Mechanistic Manifold and New Developments of the Julia-Kocienski Reaction Angelique Fortier A. B. Charette’s Research Group Literature Meeting April 29th 2009 __________________________________________

__________________________________________ Outline Introduction The Classical Julia Olefination The Modified Julia Olefination Heterocyclic Sulfones Mechanistic Manifold Stereochemical Trends Irreversible Addition of Aliphatic Sulfones Reversible Addition of Allylic and Benzylic Sulfones Zwitterionic Intermediates Electron-Poor Aryl Sulfones α-Halogenated Sulfones Sulfonylacetamide & -acetates Methylenation Tri- & Tetrasubstitution Allylic Ethers & Alcohols ConclusionSummary

The most efficient and generally applicable methods for alkene synthesis remain those involving direct olefination of carbonyl compounds. Wittig Reaction Horner-Wittig __________________________________________ Introduction

__________________________________________ Introduction Horner-Wadsworth-Emmons Peterson Olefination

__________________________________________ The Classical Julia Olefination Requires four distinct synthetic operations metallation of a phenylsulfone addition of the metallate to an aldehyde acylation of the resulting β-alkoxysulfone reductive elimination of the β-acyloxysulfone Can be carried out in a single vessel, although overall yield is improved if β-alkoxysulfone is isolated prior to functionalization

__________________________________________ The Modified Julia Olefination Replacement of the phenylsulfones with certain heteroarylsulfones alters the reaction manifold due to the presence of an electrophilic imine-like moity

__________________________________________ Heterocyclic Sulfones for Alkene Synthesis Used for modified Julia olefinations

__________________________________________ Benzothiazol-2-yl (BT) Sulfones BT sulfones are particularly suseptible to nucleophilic attack at C2 Deprotonation must be effected with non-nucleophilic bases -ie. LDA The donor-acceptor nature of metallated BT-sulfones leads to self-condensation Can be avoided by using Barbier conditions Barbier cond.: addition of base to a mixture of sulfone and aldehyde. In situ metallation of the sulfone and subsequent addition to carbonyl competes against self-condensation

__________________________________________ Pyridin-2-yl (PYR) Sulfones PYR sulfones are less susceptible to ipso substitution reactions than BT-sulfones Simple derivatives can be cleanly metallated with n - butyllithium at low temperatures Smiles rearrangement is not facile Comparative lack of electrophilicity leads to excellent stability, thus self-condensation is avoided PYR-sulfones give lower yields of olefin product than BT- sulfones, however, can give higher levels of cis selectivity

__________________________________________ 1-Phenyl-1 H -tetrazol-5-yl (PT) Sulfones Introduced by Kocienski in 1998 PT-variant is distinguished by it’s ability to provide high levels of trans selectivity in the absence of biasing electronic and/or steric factors The carbanions of PT-sulfones show reduced propensity to self-condense than their analogous BT-sulfones Trans selectivity increases with both solvent polarity and electropositivity of the base counter-cation

__________________________________________ 1- tert -Butyl-1 H -tetrazol-5-yl (TBT) Sulfones The increased stability of metallated PT-sulfones as compared to metallated BT-sulfones is presumably due to the ability of the phenyl ring sterically shielding the electrophilic sulfone- bearing carbon from intermolecular nucleophilic attack Hence substitution of this phenyl with a tert -butyl group further improves sulfone metallate stability The three types of sulfones were metallated and following protonolysis the following was observed: BT-sulfone: 0% PT-sulfone: 20% TBT-sulfone: 91% Self-condensation accounted for the mass balance

__________________________________________ Commonly Accepted Mechanistic Manifold

__________________________________________ Stereochemical Trends for Heteroaryl Sulfones The diastereocontrol of E : Z ratio of the product olefins accurately reflects the anti : syn ratio of the intermediate β-alkoxysulfones for irreversible reactions... In order to undergo the Smiles rearrangement, A1 and A2 fold into conformations B1 and B2 Less likely for tetrazoyl sulfones due to undesirable steric interactions

__________________________________________ Stereochemical Trends for Heteroaryl Sulfones Irreversible Smiles rearrangement through spirocyclic intermediates C1 and C2 would lead to D1 and D2 respectively The gauche interaction in B1 and the eclipsed interaction in C1 between R 1 and R 2 will lead to a slower Smiles rearrangement in A1 than A2 (k 1 < k 2 )

__________________________________________ Stereochemical Trends for Heteroaryl Sulfones Intermediates D1 and D2 must be in an antiperiplanar conformation (E1 and E2) to undergo β-elimination of the heterocyclic moiety via extrusion of sulfur dioxide

__________________________________________ Stereochemical Trends for Heteroaryl Sulfones In the case of irreversible reaction between metallated sulfones and aldehydes, the final olefins ratio is determined by the k a /k s ratio In the case of a reversible reaction between metallated sulfones and aldehydes, the final olefin ratio is dictated by a larger set of kinetic constants (k a, k -a, k s, k -s, k 1, and k 2 ) if {k 1, k 2 } << {k a, k -a, k s, k -s } then the stereochemical outcome is dictated by the relative rate of Smiles rearrangement of A1 and A2 (k 1 /k 2 ) and the Z-olefin would be favoured since k 1 < k 2...but there is more to the story which we will see later

__________________________________________ Irreversible Addition of Aliphatic Sulfones Kocienski showed that the counterion of the base and the polarity of the solvent play an important role KHMDS and DME afforded E-olefins almost exclusively in all cases studied

__________________________________________ Irreversible Addition of Aliphatic Sulfones Polar versus non-polar solvents for PT-sulfones non-polar solvents: polar solvents: Hence...

__________________________________________ Irreversible Addition of Aliphatic Sulfones BT-sulfones are not so straightforward... Kocienski showed that reactions of non-branched BT-sulfones with aldehydes did not show strong dependance on the nature of the base counterion Charette brought to evidence strong solvent effects on the stereochemical outcome of the reaction under Barbier conditions The E/Z ratio of olefins were inverted by replacement of solvents Although stereoselectivities of the reactions involving aliphatic BT sulfonyl carbanions are less predictable than those involving their PT counterparts, E-olefins are obtained in high yields when α- branched substrates are used

__________________________________________ Reversible Addition of Allylic and Benzylic Sulfones The stereochemical outcome of reactions between allylic and benzylic sulfones with saturated aldehydes strongly depends on the heterocyclic sulfone moiety E,Z-dienes are favoured upon reaction with allylic and benzylic TBT-sulfones

__________________________________________ Reversible Addition of Allylic and Benzylic Sulfones This can be explained by the reversibility of the reaction between the aldehyde and the TBT-sulfonyl carbanion If {k 1, k 2 } << {k a, k -a, k s, k -s }, then the stereoselectivity of the reaction is only dependant on the k 1 /k 2 ratio Since the syn alkoxide should undergo the Smiles rearrangement forming E,Z-dienes faster than the anti alkoxide towards E,E-dienes (k 1 < k 2 ), then E,Z-dienes are favoured In addition, the bulky tert-butyl group of TBT-sulfones further ensures the proper kinetic ratio by decreasing the rate of the Smiles rearrangement

__________________________________________ Reversible Addition of Allylic and Benzylic Sulfones Similarly, reversibility of the initial condensation could also apply to benzylic and allylic BT and PT-sulfones However, the Smiles rearrangement is faster for BT and PT- sulfones than for TBT-sulfones {k 1, k 2 } and {k a, k -a, K s, k -s } can have a more subtle influence and the stereochemical outcome is henceforth case dependent

__________________________________________ Reversible Addition of Allylic and Benzylic Sulfones E-selectivity has been observed in sterically hindered aldehyde reactions with benzylic sulfones The initial condensation is likely to be reversible, however, stereoselectivity cannot be determined by the Smiles rearrangement As this would favour Z-olefins We can assume the following: syn alkoxides are formed only transiently (brief moment of existance) and their collapse into sm is much faster than the Smiles rearrangement anti alkoxides are formed and undergo the Smiles rearrangement

__________________________________________ Zwitterionic Intermediates -Aliphatic Sulfones S. Julia demonstrated stereoselective formation of E-olefins when BT-sulfones reacted with benzaldehydes having electron-donating substituents on it’s phenyl ring This was rationalized by the formation of a positive charge at the benzylic position through rapid collapse of intermediates 1 and 2 in forming 3 and 4 respectively by means of E1 elimination Steric repulsions between R 1 and R 2 would favour 4, leading to E-olefins

__________________________________________ Zwitterionic Intermediates -Aliphatic Sulfones Predominant formation of E-olefins are formed upon reaction with aliphatic BT and PT-sulfones The zwitterionic pathway can also be invoked for reactions of α, β-unsaturated aldehydes with BT and PT-sulfones forming E,E-dienes

__________________________________________ Zwitterionic Intermediates -Aliphatic Sulfones Conversely, Charette showed the selective preparation of E,Z-dienes The PYR-sulfonyl carbanion is stable at room temperature (for at least 5 minutes) due to its weak electrophilicity similar to TBT-sulfones Selectivity is controlled during the Smiles rearrangement since {k 1, k 2 } << {k a, k -a, k s, k -s } and (k 1 < k 2 ) Moreover, the zwitterionic pathway is probably disfavoured in apolar solvents

__________________________________________ Zwitterionic Intermediates -Allylic Sulfones Reactions of allylic-sulfones with α, β-unsaturated aldehydes or benzaldehydes are also case dependent However, most cases of reactions between allylic-sulfones and α, β-unsaturated aldehydes show strong stereochemical preference in favour of E,Z,E-trienes Implying that the zwitterionic pathway does not play an important role Aliphatic BT-sulfones did not show linear dependence to the size of the base counterion The E,Z,E-triene stereoselectivity is controlled by the Smiles rearrangement in reactions of reversible addition of the sulfonyl carbanion on aldehydes

__________________________________________ Zwitterionic Intermediates -Allylic Sulfones

__________________________________________ Zwitterionic Intermediates -Propargylic Sulfones Not many examples are found in the literature for propargylic-sulfones Some examples suggest that the reaction of propargylic sulfonyl carbanions with α, β-unsaturated and aromatic aldehydes are reversible Hence the stereoselectivity of the reaction would be dictated by the Smiles rearrrangement of the syn alkoxide intermediate as opposed to the zwitterionic mechanism Accordingly, Z-olefins are obtained

__________________________________________ Electron-Poor Aryl Sulfones Recently, Makosza has reported that pentachlorophenyl sulfones could afford benzylidenecyclopropanes upon treatment with tert -butoxide and reaction with aldehydes and ketones Strong current interest for syntheses These were obtained with both electron-poor and electron-rich aldehydes It was found that Z-isomers were obtained preferentially

__________________________________________ Electron-Poor Aryl Sulfones Zhu described the reactivity of para -nitrophenyl and n -hexyl- para -nitrophenyl sulfones with aromatic aldehydes Electron-rich aromatic aldehydes do not show better E-selectivities than electron-poor aldehydes (entry 2 & 3) and tended to give equimolar mixtures (6 & 7) Electron-rich aldehydes favour the zwitterionic pathway, which is non-stereoselective unless the aldehyde is equipped with a sterically hindering group (4 & 8) In the case of electron-poor aromatic aldehydes, the stereoselectivities are controlled by the Smiles rearrangement faster for the anti alkoxides than their syn isomers...in contrast with the normally accepted mechanism of the Julia-Kocienski reaction

__________________________________________ α-Halogenated BT and PT Sulfones Berthelette found a method to form both E and Z halogenated olefins by addition of additives HMPA afforded an 8:92 ratio favouring the Z alkenyl chloride isomer MgBr 2 /Et 2 O favoured the E alkenyl chloride isomer in 93:7 The role of these additives however has yet to be rationalized >95% yields Good scope, limitation: ortho substitution Electronic and steric effects seem to play an important role

__________________________________________ α-Halogenated BT and PT Sulfones Lequeux and Pazenok were the first to describe the reaction of α-monofluorinated BT-sulfones with α,β-unsaturated aldehydes and ketones to obtain vinyl fluorides under Barbier- type reactions Isolated yields were moderate to very good, however, stereoselectivities remained poor Reaction with ketones were improved when NaHMDS was used as the base

__________________________________________ α-Halogenated BT and PT Sulfones Zajc only obtained excellent selectivities with the following aldehydes The rest of the scope (ketones and aldehydes) gave moderate selectivities

__________________________________________ 2-Sulfonylacetamide and 2-Sulfonylacetate Another extention for the scope of the Julia-Kocienski olefination, forming stereoselective α,β-unsaturated esters and Weinreb amides via BTFP-sulfones Elecrton-rich and electron-poor aromatic aldehydes gave similar results, contradicting the zwitterionic pathway prompting mechanistic studies

__________________________________________ 2-Sulfonylacetamide and 2-Sulfonylacetate Computational studies of BTFP-sulfones revealed a possible non-concerted final elimination of SO 2 and 3,5-bis(trifluoromethyl)phenoxide According to these calculations, after the reversable attack of the stabilized sulfonyl carbanions onto aldehydes, syn alkoxide would undergo a rapid reaction forming a spirocyclic intermediate It would first liberate SO 2 before final elimination of the phenoxide Thereby forming E-olefins

__________________________________________ 2-Sulfonylacetamide and 2-Sulfonylacetate Furthermore, Blakemore showed that the carbanion reacts with the aldehyde under kinetic conditions to give Z- olefins, whilst under thermodynamic conditions, E-olefins are obtained Stereocontrol at low temperatures follow the classical Smiles rearrangement by a concerted antiperiplanar elimination Raising the temperature could enable the collapse of the spirocyclic intermediate into an enolate This rationale is in accordance with Nájera (previous slide)

__________________________________________ 2-Sulfonylacetamide and 2-Sulfonylacetate Zajc showed an inversion of stereoselectivities with 2-fluoro-2-sulfonylacetates can be explained by the destabilizing effect of fluorine adjacent to the positive charge present in the zwitterionic pathway Instead, the stereochemical outcome is controlled by the Smiles rearrangement favouring the Z-isomer

__________________________________________ Methylenation Until recently not many examples were known Nájera, reported moderate yields when aliphatic, aromatic, and α,β-unsaturated aldehydes or ketones were treated with BTFP-sulfones and phosphazene Independently, Aïssa disclosed two improved procedures for the methylenation of ketones and aldehydes

__________________________________________ Methylenation -scope ( Aïssa)

__________________________________________ Methylenation Moreover, Gueyard also reported a two-step methylenation protocol Noteworthy, substrates prone to enolization can be submitted to conditions A without compromising the labile stereocenters

__________________________________________ Tri- & Tetrasubstitution Access to trisubstituted olefins via the Julia-Kocienski reaction between ketones & primary alkyl sulfones or aldehydes & secondary alkyl sulfones was quite limited until recently Although yields are good, stereoselectivities remain poor Nájera was able to make tri- and tetrasubstituted olefins in low to excellent yields under mild Barbier conditions with BTFP- sulfones Either with symmetrical sulfones or aldehydes & ketones

__________________________________________ Tri- & Tetrasubstitution More interestingly, Nájera was able to obtain Z-selectivity using unsymmetrical BTFP-sulfones Best selectivities were obtained at lower temperatures although this resulted in lower yields

__________________________________________ Tri- & Tetrasubstitution Gueyard used the same two step procedure as seen before for the preparation of tri- and tetrasubstituted exoglycols For unsymmetrical tri-substituted olefins, they obtained E isomers preferentially Additional studies are underway to address the stereochemical issue

__________________________________________ Allylic Ethers and Alcohols Markó has recently reported an efficient stereoselective synthesis of allylic ethers and alcohols using PT-sulfones In all cases E-isomers were obtained predominantly in excellent yields tert-butyldimethylsilyloxy was crutial as poor leaving group for the success of the reaction Probably due to the propensity of the sulfonyl carbanion to undergo the β-elimination when adjacent to a C-O bond

__________________________________________ Conclusion The Julia-Kocienski olefination is operationally simple and enables straightforward assembly of functionalized intermediates in total syntheses The scope of the reaction has recently been extended to terminal olefins, tri- and tetrasubstituted olefins, halogenated olefins, and α,β-unsaturated esters and amides Beyond aldehydes and ketones, the scope of electrophiles has been extended to lactones and acylsilanes Although it is difficult to generalize the stereochemical outcome, some trends have emerged for BT, PT and PYR sulfones

__________________________________________ Summary I. -E-olefins are obtained predominantly from reactions between aliphatic aldehydes and aliphatic sulfones (especially PT-sulfones in polar solvents -DME, DMF and large base counterions -K + -Moreover, trapping additives (18-crown-6) may further aid II. -Isomer ratio is more substrate dependant in reactions between allylic or benzylic sulfones and aldehydes -Z-selectivity however, can be obtained by Smiles rearrangement control when the initial addition of the α-sulfonyl carbanions is reversible III. -Reactions of aliphatic BT or PT sulfones with aromatic or α,β- unsaturated aldehydes give rise to E-isomers predominantly when carried out in polar solvents -THF, DME -However, PYR-sulfones in apolar solvents -toluene, should afford Z-olefins IV. -All reported reactions of propargylic sulfones gave Z-olefins V. -Most reactions between allylic sulfones and α,β-unsaturated aldehydes gave conjugated trienes embedding a central Z- configured C=C bond

__________________________________________ Thank You