a-Phenylsulfonylethyllithium

(R = H)

[69291-71-0]  · C8H9LiO2S  · a-Phenylsulfonylethyllithium  · (MW 176.18)

(versatile stabilized carbon nucleophile for forming C-C, C=C, and C&tbond;C bonds with a wide range of carbon and heteroatom electrophiles1-3)

Physical Data: pKa in DMSO 31.0.

Solubility: sol THF, Et2O.

Preparative Methods: prepared in situ as needed by metalation of ethyl phenyl sulfone with n-Butyllithium or Lithium Diisopropylamide.

Handling, Storage, and Precautions: moisture sensitive; handle under nitrogen or argon.

General Considerations.

The sulfone group is perhaps second only to the carbonyl group in its versatility and utility. It serves the dual role of C-H activator and leaving group under a wide range of conditions,1 thereby enabling creation of up to three C-C bonds from a single functional group. Alkyl aryl sulfones have a pKa of ca. 31 and are therefore quantitatively deprotonated by strong bases such as n-Butyllithium, Lithium Diisopropylamide, or Grignard reagents. The resultant colored carbanions (yellow or red-orange)4 are usually stable at rt. It is also possible to form an a,a-dianion which reacts with even relatively poor electrophiles.5 In the following discussion, a-phenylsulfonylethyllithium serves as a paradigm for the class of a1d1 reagents represented by ArSO2-CH(M)R.

a-Phenylsulfonylethyllithiums as Donors.

a-Arylsulfonylalkyllithiums react with all the typical carbon electrophiles to form a C-C bond in generally good yield; some indication of the scope of the procedure can be gleaned from eqs 1-9. For example, alkylation with primary alkyl bromides (or iodides; eq 1),6 tosylates (eq 2),7 or triflates8 occurs even when there is an a-branch in the chain. In the case of sluggish reactions, additives such as Hexamethylphosphoric Triamide or N,N,N,N-Tetramethylethylenediamine can be added to accelerate alkylation.

The reaction of sulfonyl carbanions with halocarbenoids (see Tribromomethyllithium) gives a 1,1-dibromoalkene or a 1-bromoalkene (eq 3).9 The reaction probably does not involve a carbene intermediate.

Terminal epoxides react slowly with sulfonyl carbanions such as the homoenolate equivalent (1) (eq 4).10 With disubstituted epoxides and cyclic epoxides the reactions are slower still. For example, reaction of the lithio derivative of ethyl phenyl sulfone with cyclopentene oxide occurs in excellent yield (98%) after 10 h reflux in toluene.11 It has been reported that, in some cases, the addition of a Lewis acid (Magnesium Bromide,12 Boron Trifluoride Etherate,13,14 Titanium Tetraisopropoxide,15 MeOAl(i-Bu)216) or HMPA17 improves the yield dramatically.

In the presence of HMPA, the homoenolate equivalent (1) underwent conjugate addition to cyclohexenone. In the absence of HMPA, a mixture of 1,2- and 1,4-adducts was obtained (eq 5).18,19

The addition of metalated sulfones to aldehydes is reversible and in simple cases the reaction displays modest selectivity for the erythro isomer (eq 6).20 The reverse reaction is favored when the adducts are sterically compressed (e.g. ketone adducts) or when the sulfone anion is stabilized by conjugation (i.e. allylic or benzylic sulfones) or proximate heteroatoms. However, in unfavorable cases the position of the equilibrium can be tuned by varying the metal. For example, the lithio sulfone (2) did not give a stable adduct with aldehyde (4) but the ate complex derived from the lithio derivative and BF3 gave the desired adduct (5) (eq 7).21

a-Phenylsulfonylethyllithium adds to acylsilanes to give an adduct which undergoes a Brook rearrangement with subsequent loss of benzenesulfinate anion. The product of the reaction is an enol silane (eq 8).22

Reaction of the metalated sulfones with esters,23,24 lactones,25,26 amides and carbonates27 leads to the corresponding b-keto sulfone (eq 9).23 The b-keto sulfones thus formed display chemistry reminiscent of b-keto esters in their enhanced acidity and tendency to undergo C- and O-alkylation and acylation.

Aryl Sulfones as Acceptors: Desulfonylation Reactions.

The sulfone group is a powerful electron acceptor which can be cleaved under a wide range of conditions. We have already seen that mild base will cause elimination of benzenesulfinate from b-arylsulfonyl-substituted carbonyl derivatives (eq 5). a-Arylsulfonyl-substituted carbonyl derivatives undergo reductive desulfonylation28 under very mild conditions using Aluminum Amalgam (eq 10),29 but in the absence of carbonyl activation, reductive cleavage of the sulfone group requires much stronger reducing agents such as Sodium Amalgam in MeOH buffered with Na2HPO4,30 Sodium-Ammonia,31 Magnesium in refluxing MeOH,32 or Samarium(II) Iodide in THF-HMPA.33

The Julia Alkenation and Related Reactions.

In 1973, Julia and Paris34 reported a new connective and regioselective alkene synthesis (eq 10) based on the reductive elimination of b-acyloxy sulfones. The Julia alkenation is now one of the principal methods for fragment linkage in complex natural product synthesis.35,36 Mono-, di-, tri-, and tetrasubstituted alkenes can be prepared in moderate to good yield, depending on the substrate. The three-step sequence, illustrated in eq 11, entails (a) condensation of a metalated sulfone with an aldehyde or ketone, (b) O-functionalization of the adduct as the acetate, benzoate, or mesylate (to prevent retroaldolization), and (c) reductive elimination using 6% Na(Hg) in THF-MeOH (3:1) at -20 °C.37 In favorable cases, step (b) can be omitted and the reductive elimination performed on a b-hydroxy sulfone intermediate. Potential problems attending each step have been summarized.35

A detailed investigation of the scope and stereochemistry of the reductive elimination leading to 1,2-disubstituted alkenes revealed high trans stereoselectivity which is independent of the stereochemistry of the b-acyloxy sulfone adducts.37,38 Furthermore, the stereoselectivity increases with increasing steric congestion about the nascent alkene and maximum yields and rate are observed for the formation of conjugated dienes and trienes. The Julia procedure has also been adapted to the synthesis of alkynes (eq 12).39,40

There are two further variants of the Julia alkenation which deserve wider recognition. Both methods surmount the inherent limitation in scale of the reductive elimination step imposed by the use of Na(Hg). The first method involves a radical-induced elimination of thiocarbonyl derivatives of b-hydroxy sulfones,41 as illustrated in eq 13.42

The second recent variant, developed by Julia and co-workers, avoids reductive elimination altogether and provides a remarkable one-pot connective synthesis of alkenes.43 The procedure, illustrated in eq 14, involves condensation of an aldehyde or ketone with a lithiated benzothiazolyl alkyl sulfone to give an adduct which first cyclizes and then fragments with extrusion of sulfur dioxide, benzothiazolone (which then tautomerizes to 2-hydroxybenzothiazole), and the alkene. Generally a mixture of (E)- and (Z)-alkenes is obtained, but in sterically hindered substrates the (E) isomer can be obtained selectively. The same reaction has been observed with the pyridinyl sulfone analogs, in which case the separable b-hydroxy sulfone intermediates undergo stereospecific anti elimination to the corresponding alkene.

Alternative Desulfonylation/C-C Bond-Forming Procedures.

The foregoing discussion has focussed on reductive methods for removing sulfones and, in the case of the Julia alkenation, desulfonylation is accompanied by the formation of a new C-C bond. Another method which accomplishes desulfonylation with the concomitant construction of a C=C bond entails fluoride-induced elimination of b-silyl sulfones (see (2-Phenylsulfonylethyl)trimethylsilane).

Allylic sulfones undergo SN2 displacement by cyanocuprates with high syn stereoselectivity (eq 15).44 Stabilized enolates also displace allylic arylsulfonyl groups in the presence of Pd0 or Ni0 catalysts.45

Allylic and tertiary alkyl sulfones can also participate in electrophilic cyclizations in the presence of Aluminum Chloride (Friedel-Crafts reaction; eq 16).46

Base-catalyzed elimination of b-acetoxy sulfones is highly stereoselective, leading to (E)-alkenyl sulfones which undergo transition metal-catalyzed coupling with Grignard reagents with retention of configuration to provide a stereoselective synthesis of trisubstituted alkenes.47 Either Nickel(II) Acetylacetonate, Tris(acetylacetonato)iron(III), or Iron(III) Chloride can be used as the catalyst (eq 17).48

Oxidative Desulfonylation of Arylsulfonylalkyllithiums.

Aryloxysulfonylalkyllithiums can be converted to ketones in one pot by reaction with Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide),49 Bis(trimethylsilyl) Peroxide,50 or Chlorodimethoxyborane/m-Chloroperbenzoic Acid.51

Related Reagents.

Methyl Phenyl Sulfone; 4-Phenylsulfonyl-2-butanone Ethylene Acetal; 3-(Phenylsulfonyl)propanal Ethylene Acetal.


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Georges Hareau & Philip Kocienski

Southampton University, UK



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