocyclic moiety via extrusion of sulfur dioxidethe heterocyclic moiety via extrusion of sulfur dioxide

R1 O

SO2M

R2

D1

BT R1 R2

SO2M

OBT

S

NMOSO2

R1 R2

E-olefin

R1 O

SO2M

R2

D2

BT R1 R2

SO2M

OBT

R1

Z-olefin

R2

E1

E2


In the case of irreversible reaction between metallated In the case of irreversible reaction between metallated sulfones and aldehydes, the final olefins ratio is sulfones and aldehydes, the final olefins ratio is determined by the kdetermined by the kaa/k/kss ratio ratio

In the case of a reversible reaction between In the case of a reversible reaction between metallated sulfones and aldehydes, the final olefin metallated sulfones and aldehydes, the final olefin ratio is dictated by a larger set of kinetic constants (kratio is dictated by a larger set of kinetic constants (kaa, , kk-a-a, k, kss, k, k-s-s, k, k11, and k, and k22))

if {kif {k11, k, k22} << {k} << {kaa, k, k-a-a, k, kss, k, k-s-s} then the stereochemical } then the stereochemical outcome is dictated by the relative rate of Smiles outcome is dictated by the relative rate of Smiles rearrangement of A1 and A2 (krearrangement of A1 and A2 (k11/k/k22) and the Z-olefin would ) and the Z-olefin would be favoured since kbe favoured since k11< k< k22

...but there is more to the story which we will see later...but there is more to the story which we will see later

____________________________________________________________________________________Irreversible Addition of Aliphatic Sulfones Irreversible Addition of Aliphatic Sulfones

Kocienski showed that the counterion of the base and Kocienski showed that the counterion of the base and the polarity of the solvent play an important rolethe polarity of the solvent play an important role

KHMDS and DME afforded E-olefins almost exclusively in KHMDS and DME afforded E-olefins almost exclusively in all cases studiedall cases studied

PTO2SO

O

OBn

TBSO O5

KHMDS

DME, −56 °C to r.t.

OO

OBn

TBSO5

76%, E only

____________________________________________________________________________________Irreversible Addition of Aliphatic Sulfones Irreversible Addition of Aliphatic Sulfones

Polar versus non-polar solvents for PT-sulfonesPolar versus non-polar solvents for PT-sulfones

non-polar solvents:non-polar solvents:

polar solvents:polar solvents:

Hence...Hence...

N NN

N

Ph

SO O

M

HR1

O

R2

HN N

NN

Ph

SO

OM

HR1

O

R2H

NNN

NPh

S

O

O M

H

R1 OR2

H

NN N

N Ph

S

O

OM

H

R1

O R2

H1 2 3

N NN

N

Ph

SO O

HR1O

R2

HM(solvent)n N N

NNPh

SO O

HR1O

R2

H M(solvent)n

4 5

1, 2, 3 4, 5 R1 R2

SO2PT

OMR1 R2

SO2PT

OM

Smiles

Rearrangement

Smiles

RearrangementR1 R2

R1 R2

syn anti

____________________________________________________________________________________Irreversible Addition of Aliphatic SulfonesIrreversible Addition of Aliphatic Sulfones

BT-sulfones are not so straightforward...BT-sulfones are not so straightforward...

Kocienski showed that reactions of non-branched BT-sulfones Kocienski showed that reactions of non-branched BT-sulfones with aldehydes did not show strong dependance on the with aldehydes did not show strong dependance on the nature of the base counterionnature of the base counterion

Charette brought to evidence strong solvent effects on the Charette brought to evidence strong solvent effects on the stereochemical outcome of the reaction under Barbier stereochemical outcome of the reaction under Barbier conditionsconditions

The E/Z ratio of olefins were inverted by replacement of solventsThe E/Z ratio of olefins were inverted by replacement of solvents

Although stereoselectivities of the reactions involving Although stereoselectivities of the reactions involving aliphatic BT sulfonyl carbanions are less predictable than aliphatic BT sulfonyl carbanions are less predictable than those involving their PT counterparts, E-olefins are obtained those involving their PT counterparts, E-olefins are obtained in high yields when α-branched substrates are usedin high yields when α-branched substrates are used

OTIPSO BTO2S

TIPSO

NaHMDS E/Z

toluene, -78 °CDCM, -78 °CEt2O, -78 °C

1:101:101:7.7

NaHMDS E/Z

THF, -78 °CDME, -78 °CDMF, -60 °C

1.1:12.4:13.5:1

____________________________________________________________________________________Reversible Addition of Allylic and Benzylic Reversible Addition of Allylic and Benzylic SulfonesSulfones

The stereochemical outcome of reactions between The stereochemical outcome of reactions between allylic and benzylic sulfones with saturated allylic and benzylic sulfones with saturated aldehydes strongly depends on the heterocyclic aldehydes strongly depends on the heterocyclic sulfone moietysulfone moiety

E,Z-dienes are favoured upon reaction with allylic and E,Z-dienes are favoured upon reaction with allylic and benzylic TBT-sulfonesbenzylic TBT-sulfones

SO2TBT1) KHMDS, DME, −60 °C

2) n-C9H19CHO, −60 °C to r.t.60%, E/Z = 4:96

n-C9H19

SO2TBT1) KHMDS, DME, −60 °C

2) RCHO, −60 °C to r.t.60%, E/Z = 4:96

R


This can be explained by the reversibility of the This can be explained by the reversibility of the reaction between the aldehyde and the TBT-reaction between the aldehyde and the TBT-sulfonyl carbanionsulfonyl carbanion

If {kIf {k11, k, k22} << {k} << {kaa, k, k-a-a, k, kss, k, k-s-s}, then the stereoselectivity of }, then the stereoselectivity of the reaction is only dependant on the kthe reaction is only dependant on the k11/k/k22 ratio ratio

Since the Since the synsyn alkoxide should undergo the Smiles alkoxide should undergo the Smiles rearrangement forming E,Z-dienes faster than the rearrangement forming E,Z-dienes faster than the antianti alkoxide towards E,E-dienes (kalkoxide towards E,E-dienes (k11< k< k22), then E,Z-dienes ), then E,Z-dienes are favouredare favoured

In addition, the bulky tert-butyl group of TBT-sulfones In addition, the bulky tert-butyl group of TBT-sulfones further ensures the proper kinetic ratio by decreasing further ensures the proper kinetic ratio by decreasing the rate of the Smiles rearrangement the rate of the Smiles rearrangement

N

NNN

SO2

R1

OK

R2tBu

starting materials

N

NNN

SO2

R1

OK

R2tBu

k2 k1E,Z-dienes E,E-dienes


Similarly, reversibility of the initial condensation could Similarly, reversibility of the initial condensation could also apply to benzylic and allylic BT and PT-also apply to benzylic and allylic BT and PT-sulfonessulfones

However, the Smiles rearrangement is faster for BT and However, the Smiles rearrangement is faster for BT and PT-sulfones than for TBT-sulfonesPT-sulfones than for TBT-sulfones

{k{k11, k, k22} and {k} and {kaa, k, k-a-a, K, Kss, k, k-s-s} can have a more subtle } can have a more subtle influence and the stereochemical outcome is henceforth influence and the stereochemical outcome is henceforth case dependentcase dependent

SO2PT

O

NH

OTBS KHMDS

DME, −60 °C to r.t.90%, Z only

NH

OTBS


E-selectivity has been observed in sterically hindered E-selectivity has been observed in sterically hindered aldehyde reactions with benzylic sulfones aldehyde reactions with benzylic sulfones

The initial condensation is likely to be reversible, The initial condensation is likely to be reversible, however, stereoselectivity cannot be determined by the however, stereoselectivity cannot be determined by the Smiles rearrangementSmiles rearrangement

As this would favour Z-olefinsAs this would favour Z-olefins

We can assume the following:We can assume the following:

syn alkoxides are formed only transiently (brief moment of syn alkoxides are formed only transiently (brief moment of existance) and their collapse into sm is much faster than the existance) and their collapse into sm is much faster than the Smiles rearrangementSmiles rearrangement

anti alkoxides are formed and undergo the Smiles anti alkoxides are formed and undergo the Smiles rearrangementrearrangement

S

N

SO2BT

N

S

MeO2C

OMe OTBS

O

MeO2C

OMe OTBS

S

N

N

S

1) LiHMDS, THF, −50 °C

2) −50 °C to r.t.

84%, E/Z = 95:5

____________________________________________________________________________________Zwitterionic Intermediates -Aliphatic SulfonesZwitterionic Intermediates -Aliphatic SulfonesS. Julia demonstrated stereoselective formation of S. Julia demonstrated stereoselective formation of E-olefins when BT-sulfones reacted with E-olefins when BT-sulfones reacted with benzaldehydes having electron-donating substituents benzaldehydes having electron-donating substituents on it’s phenyl ringon it’s phenyl ring

This was rationalized by the formation of a positive This was rationalized by the formation of a positive charge at the benzylic position through rapid collapse of charge at the benzylic position through rapid collapse of intermediates 1 and 2 in forming 3 and 4 respectively by intermediates 1 and 2 in forming 3 and 4 respectively by means of E1 eliminationmeans of E1 elimination

Steric repulsions between RSteric repulsions between R11 and R and R22 would favour 4, would favour 4, leading to E-olefinsleading to E-olefinsN

S

SO2

O

R2

NS

O2SOLi

R1

R2

NS

O2SOLi

R1

R2

R1 R2

NS

OLi

R1

SO2

R2R1

SO2

R2

R1 R2R1 R2

SO2SO2

R11 2

3 4

____________________________________________________________________________________Zwitterionic Intermediates -Aliphatic SulfonesZwitterionic Intermediates -Aliphatic Sulfones

Predominant formation of E-olefins are formed upon Predominant formation of E-olefins are formed upon reaction with aliphatic BT and PT-sulfones reaction with aliphatic BT and PT-sulfones

The zwitterionic pathway can also be invoked for The zwitterionic pathway can also be invoked for reactions ofreactions of αα,,β-unsaturated aldehydes with BT and β-unsaturated aldehydes with BT and PT-sulfones forming E,E-dienesPT-sulfones forming E,E-dienes

PMBO O

O SO2BT

1) LDA, THF, −78 °C

2) −78 °C to r.t.

Br

OMe

OMe

O

PMBO O

O

Br

OMe

OMe

80%, E only

____________________________________________________________________________________Zwitterionic Intermediates -Aliphatic SulfonesZwitterionic Intermediates -Aliphatic Sulfones

Conversely, Charette showed the selective preparation Conversely, Charette showed the selective preparation of E,Z-dienesof E,Z-dienes

The PYR-sulfonyl carbanion is stable at room temperature The PYR-sulfonyl carbanion is stable at room temperature (for at least 5 minutes) due to its weak electrophilicity(for at least 5 minutes) due to its weak electrophilicity

similar to TBT-sulfonessimilar to TBT-sulfones

Selectivity is controlled during the Smiles rearrangement Selectivity is controlled during the Smiles rearrangement since {ksince {k11, k, k22} << {k} << {kaa, k, k-a-a, k, kss, k, k-s-s} and (k} and (k11< k< k22))

Moreover, the zwitterionic pathway is probably Moreover, the zwitterionic pathway is probably disfavoured in apolar solventsdisfavoured in apolar solvents

PYRO2SOTIPS 1) KHMDS, toluene, r.t.

2)

R2

R1 O R2

R1

OTIPS

R1 = H, R2 = Me: 67%, E/Z = 9:91R1 = H, R2 = n-Pr: 64%, E/Z = 10:90R1 = H, R2 = Ph: 70%, E/Z = 8:92

____________________________________________________________________________________Zwitterionic Intermediates -Allylic SulfonesZwitterionic Intermediates -Allylic Sulfones

Reactions of allylic-sulfones with αReactions of allylic-sulfones with α,,β-unsaturated β-unsaturated aldehydes or benzaldehydes are also case dependentaldehydes or benzaldehydes are also case dependent

However, most cases of reactions between allylic-However, most cases of reactions between allylic-sulfones and αsulfones and α,,β-unsaturated aldehydes show strong β-unsaturated aldehydes show strong stereochemical preference in favour of E,Z,E-trienesstereochemical preference in favour of E,Z,E-trienes

Implying that the zwitterionic pathway does not play an Implying that the zwitterionic pathway does not play an important roleimportant role

Aliphatic BT-sulfones did not show linear dependence Aliphatic BT-sulfones did not show linear dependence to the size of the base counterionto the size of the base counterion

The E,Z,E-triene stereoselectivity is controlled by the The E,Z,E-triene stereoselectivity is controlled by the Smiles rearrangement in reactions of reversible Smiles rearrangement in reactions of reversible addition of the sulfonyl carbanion on aldehydes addition of the sulfonyl carbanion on aldehydes

____________________________________________________________________________________Zwitterionic Intermediates -Allylic SulfonesZwitterionic Intermediates -Allylic Sulfones

BTO2S

OTBS

KHMDS, THF

−78 °C to r.t.

OSS

O OSS

OTBS

M yield(%) E/ZLi 75 29:71Na 79 43:57K - 18:82

H

SO2BTOH

O SnBu3

1) NaHMDS,THF, −78 °C

2) −78 °C

H

OH

Bu3Sn79%, E/Z = 1:5

____________________________________________________________________________________Zwitterionic Intermediates -Propargylic SulfonesZwitterionic Intermediates -Propargylic Sulfones

Not many examples are found in the literature for Not many examples are found in the literature for propargylic-sulfones propargylic-sulfones

Some examples suggest that the reaction of Some examples suggest that the reaction of propargylic sulfonyl carbanions with αpropargylic sulfonyl carbanions with α,,β-unsaturated β-unsaturated and aromatic aldehydes are reversibleand aromatic aldehydes are reversible

Hence the stereoselectivity of the reaction would be Hence the stereoselectivity of the reaction would be dictated by the Smiles rearrrangement of the dictated by the Smiles rearrrangement of the synsyn alkoxide intermediate as opposed to the zwitterionic alkoxide intermediate as opposed to the zwitterionic mechanismmechanism

Accordingly, Z-olefins are obtainedAccordingly, Z-olefins are obtained

Me3Si

SO2BT O KHMDS, THF

−55 °C to r.t. Me3Si

80%, E/Z = 4:96

____________________________________________________________________________________Electron-Poor Aryl SulfonesElectron-Poor Aryl Sulfones

Recently, Makosza has reported that Recently, Makosza has reported that pentachlorophenyl sulfones could afford pentachlorophenyl sulfones could afford benzylidenecyclopropanes upon treatment with benzylidenecyclopropanes upon treatment with terttert--butoxide and reaction with aldehydes and ketonesbutoxide and reaction with aldehydes and ketones

Strong current interest for synthesesStrong current interest for syntheses

These were obtained with both electron-poor and These were obtained with both electron-poor and electron-rich aldehydeselectron-rich aldehydes

It was found that Z-isomers were obtained It was found that Z-isomers were obtained preferentiallypreferentiallyCl

O2S

Cl

Cl

Cl

Cl

R1

X1) tBuOK, DMF, −30 °C

2) ArCOR2, tBuOK, −35 °C to 60 °C

R1Ar

R2

Ar = Ph, 4-MeC6H4, 4-Me2NC6H4, 4-MeOC6H4, 4-Cl-C6H4R1 = R2 = H, X = Br : 52-63%R1 = H, R2 = Ph, X = Br : 60%R1 = Me, R2 = H, X = Cl : 47-57%, E/Z = 23:77

____________________________________________________________________________________Electron-Poor Aryl SulfonesElectron-Poor Aryl SulfonesZhu described the reactivity of Zhu described the reactivity of parapara-nitrophenyl and -nitrophenyl and nn--hexyl- hexyl- parapara-nitrophenyl sulfones with aromatic -nitrophenyl sulfones with aromatic aldehydesaldehydes

Electron-rich aromatic aldehydes do not show better E-selectivities than Electron-rich aromatic aldehydes do not show better E-selectivities than electron-poor aldehydes (entry 2 & 3) and tended to give equimolar mixtures electron-poor aldehydes (entry 2 & 3) and tended to give equimolar mixtures (6 & 7)(6 & 7)

Electron-rich aldehydes favour the zwitterionic pathway, which is non-Electron-rich aldehydes favour the zwitterionic pathway, which is non-stereoselective unless the aldehyde is equipped with a sterically hindering stereoselective unless the aldehyde is equipped with a sterically hindering group (4 & 8)group (4 & 8)

In the case of electron-poor aromatic aldehydes, the stereoselectivities are In the case of electron-poor aromatic aldehydes, the stereoselectivities are controlled by the Smiles rearrangementcontrolled by the Smiles rearrangement

faster for the faster for the antianti alkoxides than their alkoxides than their synsyn isomers isomers

...in contrast with the normally accepted mechanism of the Julia-Kocienski reaction...in contrast with the normally accepted mechanism of the Julia-Kocienski reaction

O2N

SO2 R2

O

R1

NaH, DMF, r.t.R1 R2

EntryResult

R1 = n-C5H11

1 R2 = Ph2 R2 = 4-NO2C6H43 R2 = 4-MeOC6H44 R2 = 2,4,6-(MeO)3C6H2

43%, E/Z = 94:668%, E/Z = 80:2078%, E/Z = 81:1954%, E/Z > 99:1

EntryResult

R1 = Ph

5 R2 = Ph6 R2 = 4-NO2C6H47 R2 = 4-MeOC6H48 R2 = 2,4,6-(MeO)3C6H2

73%, E/Z = 63:3797%, E/Z = 70:3078%, E/Z = 53:4797%, E/Z > 99:1

____________________________________________________________________________________α-Halogenated BT and PT Sulfonesα-Halogenated BT and PT SulfonesBerthelette found a method to form both E and Z Berthelette found a method to form both E and Z halogenated olefins by addition of additiveshalogenated olefins by addition of additives

HMPA afforded an 8:92 ratio favouring the Z alkenyl HMPA afforded an 8:92 ratio favouring the Z alkenyl chloride isomerchloride isomer

MgBrMgBr22/Et/Et22O favoured the E alkenyl chloride isomer in 93:7O favoured the E alkenyl chloride isomer in 93:7

The role of these additives however has yet to be rationalizedThe role of these additives however has yet to be rationalized

>95% yields>95% yields

Good scope, limitation: ortho substitutionGood scope, limitation: ortho substitution

Electronic and steric effects seem to play an important Electronic and steric effects seem to play an important rolerole

MeO

H

O

Cl SO2PTBase, additive

Solvent

MeO

H

Cl

LiHMDS, THF, HMPA, E/Z = 8:92LiHMDS, THF, MgBr2•Et2O, E/Z = 93:7

____________________________________________________________________________________α-Halogenated BT and PT Sulfonesα-Halogenated BT and PT Sulfones

Lequeux and Pazenok were the first to describe the Lequeux and Pazenok were the first to describe the reaction of α-monofluorinated BT-sulfones with α,β-reaction of α-monofluorinated BT-sulfones with α,β-unsaturated aldehydes and ketones to obtain vinyl unsaturated aldehydes and ketones to obtain vinyl fluorides under Barbier-type reactionsfluorides under Barbier-type reactions

Isolated yields were moderate to very good, however, Isolated yields were moderate to very good, however, stereoselectivities remained poorstereoselectivities remained poor

Reaction with ketones were improved when NaHMDS was Reaction with ketones were improved when NaHMDS was used as the baseused as the base

BTO2S

F

R1 R2

O NaHMDS, THF, −78 °C to r.t.or

tBuOK, THF, −15 °C R1 R2

F45-88%

E/Z = 45:55-63:37

____________________________________________________________________________________α-Halogenated BT and PT Sulfonesα-Halogenated BT and PT Sulfones

Zajc only obtained excellent selectivities with the Zajc only obtained excellent selectivities with the following aldehydesfollowing aldehydes

The rest of the scope (ketones and aldehydes) gave The rest of the scope (ketones and aldehydes) gave moderate selectivitiesmoderate selectivities

FeFe

O Ar

F

>96%E/Z = 1:15.8 to 0:100

Ar = Ph, 2-thionyl, 2-naphthyl

N

S

SLHMDS

THF, 0°C

SO2BT

F

Ar

____________________________________________________________________________________2-Sulfonylacetamide and 2-Sulfonylacetate2-Sulfonylacetamide and 2-Sulfonylacetate

Another extention for the scope of the Julia-Kocienski Another extention for the scope of the Julia-Kocienski olefination, forming stereoselective α,β-unsaturated olefination, forming stereoselective α,β-unsaturated esters and Weinreb amides via BTFP-sulfonesesters and Weinreb amides via BTFP-sulfones

Elecrton-rich and electron-poor aromatic aldehydes Elecrton-rich and electron-poor aromatic aldehydes gave similar results, contradicting the zwitterionic gave similar results, contradicting the zwitterionic pathwaypathway

prompting mechanistic studiesprompting mechanistic studies

BTFPO2SOt-Bu

O

BTFPO2SN

O

OMe

R H

OK2CO3 (18 equiv.)nBu4NBr (0.2 equiv.)

DMF, 120 °C

R R'

O

(R' = OtBu): 31-96%, E/Z > 99:1(R' = N(Me)OMe): 20-84%, E/Z > 99:1

S

O2N

OEt

OO O

BTO2SN

O

OMe BTO2SOEt

O

Cs2CO3, THFr.t. or reflux temp.

yield 41-50%, E/Z > 99:1

NaH, THF, r.t.yield 44-72%, E only

DBU, CH2Cl2, r.t.yield 57-89%

E/Z = 80:20 to >98:2

____________________________________________________________________________________2-Sulfonylacetamide and 2-Sulfonylacetate2-Sulfonylacetamide and 2-SulfonylacetateComputational studies of BTFP-sulfones revealed a Computational studies of BTFP-sulfones revealed a possible non-concerted final elimination of SO possible non-concerted final elimination of SO22 and 3,5-and 3,5-bis(trifluoromethyl)phenoxidebis(trifluoromethyl)phenoxide

According to these calculations, after the reversable According to these calculations, after the reversable attack of the stabilized sulfonyl attack of the stabilized sulfonyl carbanions onto carbanions onto aldehydes, aldehydes, synsyn alkoxide would alkoxide would undergo a rapid undergo a rapid reaction forming a reaction forming a spirocyclic intermediate spirocyclic intermediate

It would first liberate SOIt would first liberate SO22 before final before final elimination of the phenoxide elimination of the phenoxide

Thereby forming E-olefinsThereby forming E-olefins

t-BuO

O

R

O

O2S

CF3

CF3

fast

CF3

CF3

O2S

O

R

t-BuO

OO

t-BuO

R

SO2

O

t-BuO

SO2

R

zwitterionic pathway

Ot-BuO

HH

R O

CF3

CF3

O

t-BuO Rphenoxide

____________________________________________________________________________________2-Sulfonylacetamide and 2-Sulfonylacetate2-Sulfonylacetamide and 2-SulfonylacetateFurthermore, Blakemore showed that the carbanion Furthermore, Blakemore showed that the carbanion reacts with the aldehyde under kinetic conditions reacts with the aldehyde under kinetic conditions to give Z-olefins, whilst under thermodynamic to give Z-olefins, whilst under thermodynamic conditions, E-olefins are obtainedconditions, E-olefins are obtained

Stereocontrol at low temperatures follow the classical Stereocontrol at low temperatures follow the classical Smiles rearrangement by a concerted antiperiplanar Smiles rearrangement by a concerted antiperiplanar elimination elimination

Raising the temperature could enable the collapse of the Raising the temperature could enable the collapse of the spirocyclic intermediate into an enolatespirocyclic intermediate into an enolate

This rationale is in accordance with Nájera (previous This rationale is in accordance with Nájera (previous slide)slide)n-C5H11

CO2EtNaHMDS,THF

0 °C to refluxn-C5H11CHO

DBU, CH2Cl2

−78 °C n-C5H11 CO2Et

O

OEt

O

O2S

S

N

n-C5H11

O

EtOSO2

O

n-C5H11

BT

OEtO

HH

n-C5H11OS

N

BTO2S OEt

O

BTO2S OEt

O

____________________________________________________________________________________2-Sulfonylacetamide and 2-Sulfonylacetate2-Sulfonylacetamide and 2-SulfonylacetateZajc showed an inversion of stereoselectivities with Zajc showed an inversion of stereoselectivities with 2-fluoro-2-sulfonylacetates 2-fluoro-2-sulfonylacetates

can be explained by the destabilizing effect of fluorine can be explained by the destabilizing effect of fluorine adjacent to the positive charge present in the zwitterionic adjacent to the positive charge present in the zwitterionic pathwaypathway

Instead, the stereochemical outcome is controlled by Instead, the stereochemical outcome is controlled by the Smiles rearrangement favouring the Z-isomerthe Smiles rearrangement favouring the Z-isomer

F

CO2tBuSO2

OBTO2S

O

OEt

DBU, DCM

r.t

CO2Et

65%, E/Z = 93:7

OBTO2S

O

OtBu

DBU, DCM

r.t

F

78%, E/Z = 22:78F

CO2tBu

____________________________________________________________________________________MethylenationMethylenation

Until recently not many examples were knownUntil recently not many examples were known

Nájera, reported moderate yields when aliphatic, Nájera, reported moderate yields when aliphatic, aromatic, and α,β-unsaturated aldehydes or ketones aromatic, and α,β-unsaturated aldehydes or ketones were treated with BTFP-sulfones and phosphazenewere treated with BTFP-sulfones and phosphazene

Independently, Aïssa disclosed two improved Independently, Aïssa disclosed two improved procedures for the methylenation of ketones and procedures for the methylenation of ketones and aldehydesaldehydes

O

O

OO

O

F3C SO2Me

CF3

P

N

NN

N

P(NMe2)3

P(NMe2)3(Me2N)3P

1341%

1, 3 (1.2 equiv.)

THF, 0 °C to r.t.

O

O

OO

O

N

N N

N

A: 90%B: 86%

A: 2 (1.2 equiv.), NaHMDS (1.3 equiv.), THF, −78 °C to r.t.B: 2 (1.3 equiv.), Cs2CO3 (3 equiv.), THF/DMF (3.1), 65 °C

____________________________________________________________________________________Methylenation -scope (Methylenation -scope (Aïssa)Aïssa)OPMB

OPMB MeO2CMeO

MeO

Br

OMe

SiMe3

MeO

A, 77B, 63

B, 96

B, 92B, 80B, 93B, 93

EtO2C

B, 80

OMeO

OA,90B, 84 B, 45

NBoc

Me H

Me

H

H H

H

Me

B, 57

A, 76

A, 92B, 93

MeO2C

O

O

A, 99

OTBS

OMOM

A, 77

NO

OPMB

O

O

O

O

A, 85

A, 59B, 93

CO2t-Bu

OTBDPS

A, 90

N

O

A, 71

____________________________________________________________________________________MethylenationMethylenation

Moreover, Gueyard also reported a two-step Moreover, Gueyard also reported a two-step methylenation protocolmethylenation protocol

Noteworthy, substrates prone to enolization can be Noteworthy, substrates prone to enolization can be submitted to conditions A without compromising the submitted to conditions A without compromising the labile stereocenterslabile stereocenters

O OBnO

OBnBnO

OBnO

OBnBnO

OH

SO2BTO

BnO

OBnBnO

MeSO2BT (1.2 equiv.)LiHMDS (2.4 equiv.)

THF, −78 °C

DBUTHF

r.t.

66%

O H H

HO H

Procedure A

65%

epi-lidiene

iso-lindiene

NO

OPMB

85% (procedure A)

____________________________________________________________________________________Tri- & TetrasubstitutionTri- & TetrasubstitutionAccess to trisubstituted olefins via the Julia-Kocienski Access to trisubstituted olefins via the Julia-Kocienski reaction between ketones & primary alkyl sulfones reaction between ketones & primary alkyl sulfones or aldehydes & secondary alkyl sulfones was quite or aldehydes & secondary alkyl sulfones was quite limited until recentlylimited until recently

Although yields are good, stereoselectivities remain poorAlthough yields are good, stereoselectivities remain poor

Nájera was able to make tri- and tetrasubstituted Nájera was able to make tri- and tetrasubstituted olefins in low to excellent yields under mild Barbier olefins in low to excellent yields under mild Barbier conditions with BTFP-sulfonesconditions with BTFP-sulfones

Either with symmetrical sulfones or aldehydes & ketonesEither with symmetrical sulfones or aldehydes & ketones

RO2S1) LiHMDS, −78 °C, THF

2) −78 °C to r.t.

O

OMOM

H

OMOM

HR = BT, 52%, E/Z = 1:1R = PT, 89%, E/Z = 1:1

RR

(R = Cl): 71%(R = OMe): 10%

____________________________________________________________________________________Tri- & TetrasubstitutionTri- & Tetrasubstitution

More interestingly, Nájera was able to obtain Z-More interestingly, Nájera was able to obtain Z-selectivity using unsymmetrical BTFP-sulfonesselectivity using unsymmetrical BTFP-sulfones

Best selectivities were obtained at lower temperatures Best selectivities were obtained at lower temperatures although this resulted in lower yieldsalthough this resulted in lower yields

P

N

NN

N

P(NMe2)3

P(NMe2)3(Me2N)3P

3

aldehyde3 (2.4 equiv.)

−78 °C (to r.t.)bolefin

MeOPh

50%, Z/E = 65:35

Ph

Ph

77%b, Z/E = 70:3050%, Z/E = 85:15

PhEt

Ph

63%b, Z/E = 93:7

____________________________________________________________________________________Tri- & TetrasubstitutionTri- & TetrasubstitutionGueyard used the same two step procedure as seen Gueyard used the same two step procedure as seen before for the preparation of tri- and before for the preparation of tri- and tetrasubstituted exoglycolstetrasubstituted exoglycols

For unsymmetrical tri-substituted olefins, they obtained For unsymmetrical tri-substituted olefins, they obtained E isomers preferentiallyE isomers preferentially

Additional studies are underway to address the Additional studies are underway to address the stereochemical issuestereochemical issue

O OBnO

OBnBnO

OBnO

OBnBnO

60-77%

R2BTO2S

R1

1) LiHMDS, THF, −78 °C

2) DBU, THF, r.t. R2

R2

OBnO

OBn

BnO Me

(77%) E/Z = 8:2

OBnO

OBn

BnO C6H13

(63%) E/Z = 9:1

OBnO

OBn

BnO

(63%) E/Z = 9:1

OTHPOBnO

OBn

BnO

(64%) E/Z > 9:1

____________________________________________________________________________________Allylic Ethers and AlcoholsAllylic Ethers and Alcohols

Markó has recently reported an efficient Markó has recently reported an efficient stereoselective synthesis of allylic ethers and stereoselective synthesis of allylic ethers and alcohols using PT-sulfonesalcohols using PT-sulfones

In all cases E-isomers were obtained predominantly in In all cases E-isomers were obtained predominantly in excellent yieldsexcellent yields

tert-butyldimethylsilyloxy was crutial as poor leaving tert-butyldimethylsilyloxy was crutial as poor leaving group for the success of the reactiongroup for the success of the reaction

Probably due to the propensity of the sulfonyl carbanion Probably due to the propensity of the sulfonyl carbanion to undergo the β-elimination when adjacent to a C-O bondto undergo the β-elimination when adjacent to a C-O bond

R O PTO2SOTBS R OTBS

KHMDS, THF

−78 °C to r.t.83-93%, E/Z = 84:16-99:1

____________________________________________________________________________________ConclusionConclusion

The Julia-Kocienski olefination is operationally simple The Julia-Kocienski olefination is operationally simple and enables straightforward assembly of and enables straightforward assembly of functionalized intermediates in total synthesesfunctionalized intermediates in total syntheses

The scope of the reaction has recently been extended The scope of the reaction has recently been extended to terminal olefins, tri- and tetrasubstituted olefins, to terminal olefins, tri- and tetrasubstituted olefins, halogenated olefins, and α,β-unsaturated esters and halogenated olefins, and α,β-unsaturated esters and amidesamides

Beyond aldehydes and ketones, the scope of Beyond aldehydes and ketones, the scope of electrophiles has been extended to lactones and electrophiles has been extended to lactones and acylsilanesacylsilanes

Although it is difficult to generalize the stereochemical Although it is difficult to generalize the stereochemical outcome, some trends have emerged for BT, PT outcome, some trends have emerged for BT, PT and PYR sulfonesand PYR sulfones

____________________________________________________________________________________SummarySummaryI.I.-E-olefins are obtained predominantly from reactions between -E-olefins are obtained predominantly from reactions between

aliphatic aldehydes and aliphatic sulfones (especially PT- aliphatic aldehydes and aliphatic sulfones (especially PT-sulfones in polar solvents -DME, DMF and large base sulfones in polar solvents -DME, DMF and large base counterions -Kcounterions -K+ + -Moreover, trapping -Moreover, trapping additives (18-crown-6) may further aidadditives (18-crown-6) may further aid

II.II.-Isomer ratio is more substrate dependant in reactions -Isomer ratio is more substrate dependant in reactions between allylic or benzylic sulfones and aldehydes between allylic or benzylic sulfones and aldehydes -Z-selectivity however, can be -Z-selectivity however, can be obtained by Smiles rearrangement control when the initial obtained by Smiles rearrangement control when the initial addition of the α-sulfonyl carbanions is reversibleaddition of the α-sulfonyl carbanions is reversible

III.III.-Reactions of aliphatic BT or PT sulfones with aromatic or α,β--Reactions of aliphatic BT or PT sulfones with aromatic or α,β-unsaturated aldehydes give rise to E-isomers predominantly unsaturated aldehydes give rise to E-isomers predominantly when carried out in polar solvents -THF, DME when carried out in polar solvents -THF, DME -However, PYR-sulfones in apolar solvents - -However, PYR-sulfones in apolar solvents -toluene, should afford Z-olefinstoluene, should afford Z-olefins

IV.IV.-All reported reactions of propargylic sulfones gave Z-olefins-All reported reactions of propargylic sulfones gave Z-olefins

V.V.-Most reactions between allylic sulfones and α,β-unsaturated -Most reactions between allylic sulfones and α,β-unsaturated aldehydes gave conjugated trienes embedding a central Z-aldehydes gave conjugated trienes embedding a central Z-configured C=C bond configured C=C bond

____________________________________________________________________________________Thank YouThank You

Mechanistic Manifold and New Developments of the Julia-Kocienski Reaction Angelique Fortier A. B....

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Transcript of Mechanistic Manifold and New Developments of the Julia-Kocienski Reaction Angelique Fortier A. B....