Diastereoselective additions of organometallic reagents to ( S Fc )-2- p - tolylsulfanylferrocene carboxyaldehyde and to ( S Fc )-2- p - tolylsulfanyl ferrocenyl imines. Synthesis of new central and planar chiral ferrocenyl alcohols and amines

Enantiomerically pure 2-hydroxyalkyl, 2-aminoalkyl and 2-iminoalkyl ferrocenyl p -tolylsulfides are easily prepared in good yields and with complete diastereocontrol from ( S )-(2-p - tolylthio)ferrocencarboxyaldehyde. This aldehyde provides also an easy access to the first enantiomerically pure planar chiral ferrocenyl cyanohydrin. The absolute configuration of the new stereocenters has been determined by single-crystal X-ray analysis


Introduction
The design and the synthesis of new ferrocenyl derivatives possessing planar and/or central chirality are of great importance in the development of new versatile and effective ligands as well as of useful chiral auxiliaries and building blocks 1 for asymmetric synthesis.It is noteworthy that planar chiral ferrocenes have also found considerable applications in industrial processes. 2n general, the synthesis of enantiopure or enantiomerically enriched 1,2-disubstituted ferrocenes involves either a traditional resolution of racemic intermediates 3 or a stereoselective ortho-metallation step.The stereoselective ortho-metallation methods reported to date rely on a diastereoselective lithiation of ferrocenyl sulfoxides, 4 acetals, 5 amines, 6 oxazolines, 7 hydrazones, 8 sulfoximines, 9 azepines, 10 methylethers, 11 methoxymethylpyrrolidines 3b, 12 and Omethylephedrines 13 or on an enantioselective lithiation of achiral ferrocenyl phosphinoxides, 14 amides 15 or amines 16 using a chiral lithium amide or external chiral auxiliaries such as (-)sparteine or cyclohexanediamine.
1,2-Disubstituted enantiomerically pure planar chiral ferrocenylaldehydes have been recently employed as precursors of more complex molecules, 17 in particular the formyl group could be stereoselectively alkylated 18 by reaction with organometallic reagents.Asymmetric additions of organometallic reagents to the C=N functional group are of great interest for the preparation of chiral amines and derivatives. 19Only few examples have been reported so far on the 1,2-addition of organometallic reagents to ferrocenyl imines.In particular chiral ferrocenyl amines possessing central chirality have been obtained via highly stereoselective additions of organolithium 20 or organozinc 21 reagents to chiral ferrocenyl imines deriving from enantiomerically pure amines or by enantioselective addition of dialkylzinc reagents to achiral ferrocenyl imines in the presence of chiral ligands. 22Moreover, new planar chiral ferrocenyl diamines have been synthesized starting from 2-(N,N-dimethylaminomethyl) ferrocencarboxaldehyde via the corresponding imine. 23s a part of our ongoing interest in sulfur containing compounds 24 and in molecules bearing the sulfur and the ferrocene moiety, 25 we have recently synthesized enantiomerically pure βhydroxyalkyl, β-aminoalkyl and β-iminoalkyl ferrocenyl sulfides having only the central chirality.Some of these derivatives were successfully employed as ligands in palladiumcatalyzed allylic substitution with asymmetric induction up to 99%. 26 Herein we wish to report our results on the synthesis of 2-(hydroxyalkyl)-1, 2-(aminoalkyl)ferrocenyl p-tolylsulfides 2 with planar and central chirality, and 2-(iminoalkyl)-ferrocenyl ptolylsulfides 3 with planar chirality taking advantage of (S)-(2-p-tolylthio) ferrocencarboxyaldehyde 4 5b as the key compound (Scheme 1).The enantiomerically pure 4 can react with organometallic reagents affording 1 and with amines allowing the preparation of ferrocenyl imines 3, which in turn may be converted into 2 by reaction with organometallic reagents thus introducing a new stereogenic center beside the planar chirality.An alternative procedure, developed by us, for synthesizing aldehyde (S)-4 is based on the diastereoselective ortho-lithiation of (S)-ferrocenyl p-tolyl sulfoxide 5 4c (Scheme 3) with a sterically hindered base such as 2,4,6-triisopropylphenyllithium, 4b followed by electrophilic trapping with ethyl formate.The obtained (S Fc ,S S )-2-p-tolylsulfinyl ferrocenecarboxy aldehyde 6 was directly reduced to the corresponding aldehyde (S)-4 by treatment with sodium iodide and trifluoroacetic anhydride in acetone. 27The enantiopure aldehyde (S)-4 was obtained in 45% overall yield and showed spectroscopic and optical properties identical with the product obtained following the Kagan's procedure.

Scheme 3
The reaction of aldehyde (S)-4 with organometallic reagents, namely Grignard reagents, organolithium derivatives, tetraallyltin, and with diethylaluminiumcyanide and trimethylsilyl cyanide afforded the corresponding secondary alcohols 1 in very good yields, very short reaction time (only few minutes) and high diastereoselectivity as determined by 1 H-NMR spectra of the crude reaction mixture.Only one set of signals was detected in the reactions with methylmagnesium bromide (entry 1), vinylmagnesiumbromide (entry 3), tetraallyltin (entry 6), diethylaluminiumcyanide (entry 7) and trimethylsilyl cyanide (entry 8).On the contrary the reaction with phenylmagnesiumbromide (entry 4), methyllithium (entry 2) and n-butyllithium (entry 5) showed two sets of signals.In these cases the two diastereoisomers could be separated by preparative thin layer chromatography.Although (R)-(+)-ferrocenecyanohydrin acetate has been previously obtained 28 by Lipase catalyzed acylation of the racemic ferrocenecyanohydrin and (R)-(+)-ferrocenecyanohydrin has been synthesized from formyl ferrocene employing the hydroxynitrile lyase from Hevea brasiliensis, 29 products 1f and 1g represent the first enantiomerically pure ferrocenecyanohydrins containing both the central and the planar chirality.
The absolute configuration of the new stereocenters has been determined by single-crystal Xray analysis on the major diastereoisomer of product 1c 30 indicating (S)-configuration (Figure 1).We could therefore assign the (S,S Fc ) configuration to products 1.This stereochemical outcome can be rationalized by an exo attack of the organometallic species on the less congested Si-face of the aldehyde away from the sterically hindered lower cyclopentadienyl ring (Figure 2).These results are in agreement with the assumption of Ugi 31 and of Kagan. 32 Then we turned our attention to the preparation of planar chiral ferrocenyl imines 3 that was readily achieved by treatment of the aldehyde (S)-4 with the appropriate amine in the presence of powdered molecular sieves (4 Å) in toluene.The 2-iminoalkyl ferrocenyl p-tolyl sulfides 3a and 3b were obtained in excellent yields (Table 2) and were purified by crystallization from MeOH.The yield of product 3c was increased by reacting (S)-4 with TsNH 2 in the presence of TiCl 4 and Et 3 N using CH 2 Cl 2 as the solvent. 33Imines 3 were obtained as geometrically (E)-homogeneous compounds according to the 1 H-NMR spectra.Moreover, they are very stable and in particular 3c could also be purified by column chromatography on silica gel.The reactivity of ferrocenyl imines 3 with organometallic reagents and the possibility of obtaining 2-aminoalkyl ferrocenyl p-tolylsulfides 2 were tested upon derivatives 3a and 3c as model compounds.
As can be deduced from the results reported in Table 3 both imines 3a and 3c can be successfully allylated with tetraallyltin in the presence of catalytic amount of Sc(OTf) 3 affording the corresponding homoallylic amines 2a and 2b in good yields and very goods diastereoselectivity (entries 1 and 2).The N-PMP ferrocenyl imine 3a does not react with Grignard reagents even in the presence of a Lewis acid as LiCl, MgBr 2 or Sc(OTf) 3 (entries 4-7); the reaction of 3a with MeLi occurs in very low yield (10%) and with 58% d.e.(entry 3).The Ntosyl ferrocenyl imine 3c shows a different behavior and readily reacts with methylmagnesium bromide, vinylmagnesium bromide and phenylmagnesiumbromide, in the presence of MgBr 2 or LiCl, the latter giving a very fast reaction and better results in term of yields.The amines 2e, 2f and 2g (entries 8, 10, 11, 13) bearing the central and the planar chirality were indeed obtained in good yields and good to very good diastereoselectivity. Product 2e was also obtained by reaction of 3c with MeLi (entry 9), but in lower yield reproducing the same behavior as observed in the case of the aldehyde 4. The reaction of 3c with EtMgBr in the presence of MgBr 2 or LiCl furnished the alkylation product 2h together with the amine 7b deriving from the reduction of the C-N double bond (Table 4 entries 3 and 4) whereas imine 3a was found unreactive (entry 1) .Recently, Szymoniak 34 and Takahashi 35 have shown that imines undergo Zr-catalyzed addition with ethylmagnesium reagents whereas the same imines are inert towards the same reagents in the absence of the zirconium catalyst.These papers prompted us to perform the same reaction on imine 3a and 3c, but also in this case imine 3a was found unreactive (entry 2) and a mixture of the amino derivatives 2h and 7b was obtained from imine 3c.This mixture was enriched in the alkylation product 2h by increasing the amount of the Grignard reagent (entries 3-5).The absolute configuration of the new stereocenters of amino derivatives 2 has been determined by single-crystal X-ray analysis on the major diastereoisomer of product 2g 36 indicating an (S)-configuration (Figure 3).We could therefore assign the (S,S Fc ) configuration to products 2. This result implies a similar behavior of the imine (S)-3 and the aldehyde (S)-4 toward the addition of organometallic reagents.

Conclusions
(S)-(2-p-Tolylthio)ferrocencarboxyaldehyde was found to be a very versatile compound that allowed the synthesis of a large variety of enantiomerically pure sulfur containing ferrocenyl derivatives.2-Hydroxyalkyl, 2-aminoalkyl and 2-iminoalkyl ferrocenyl p-tolylsulfides were easily prepared in good yields and with complete diastereocontrol.Moreover (S)-(2-ptolylthio)ferrocencarboxyaldehyde provides an easy access to the first enantiomerically pure planar chiral cyanohydrin.All these derivatives bear several functional groups, that make them attractive from a synthetic point of view, and contain different heteroatoms, useful for the coordination to a metal centers and for the preparation of new ligands for asymmetric catalysis.

Experimental Section
General Procedures.Melting points (uncorrected) were determined with a Büchi melting point apparatus. 1H NMR and 13 C NMR spectra were recorded with a Varian Gemini 300 at 300 and 75 MHz, or a Varian Gemini 400 at 400 and 100 MHz respectively, using CDCl 3 solutions of the samples.Chemical shifts (δ) are reported in ppm relative to CHCl 3 (δ = 7.26 for 1 H and δ = 77.0 for 13 C).J values are given in Hz. 13

General procedure for the reaction with Grignard reagents
To a solution of (S)-4 (0.5 mmol) in dry THF cooled at -78 °C under argon atmosphere, a solution of the Grignard reagent (1.5 mmol) was slowly added.The colour of the solution immediately change from red to yellow/orange and a TLC analysis (hexane/EtOAc 4:1) showed the complete disappearance of the starting aldehyde.The reaction mixture was quenched at -78 °C with saturated NH 4 Cl solution and extracted with Et 2 O.The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.The diastereomeric ratio was determined by 1 H and 13 C NMR spectra on the reaction mixture and then the final derivative was isolated by column chromatography eluent (eluent hexane/EtOAc 4:1).

(1S)-1-[(S Fc )-2-(p-Tolylsulfanyl)-ferrocenyl]-3-buten-1-ol (1e).
To a solution of (S)-4 (170 mg, 0.5 mmol) in dry CH 2 Cl 2 and of catalytic amounts of Sc(OTf) 3 (28 mg, 0.05 mmol) cooled at 0 °C under argon atmosphere, tetraallyltin (0.13 mL, 0.55 mmol) was added.The reaction was stirred at 0°C per 0.5 h and then quenched by adding water at the same temperature.The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure.The 1 H and 13 C NMR spectra of the crude reaction mixture showed the presence of a single diastereoisomer.Chromatography on silica gel yielded the desired compound in 86% yield as a yellow viscous oil.δ H (C 6 D 6 , 300MHz)

(S)-[(S Fc )-2-p-Tolylsulfanyl]ferrocene cyanohydrin (1f).
To a solution of (S)-4 (170 mg, 0.5 mmol) in dry THF cooled at -78 °C under argon atmosphere, a solution of the Et 2 AlCN (1.0 M in Toluene, 2.5 mL, 2.5 mmol) was slowly added.The colour of the solution immediately changed from red to yellow.The reaction mixture was quenched at -78 °C with water and extracted with Et 2 O.The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.The 1 H and 13 C NMR spectra of the crude reaction mixture showed the presence of a single diastereoisomer and a chemical purity major of 97%.M.p.

N-(4-Methoxyphenyl)-N-{(1S)-1-[2-(S Fc )-(p-tolylsulfanyl)ferrocenyl]-3-butenyl}amine (2a).
(Table 3 3 entry 2) To a stirred solution of 3c (125 mg, 0.25 mmol) and of a catalytic amounts of Sc(OTf) 3 (14 mg, 0.025 mmol) in dry CH 2 Cl 2 cooled at -15 °C under argon atmosphere, tetraallyltin (0.07mL, 0.275 mmol) was added.The reaction was stirred at -15 °C for 32 h and then quenched by adding water at the same temperature.The organic layer was extracted washed, dried over magnesium sulfate and concentrated under reduced pressure.The 1 H and 13 C NMR spectra of the crude reaction mixture showed the presence of a single diastereoisomer.Chromatography on silica gel yielded the desired compound in 88% yield (93 mg, 0. General procedure for the reaction of imines 3a and 3c with Grignard reagents in the presence a Lewis Acid (Table 3) To a solution of imine 3a or 3c (0.2 mmol) and a Lewis Acid (MgBr 2 or LiCl) (0.4 mmol) in dry THF (10 mL) cooled at 0 °C under argon atmosphere, a solution of the Grignard reagent (0.6 mmol) was slowly added.The solution was stirred at the temperature reported in the Table 3.The reaction was followed by TLC analysis and then quenched with saturated NH 4 Cl solution and extracted with Et 2 O.The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.The diastereomeric ratio was determined by 1 H-and 13 C-NMR spectra on the reaction mixture and then the final derivative was isolated by column chromatography (hexane/EtOAc 3:1).3  entry 8).Following the general procedure using imine 3c (98 mg), MgBr 2 (74 mg) and a 3.0 M solution in THF of MeMgBr (0.2 mL), the final product was obtained in 18 h at 0°C after chromatography as a yellow solid in 78 % yield.The d.e. was find >98% on the crude  3 entry 10).Following the general procedure using imine 3c (98 mg) MgBr 2 (74 mg) and a 1.0 M solution in THF of vinylMgBr (0.6 mL), the final product was obtained in 48 h at r.

N-{(1S)-[2-(S Fc )-(p-Tolylsulfanyl
)ferrocenyl](phenyl)methyl}p-toluenesulfonamide (2g).(Table 3 entry 13).Following the general procedure using imine 3c (98 mg), LiCl (17 mg) and a 3.0 M solution in THF of PhMgBr (0.2 mL), the final product was obtained in 20 min.The d.e. was find 77% on the crude 1 H-NMR.The two diastereoisomers were separated by chromatography on preparative TLC that afforded as the higher R f product the minor diastereoisomer in 13% yield and as the second R  4 entry 3).Following the general procedure using imine 3c (98 mg) MgBr 2 (74 mg) and a 3.0 M solution in THF of EtMgBr (0.2 mL), after 48 h at r.t. the column chromatography afforded a fraction containing product 2h as a single diastereoisomer and product 7b a 1:3 ratio in a 35% yield.The separation of the two product was attempted by preparative thin layer chromatography and afford as the first R f fraction a mixture of 2h and 7 in a 1:1 ratio and as the second R f fraction product 7 with a purity of 90%.2h.δ H (CDCl 3 , 300MHz) 0.43 (3H, t, J = 7.5 Hz, CH 3 ), 2.23 (3H, s, CH 3 ), 2.42 (3H, s, CH 3 ),  4 entry 4).Following the general procedure using imine 3c (98 mg), LiCl (17 mg) and a 3.0 M solution in THF of EtMgBr (0.3 mL), after 18 h at r.t. the column chromatography afforded as the first R f fraction a mixture containing product 2h and product 7b in a 1:1 ratio in 62% yield and as the second R f fraction the unreacted imine 3c in 20% yield.

General procedure for the reaction of imine 3c with EtMgBr in the presence of Cp 2 ZrCl 2 (Table 4, entries 5-7)
To a solution of imine 3c (98 mg, 0.2 mmol) and Cp 2 ZrCl 2 (6 mg, 0.02 mmol) in dry THF (5 mL) under argon atmosphere, the EtMgBr (3M in THF) was added and the reaction mixture was stirred until disappearance of the starting imine.The reaction was quenched with 5% NaOH (1.5 mL) and then diluted with water and extracted with Et 2 O.The combined organic layer were dried (MgSO 4 ) and concentrated.Chromatography of the crude reaction mixture furnished a fraction containing the alkylated product 2h and the reduction product 7b in variable ratio depending on the amount of EtMgBr used.(3 equivalents of EtMgBr: ratio 2h : 7b = 1:3 total yield 88%; 10 equivalents of EtMgBr: ratio 2h : 7b = 1:2 total yield 89%; 25 equivalents of EtMgBr: ratio 2h : 7b = 1.2:1 total yield 89%) Scheme 2

Table 1 .
Reaction of aldehyde (S)-4 with organometallic reagents bDetermined by 1 H-NMR on the crude reaction mixture.c In the presence of 10 mol% of Sc(OTf) 3 .d In the presence of 10 mol% of ZnI 2 .

Table 2 .
Synthesis of 2-iminoalkyl ferrocenyl p-tolylsulfides 3 Determined by 1 H-NMR on the crude reaction mixture.cIn the presence of a catalytic amount of p-toluensulfonic acid.d Reaction performed with TiCl 4 in the presence of Et 3 N using CH 2 Cl 2 as the solvent. b
Ts 7b The resulting solution was warmed to -40 °C over 1.5h and then stirred at -40 °C for another 1.5h.The solution was cooled again to -78 °C and freshly distilled ethyl formate was added.After 10 min the reaction was quenched with acetic acid and the mixture was concentrated under reduced pressure.The crude was diluted with Et 2 O, washed with water, dried After stirring for 30 min at 0 °C, the reaction mixture was concentrated in vacuo and water (4 mL) was added.The mixture was extracted with CHCl 3 (3 x 5 mL) and the organic layer was washed with a 10% solution of Na 2 S 2 O C NMR spectral assignments were made by DEPT experiments.IR spectra were recorded on a Perkin-Elmer model 257 grating spectrometer.Mass spectra were obtained using a VG 7070-E spectrometer at an ionizing voltage of 70 eV or with an electrospray ionization source (ESIMS).All the ESIMS spectra were performed using MeOH as the solvent.[α]Dvalues were measured with Perkin Elmer Polarimeter 341 and are given in 10 -1 degcm 2 g -1 .The originality of all compounds was checked by a CAS-on-line structure search.Reactions were conducted in oven-dried (120 °C) glassware under a positive Ar atmosphere.Transfer of anhydrous solvents or mixtures was accomplished with oven-dried syringes/septum techniques.THF was distilled from sodium/benzophenone prior to use and stored under Ar.CH 2 Cl 2 was passed through basic alumina and distilled from CaH 2 prior to use.Other solvents were purified by standard procedures.Light petroleum ether refers to the fraction with a bp 40-60 °C.The reactions were monitored by TLC, using silica gel plates (Baker-flex IB2-F).Column chromatography was performed with Merck silica gel 60 (70-230 mesh).Preparative thick layer chromatography was carried out on glass plates using a 1 mm layer of Merck silica gel 60 Pf 254.All chemicals were used as obtained or purified by distillation as needed.(S)-ferrocenylp-(SFc S S )-2-(p-Tolylsulfinyl)-ferrocenecarboxaldehyde (6).A solution of of (S)-ferrocenyl ptolyl sulfoxide 5 (0.2 g, 0.6 mmol) in dry THF (5 mL) cooled at-78 °C under argon atmosphere was transferred via cannula into a cooled solution of 2,4,6-triisopropylphenyllithium 4b (1.2 mmol) in THF (5 mL) prepared from 1-bromo-2,4,6-triisopropylbenzene and t-BuLi at -ISSN 1424-6376 Page 81 © ARKAT USA, Inc 78 °C for 2.5 h. 3 , dried and concentrated.The residue was purified by chromatography on silica gel (light petroleum/EtOAc 2:3) giving 4 as a red solid (62 mg, 65%).
© ARKAT USA, Inc 13try 1) To a stirred solution of 3a (110 mg, 0.25 mmol) and of a catalytic amounts of Sc(OTf) 3 (14 mg, 0.025 mmol) in dry CH 2 Cl 2 cooled at 0°C under argon atmosphere, tetraallyltin (0.07 mL, 0.275 mmol) was added.The reaction was stirred at 0°C per 18 h and then quenched by adding water at the same temperature.The organic layer was extracted washed, dried over magnesium sulfate and concentrated under reduced pressure.The 1 H and13C NMR spectra of the crude reaction mixture showed the presence of a single diastereoisomer.Chromatography on silica gel yielded the desired compound in 72% yield (70 mg, 0.14 mmol) as a viscous yellow/orange oil.δ H (CDCl 3 , 400MHz) 2.11 (1H, m, H a -CH 2 ), 2.26 (3H, s, CH 3 ), 2.