Lithiated Sulfoxides : α-Sulfinyl Functionalized Car-banions

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Introduction
6][7] An important property of the sulfur atom is its ability to activate an α-hydrogen atom of an attached alkyl group, with an increased activation in the order -S-< -S(O)-< -S(O) 2 -.][10][11] α-Sulfinyl functionalized alkyl aryl lithium compounds of the type Li[CRR′S(O)Ar] are of special interest, because on the one hand they possess a Lewis-basic heteroatom (nonbonding electron pair at the sulfur atom) and on the other hand a dipole stabilized heteroatomic center. 124][15][16][17] Thus, Durst et al. found that methylation and deuteration of lithiated sulfoxides proceeded with good diastereoselectivities. 18,19On the basis of these and further findings, [20][21][22][23][24][25][26][27][28][29][30][31] it was stated that the diastereofacial differentiation in reactions of α-sulfinyl functionalized alkyl aryl lithium compounds is determined by the chiral sulfinyl group as follows: electrophiles with an oxygen-containing group like D 2 O, benzaldehyde, benzophenone or CO 2 tend to attack the anionic C atom on the side of the S-O bond due to an attractive interaction of the electrophile with the countercation Li + .In the case of CH 3 I the electrophile approaches from the opposite side, because of the lack of an attractive interaction with the countercation Li + as shown in Fig. 1. 32,33 On that basis and under consideration of quantum chemical calculations of Wolfe et al., the "ion-pair model" for α-sulfinyl functionalized alkyl aryl lithium compounds of the type Li[CRR′S(O)Ar] was established (cf.Fig. 1). 7,34,35The first X-ray crystal structure analysis of a lithiated sulfoxide, [Li 2 {CMePhS(O)Ph} 2 -(TMEDA) 2 ], was reported by Boche et al. in 1986. 36The lithium compound crystallized in a dimer fashion with a Li 2 O 2 fourmembered ring as main structural feature.Furthermore, this lithium compound is characterized by a "free" carbanion, meaning that there are no interactions between Li + and the carbanionic C atom.Thus, the formerly postulated "ion-pair model" was found to be in accordance with the crystal structure determination of Boche et al.Since then no further crystal structure analyses of lithiated sulfoxides have been described.Here, we report on the synthesis, characterization and solid state structures of lithiated sulfoxides of the type [Li 2 {CRR′-S(O)Ar} 2 (TMEDA) 2 ].Furthermore, the stereoselective C-C bond formation of the lithiated sulfoxides with benzaldehyde and benzophenone was investigated under the aspect of a diastereofacial differentiation.

Synthesis of lithiated alkyl aryl sulfoxides
Lithiated alkyl aryl sulfoxides of the type [Li 2 {CRR′S(O)-Ar} 2 (TMEDA) 2 ] (1-5) were prepared by metallation of the corresponding sulfoxide with n-BuLi/TMEDA in diethyl ether/ n-pentane according to Scheme 1.The products were obtained as strongly moisture-and oxygen-sensitive yellowish crystals in yields between 61 and 84%.All complexes were characterized by NMR spectroscopy ( 1 H, 13 C, 7 Li) and, with exception of 5, by single-crystal X-ray structure analyses.Selected NMR spectroscopic parameters of complexes 1-5 are given in Table 1.The 1 H and 13 C NMR spectra of 1-5 give proof of the selective metallation of the α-C atoms of the alkyl aryl sulfoxides.Thus, an ortho-metallation of the aryl rings can be fully excluded.   Two nitrogen atoms of the chelating TMEDA ligands complete the distorted coordination tetrahedrons around the lithium atoms.The shortest Li⋯C α distance (3.769(7) Å) was found in 4•Et 2 O. Thus, in no compound is an evidence for an intramolecular interaction between Li + and the carbanionic α-C atom.For a more detailed description of the molecular structures of the dinuclear lithium compounds 1-4 quantum-chemical calculations on the DFT level of theory were performed using the B3LYP functional and high-quality basis sets for all atoms (details see Experimental).0][41] Comparison of the solid-state structures [Li 2 {CRR′S(O)Ar} 2 (TMEDA) 2 ] (1-4) with the analogous calculated structures 1*-4* ‡ revealed a good agreement including the conformation of the Li 2 O 2 rings and the Li⋯C α distances (cf.Table S1 †).Of special interest is the degree of pyramidalization of the carbanionic α-C atoms, which can be evaluated by the sum of angles around the α-C atom and its deviation Δd from the plane spanned by its substituents (S, C/H, C/H) (cf.Table S2 †).For 1*-3* (R/R′ = H/H, Me/Me) slightly pyramidalized α-C atoms were found (sum of angles: 347.0-354.7°;Δd = 0.210-0.260Å), as also found in crystals of 3 (sum of angles: 355.0°;Δd = 0.208 Å).On the other hand, the sulfinyl substituted benzyl carbanion in 4* (R/R′ = H/Ph) is almost trigonalplanar (sum of angles: 359.5°;Δd = 0.059 Å), as also in the compound with R/R′ = Me/Ph (sum of angles: 357.0°;Δd = 0.120 Å). 36 This planarization can be traced back to a π bond between the p orbitals of the carbanions and the phenyl rings.Similar conclusions were drawn from 13 C NMR spectroscopic data of Li[CHPhS(O)Me], Li[CHPhS(O)t-Bu] and Li[CHPh-S(O) 2 t-Bu]. 42,43urthermore, in all compounds the S-C α bond lengths, both the experimental and the calculated values, were found to be significantly shorter (1.572(1)-1.666(5)/1.677-1.687Å, 1-4/1*-4*) than the S-C i bond lengths (1.795(3)-1.844(4)/1.826-1.834Å, 1-4/1*-4*), albeit the C i atoms are clearly sp 2 hybridized.An analysis of the Wiberg bond indices (WBI) of the S-C bonds in the lithiated sulfoxides 1*-4* and the corresponding nonlithiated (neutral) sulfoxides H-CRR′S(O)Ar exhibitedas expectedextraordinarily strong S-C α bonds in 1*-4* (WBI = 1.24-1.35)compared to those in the neutral sulfoxides (WBI = 0.85-0.91)and also to the S-C i bonds (1*-4*: WBI = 0.89-0.91;neutral sulfoxides: WBI = 0.90), cf.Table S3.† The strengthening of the S-C α bonds can be attributed to a stabilizing interaction between the nonbonding orbital on the α-carbon atoms and the S-O antibonding σ* orbital in the sense of a negative hyperconjugation. 31,44The negative hyperconjugation can be reasonably assumed because the nonbonding electron pairs at the α-C atoms are bent only 16.4 to 18.4°a way from the antiperiplanar position to the S-O bond (cf.6)). 45In crystals of 4a′ the molecules are connected by O1-H⋯O2′ hydrogen bonds (O1⋯O2′ 2.710(1) Å, O1-H⋯O2′ 170°) such that centrosymmetric dinuclear units are formed (graph set: R 2 2 (12)).In contrast to 3a′ and 4a′, in molecules of 4b′ intramolecular O1-H⋯O2 hydrogen bonds (O1⋯O2 2.710(1) Å, O1-H⋯O2 158°) exist thus forming sixmembered rings (graph set: S( 6)).According to the distance criterion 46,47 all these hydrogen bonds can be characterized as moderately strong.Since 3a′, 4a′ and 4b′ crystallize in the centrosymmetric space group P2 1 /c the crystals are racemic and, hence, two enantiomers (S S R C and R S S C , 3a′; R S S C S C and S S R C R C , 4a′; S S R C and R S S C , 4b′) are present.

About the diastereoselectivity
Regarding the diastereoselection in the asymmetric C-C bond formation of the lithium compounds 1-6 with benzaldehyde and benzophenone, two reaction types have to be distinguished, namely that of an achiral carbanion center with a prochiral electrophile (type I) and vice versa (type II).The following discussion is restricted to the highly diastereoselective reactions where the configuration of the products is known from single-crystal X-ray measurements, see the formation of 3a and 4b for a type I and type II reaction, respectively (Scheme 3).Exemplarily, for 4b it has been shown that the single crystal measured is identical with the bulk material by measuring an X-ray powder diffractogram of it and comparing it with the pattern simulated from the X-ray single crystal data, see Fig. S4.† The nearly perfect match of the two diffrac-Scheme 2 Reaction of lithiated sulfoxides with benzaldehyde (A) and benzophenone (B). a Number of chiral centers in the product.b n/a = not applicable.c For unknown reasons, isolation of 5b as desired product failed.tograms gives proof that only the 4b-S S R C /R S S C diastereomer is formed in the reaction.
To understand the preferential formation of the diastereomers (3a-S S R C /R S S C and 4b-S S R C /R S S C ) in these reactions, two assumptions have to be made: first, according to the "ion-pair model" (Fig. 1) 7 for these two electrophiles (PhCHO and Ph 2 CO) a precoordination of the carbonyl O atom at the lithium center can be assumed.Second, in accordance with other reactions of lithiated sulfoxides 24,[48][49][50] and also with aldol reactions 51,52 the formation of six-membered cyclic transition states as given in Scheme 3 can be assumed.Based on the experimental findings, the diastereoselectivities observed in this work can be explained in the following way: the formation of the S S R C -and R S S C -configured products 3a and 4b suggests that the two reactions proceed via the transition state ts2.

Conclusions and summary
Lithiated sulfoxides of the type [Li 2 {CRR′S(O)Ar} 2 (TMEDA) 2 ] (1-5) were prepared and their constitution was unequivocally confirmed by NMR and single crystal X-ray diffraction studies.The lithium compounds crystallize in a dimer fashion with Li 2 O 2 four-membered rings and "free" carbanions as main structural features.As additionally revealed by quantumchemical calculations the carbanionic center is stabilized by a negative hyperconjugation 31,44 and remains to be slightly pyramidalized with exception of the benzylic one in 4.
C-C bond formation in reactions of 1-3 having an achiral α-C atom with a prochiral electrophile (PhCHO, type I) and of 4 and 6 having a chiral α-C atom with an achiral electrophile (Ph 2 CO, type II) proved to proceed with high diastereoselectivities (de >94%) with one exception (formation of 2a).In two selected cases (type I: 3 + PhCHO; type II: 4 + Ph 2 CO) it has been shown that only the S S R C /R S S C diastereomers were formed and not the S S S C /R S R C diastereomers.The stereoselection of analogous reactions (lithiated methyl 1-naphtyl sulfoxide with aromatic ketones) has been traced back to stabilizing π⋯π interactions between the aromatic rings 26 which might also be the case in the systems described here.On the other hand, the combination of both a chiral α-C atom and a chiral electrophile led to the formation of three stereogenic centers and to de values between 14 and 62% only.
Thus, the present investigations allow a deeper insight into the molecular structures of lithiated sulfoxides and their reactivity against electrophiles in asymmetric C-C bond formation reactions.

General comments
Organolithium compounds were prepared and handled under purified argon using standard Schlenk techniques.Solvents (diethyl ether, n-pentane, tetrahydrofuran) were dried over Na/benzophenone and freshly distilled prior to use.NMR spectra ( 1 H, 13 C, 7 Li) were recorded, if not otherwise stated, at 27 °C on Varian Gemini 200 and VXR 400 spectrometers. 1 H and 13 C chemical shifts are relative to solvent signals (THF-d 8 , δ H 1.72, δ C 67.21; CDCl 3 , δ H 7.26, δ C 77.16) as internal references; 7 Li NMR spectra were referenced to a solution of LiCl in D 2 O (external).The preparative centrifugally accelerated thin layer chromatography was performed using a Chromatotron (Harrison Research).Sulfoxides were prepared according to literature procedures. 53reparation of [Li 2 {CRR′S(O)Ar} 2 (TMEDA) 2 ] (1-5).At room temperature to a solution of the respective racemic sulfoxide (1.0 mmol) in diethyl ether (5 mL) a solution of n-BuLi/TMEDA (1.0 mmol; 1.6 M in n-hexane) in n-pentane (2 mL) was added while stirring.After two hours the volume of the solution was reduced in vacuum to about 1.5 mL.After 6-12 h, yellowish crystals precipitated which were filtered off, washed with n-pentane (3 × 5 mL) and dried in vacuo.

Fig. 1
Fig. 1 Diastereofacial differentiation for reactions of lithiated sulfoxides (S atom is hidden by the α-C atom) with electrophiles according to the "ion-pair model" (adapted from ref. 7).

Scheme 3
Scheme 3 Nucleophilic addition of [Li 2 {CMe 2 S(O)Ph} 2 (TMEDA) 2 ] (3) to the prochiral benzaldehyde (type I) and of [Li 2 {CHPhS(O)Ph} 2 (TMEDA) 2 ] (4) to benzophenone (type II), resulting in the formation of diastereomerically pure 3a-S S R C /R S S C and 4b-S S R C /R S S C (shown with the S S R C enantiomers as example), respectively.The six-membered cyclic transition states ts1 and ts2 are explicitly shown.§ de Values were determined by1 H NMR spectroscopy (% de = % major diastereomer -% minor diastereomer).The signal-to-noise ratios allowed to detect impurities ≥3%.With the assumption that this amount of the minor diastereomer remains to be undetected, an upper limit for de values of 94% is given.