Parallel or classical kinetic resolution of a planar chiral ferrocenylketone through asymmetric reductions

Tetrahedron: Asymmetry 21 (2010) 2631–2637

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy

Parallel or classical kinetic resolution of a planar chiral ferrocenylketone through asymmetric reductions Angela Patti ⇑, Sonia Pedotti Istituto di Chimica Biomolecolare del CNR-Via Paolo Gaifami, 18, I-95126 Catania, Italy

a r t i c l e

i n f o

Article history: Received 2 September 2010 Accepted 4 October 2010 Available online 20 November 2010

a b s t r a c t Racemic 1-acetyl-2-methoxymethylferrocene, (±)-1 was subjected to asymmetric reduction with two different methodologies and complementary results were obtained. When the reduction of (±)-1 was carried out in the presence of CBS-oxazaborolidine catalyst and BH3Me2S as the hydrogen source, both enantiomers of the substrate were converted with comparable reaction rates and selectivities. The corresponding diastereoisomeric ferrocenylalcohols 3a and 3b were obtained in a 1:1 ratio and >90% enantiomeric excess; this reaction profile being related with a parallel kinetic resolution with high ds1 and ds2 diastereofacial selectivities. On the contrary, the transfer hydrogenation of (±)-1 with HCOOH/ triethylamine in the presence of (R,R)-Noyori’s catalyst proceeded via classical kinetic resolution, so that the formed ()-3b or unreacted (+)-1 could be obtained in highly enantiopure form before or beyond 50% of the substrate conversion, respectively. Alcohol 3b with an (1Rp,S)- or (1Sp,R)-configuration is not easily accessible by the diastereoselective metallation/electrophilic quenching sequence routinely applied in the synthesis of planar chiral ferrocenes. As a result, the described procedures provide a valuable access to this useful starting material for the synthesis of homochiral related derivatives. Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction Planar chiral ferrocenes, mainly 1,2-disubstituted ferrocenyl derivatives, constitute an important class of ligands active in asymmetric catalysis1 and the established route for their synthesis in enantiopure form involves a diastereoselective metallation/electrophilic quenching sequence starting from suitable ferrocenes possessing a chiral ortho-directing group (CDG) as the substituent (Scheme 1).2 This implies that the majority of planar chiral ferrocenes also possess an additional stereogenic center, except when the CDG can be removed at end of the synthetic pathway. In addition to N,N-dimethyl-1-ferrocenylethylamine, which was first developed by Ugi et al.,2a many other derivatives bearing sulphoxide,2d acetal,2c oxazoline2b or hydrazone2e as CDG can be used as a substrate for highly diastereoselective metallation. The planar configuration is strictly dictated by the chirality of the CDG and few alternative methods have been reported for the preparation of the ‘forbidden’ diastereoisomeric ferrocenyl derivatives.3 Some planar chiral derivatives have also been prepared in enantiopure form by biocatalyzed reactions4 and recently, the non-enzymatic resolution of racemic ferrocenes by asymmetric Sharpless’ dihydroxylation,5 proline-catalyzed aldol condensation6 or enantioselective methatesis7 has also been reported.

Me

Me NMe2

major diastereoisomer

i) n-BuLi

Fe

Me

ii) EX E

E-mail address: [email protected] (A. Patti). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.10.004

NMe2 Fe

minor diastereoisomer ratio 96:4 p-Tol Other chiral directing groups with the same induction sense:

H

S

O OMe

O

O

O

N R

⇑ Corresponding author. Tel.: +39 09577338328; fax: +39 0957338310.

NMe2 E

Fe

OMe R'

N

R

Scheme 1. General strategy for the synthesis of ferrocenyl derivatives with planar and central chirality.

2632

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 21 (2010) 2631–2637

Asymmetric reductions have been efficiently applied to many structurally different ferrocenylketones and diketones8 to give the corresponding a-ferrocenylalcohols as key synthons in the synthesis of several homochiral derivatives via nucleophilic displacement of the hydroxyl group (through the corresponding acetate in most cases) with retention of configuration.9 However, these reactions have not been applied to racemic planar chiral substrates and, as a part of our ongoing research on the synthesis of ferrocenylalcohols in enantiopure form,10 we decided to investigate the asymmetric reduction of (±)-1-acetyl-2-methoxymethylferrocene (±)-1 as a model compound. Using two different catalyst/hydrogen donor systems, the resolution of the racemic substrate was achieved together with the preparation of the corresponding alcohols, one of which possessing either a (1Rp,S)or (1Sp,R)-configuration is not easily accessible by the diastereoselective metallation/electrophilic quenching sequence; herein we report the results obtained.

2.1. The CBS-oxazaborolidine promoted reduction of (±)-1 Chiral oxazaborolidines have been shown to be efficient catalysts for the reduction of ketones with borane reagents such as the hydrogen donor;13 the Corey–Bakshi–Shibata (CBS) oxazaborolidine 214 is one the most popular catalysts due to its commercial availability in both enantiomeric forms, high selectivity, and wide substrate tolerance11a including ferrocenylketones.8a,b,10 In order to investigate the CBS-promoted reduction of a planar chiral ferrocenylketone, (±)-1-acetyl-2-methoxymethyl-ferrocene (±)-1 was chosen as the model substrate and it was prepared from methoxymethylferrocene according to the procedure reported by Brocard et al.,15 with a modification in the last step of the MnO2 oxidation. The (±)-1 obtained was then subjected to asymmetric reduction in the presence of (R)-2 and BH3Me2S under our standard conditions (30 mol % catalyst, THF, 0 °C) and its complete conversion into two diastereoisomeric alcohols 3a and 3b in about a 1:1 ratio16 was observed within 30 min. Since the purification of these alcohols was difficult, the whole reaction mixture was treated with Ac2O/pyridine to afford the corresponding acetates (+)-4a and (+)-4b, which were separated by column chromatography. Each acetate was then treated with acetone/H2O in order to separately recover alcohols ()-3a with 90.4% enantiomeric excess (ee) and (+)-3b with 93.8% ee. Re-oxidation of ()-3a and (+)-3b gave the enantiomeric ketones (+)-1 and ()-1, each with the same ee and planar chirality of the parent alcohol (Scheme 2). The nucleophilic displacement of an a-acetoxy group, which occurs with retention of configuration, is routinely applied in the synthesis of ferrocenyl derivatives. As an example, (+)-4b was converted into the homochiral (1Rp,S)-5, this dimethylaminoalcohol

2. Results and discussion The asymmetric reduction of ketones is a pivotal reaction for the preparation of enantiopure secondary alcohols and many efficient stoichiometric or catalytic systems have been developed and applied to a broad range of simple or functionalised ketones.11 When the ketone also possesses another stereogenic element and it is in racemic form, the newly created stereocenter in the asymmetric reduction gives rise to a couple of diastereoisomers. The yield and the enantiomeric purity of the products could be affected by the configuration of the pre-existent stereogenic element and a kinetic resolution process could also occur when the substrate enantiomers display a substantial difference in reactivity.12

H

Ph Ph

O OMe

Me

Me Fe

OMe

Fe

OH

(R)-2 N O B (30% mol) Me

OMe OH

(±)-1

(-)-(1Sp,S)-3a 51%, 90.4% ee

OAc OMe OAc +

Fe

Fe

Me

BH3 Me2S THF, 0 °C

i) Ac2O/Py ii) Chromatographic purification

+

Fe

O

Me OMe

(+)-(1Rp,S)-3b 49%, 93.8% ee

Me OMe

Fe

Me (+)-(1Sp,S)-4a

(+)-(1Rp,S)-4b

i) aq. NHMe2, MeCN ii) H2O/montmorillonite K-10, 45°C NMe2

Acetone/H2O

Acetone/H2O

(-)-(1Sp,S)-3a

Fe

(+)-(1Rp,S)-3b

MnO2/CH2Cl2

Me OH

MnO2/CH2Cl2 (-)-(1Rp,S)-5

O OMe Me Fe

Me Fe

OMe

O (+)-(1Sp)-1

(-)-(1Rp)-1

Scheme 2. Parallel kinetic resolution of (±)-1 through CBS-promoted reduction.

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 21 (2010) 2631–2637

cannot be directly accessed by metallation of (S)-N,N-dimethyl-1ferrocenylethylamine. The treatment of ()-3a and (+)-3b with AcOH/MeOH gave the diastereoisomeric dimethoxy derivatives (+)-6a and ()-6b and the absolute configuration of (+)-6a was established as (1Sp,S) by comparison of its spectroscopic and optical properties with those of a sample prepared starting from (S)-N,N-dimethyl-1-ferrocenylethylamine, whose sense of induction in the diastereoselective metallation is already known2a (Scheme 3). The assigned configuration of the alcoholic carbon is in agreement with the known stereochemical course of the CBS-promoted reduction.11a

strate independently by its planar chirality, that is, the two hydride transfer reactions on each enantiomer occurred without mutual interference and at similar reaction rate, this feature is required for an optimal PKR process. In a quantitative analysis, the selectivity of the reaction (100 mol % of (R)-2) can be stated by the epimeric excess of the products epR and epS22

epR ¼

OMe OMe

(-)-(1Sp,S)-3a

Fe Me (+)-(1Sp,S)-6a

i) NaBH4 ii) MeOH/HOAc NMe2 Me Fe

NMe2

OHC i) n-BuLi/Et2O ii) DMF

Me Fe

OMe MeOH/HOAc (+)-(1Rp,S)-3b

Fe

½RpS ½SpS ¼ 39:1 and ds2 ¼ ¼ 42:9 ½RpR ½SpR

These ep values, that express a nearly ideal PKR process, decreased in the reaction with 30 mol % of (R)-2 catalyst (epR = 90 and epS = 94) but the stereoselectivity level remained sufficiently high enough to obtain the products with satisfactory enantiomeric purity. The access to both possible diastereoisomeric alcohols from a racemic ferrocenylketone, via PKR, could be helpful in the synthesis of the different stereoisomers of a ferrocenyl-based catalyst as well as in a comparative investigation of their catalytic activity aimed at the determination of the matched planar/central chirality required for optimal asymmetric induction.3a–c 2.2. Ruthenium-promoted transfer hydrogenation of (±)-1

(+)-(1Rp,S)

(S)

RpS  RpR SpS  SpR  100 ¼ 95 and epS ¼  100 ¼ 95:4 RpS þ RpR SpS þ SpR

or by the diastereofacial selectivities (ds), calculated from Kagan’s equations12a

ds1 ¼ MeOH/HOAc

2633

Me OMe

(-)-(1Rp,S)-6b Scheme 3. Assignment of absolute configuration of ()-3a.

Parallel experiments of asymmetric reduction with 30 mol % catalyst loading were also performed at 15 °C or following the inverse addition procedure,11a,12b for example, the addition of a THF solution of borane to the solution of (±)-1 and the catalyst; however, unsatisfactory results in terms of both reaction rate and selectivity were obtained. As could be expected, in the reduction of (±)-1 with stoichiometric (R)-2, the enantiomeric purity of both alcohols substantially increased and equimolar amounts of ()-3a and (+)-3b were isolated with 95.0% and 95.4% ee, respectively. The observed reaction course is compatible with a parallel kinetic resolution (PKR), a term introduced by Vedejs and Chen17 for a strategy aimed at circumventing the concentration effects that influence the efficiency of a classical kinetic resolution through the simultaneous removal of both enantiomers of substrate by a parallel reaction, ideally at an identical rate, leading to separable chiral products (regioisomers, diastereoisomers, etc.). Although in most cases, PKR has been achieved by using two stoichiometric chiral reagents with complementary selectivity,18 recent procedures with a single chiral reagent, either an enzyme19 or a metal catalyst,20 have been developed and until recently there has only been one report of PKR through CBS-promoted asymmetric reduction, in the context of batrachotoxin synthesis.21 In the reduction of (±)-1 described herein, the CBS catalyst was able to stereoselectively recognize the carbonyl moiety of sub-

The asymmetric transfer hydrogenation using 2-PrOH or formic acid as hydrogen donors is another well-established method for the reduction of ketones and in this context the [N-(tosyl)-1,2-diphenylethylendiamine](TsDPEN)-ruthenium(II) complex 7, developed by Noyori,23 proved to be an efficient catalyst for the reduction of several arylalkylketones;24 some examples have also been reported with ferrocenyl substrates.8e,10c The active catalyst (R,R)-7 was obtained by the in situ complexation of (R,R)-TsDPEN with an Ru(p-cymene)chloride dimer and in the presence of 2-PrOH/KOH the reduction of (±)-1 gave after 4 days 25% of ()-(1Sp,R)-3b with 91% ee, together with unreacted ()-1 with 30% ee, the other alcohol (+)-3a being present in about 1%. However, while the amount of ()-3b increased, the reverse oxidation reaction, promoted by the same ruthenium catalyst in these experimental conditions,23a became significant and a fairly constant composition of the reaction mixture was reached with a slow decrease in the ee of ()-3b over time. On the contrary, using an azeotropic mixture of HCOOH/TEA (5:2) as a hydrogen source, the reaction proceeded irreversibly, affording, in 21 h, a 43% substrate conversion into alcohol ()-3b with 95.6% ee as the highly predominant diastereoisomer (dr = 14.6), whereas the unreacted ()-1 was recovered with 67.2% ee. It was evident that the reaction evolved in a kinetic resolution fashion and ()-1 with a higher enantiomeric purity could be isolated beyond 50% of substrate conversion. Indeed, in a parallel run stopped after 65 h, ()-1 was obtained in 40% yield and 95.3% ee together with ()-3b in lower enantiomeric purity (82% ee) (Scheme 4). The efficiency of this kinetic resolution can be deduced from the stereoselectivity factor s = krel = ln[(1  C)(1  ees)]/ln[(1  C)(1 + ees)] = 16.625 while the configuration of the newly formed stereogenic carbon is in agreement with the reported stereo preference of the catalyst.23 These data support the influence of the pre-existing chirality of the substrate in the (R,R)-7 promoted transfer hydrogenation, so that only one enantiomer of (±)-1 is able to take part in the catalytic cycle being converted stereoselectively into the corresponding alcohol. This catalyst’s feature, coupled with a fast

2634

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 21 (2010) 2631–2637

O OMe

Me

Me Ph Ph

O OMe Me Fe

OMe

O

Fe

Cl

21h

(-)-(1Sp,R)-3b 40%, 95.6%ee

(-)-(Rp)-1 57%, 67.2%ee

HCOOH/TEA 5:2 50 °C

O

(±)-1

OMe

65h

Me

Me

(R,R)-7 5% mol 2-PrOH/KOH rt, 4 d

(-)-(1Sp,R)-3b 25%, 91.3%ee

OMe

Fe

+ OH

(R,R)-7 5% mol

Me

Fe

Ts N Ru N H

Fe

OMe

Fe

+ OH

(-)-(1Sp,R)-3b 53%, 81.8%ee

(-)-(Rp)-1 40%, 95.3%ee

(-)-(Rp)-1 74%, 30.5%ee

+

Scheme 4. Kinetic resolution of (±)-1 by a ruthenium-promoted transfer hydrogenation.

epimerization of the substrate, has been successfully exploited in the dynamic kinetic resolution of configurationally labile a-substituted ketones,26 but the transfer hydrogenation of stable racemic ketones has not yet been so far reported.

rently in progress for a better definition of the scope of these asymmetric reductions, varying the acyl group and/or the 2-substituent on the starting ferrocenylketone, and the rationalization of the observed divergent behavior of the CBS and Noyori’s catalysts.

3. Conclusions

4. Experimental

In conclusion, the asymmetric reduction of racemic (±)-1 with two different catalyst/hydrogen donor systems proceeded with two distinct reaction profiles and allowed us to achieve the resolution of planar chirality through the synthesis of one or both the corresponding alcohols. Since a large structural diversity of 2substituted ferrocenylketones can be obtained by nucleophilic addition of organometallic reagents to racemic ferrocenylaldehydes bearing different substituents27 and a-ferrocenylalcohols can be easily converted into homochiral compounds (Scheme 5), the two methodologies discussed herein for the asymmetric reduction of planar chiral ferrocenylketones could have valuable potential as a key step in the preparation of several enantiopure ferrocenyl derivatives, some of which are not directly accessible by the usual ortho-lithiation/electrophilic quenching sequence. Work is cur-

4.1. General methods 1 H and 13C NMR spectra were recorded at 400.13 and 100.62 MHz, respectively, in CDCl3. Chemical shifts (d) are given as ppm relative to the residual solvent peak and coupling constants (J) are in Hertz. In the NMR assignment, Cp and Cp0 refer to the substituted and unsubstituted cyclopentadienyl ring, respectively. The synthesis of (±)-1 was carried out starting from commercial ferrocenylcarboxaldehyde according to the reported procedure.15 Asymmetric reductions were carried out under argon using standard Schlenk techniques; THF and diethyl ether were distilled over sodium/benzophenone ketyl; 2-PrOH (HPLC grade) was distilled over CaH2. Oxazaborolidine (R)-2 (1 M solution in toluene), BH3Me2S (2 M solution in THF), (1R,2R)-(TsDPEN) and [RuCl2(p-cymene)]2

O CHO Fe

i) R'MX ii) oxidation

R

R' Fe

variation of acyl group

R

variation of 2-substituent (±)

(±) Asymmetric reduction OH

Nu

R Both enantiomers of substrate

R'

OH

oxidation Fe

Fe

R

R' Both diastereoisomeric alcohols in enantiopure form

R

i) Ac2O ii) NuH

R'

Nu Fe

Fe R'

Homochiral compounds

Scheme 5. Synthesis of chiral ferrocenyl derivatives from racemic 2-substituted ferrocenylketones.

R

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 21 (2010) 2631–2637

were purchased from Aldrich. Column chromatography was performed on Silica Gel 60 (Merck, 40–63 lm) using the specified eluents. Chiral HPLC analyses were carried out on a thermostatted (25 °C) ChiracelÒ OD column (Daicel Chemical Industries) using n-hexane/2-PrOH mixtures as a mobile phase at flow 0.5 mL/min and UV–vis detection (k 220 nm). Optical rotations were measured on a DIP 135 JASCO instrument. Deactivated silica gel was prepared suspending the silica powder (50 g) in n-hexane/triethylamine (95:5 v/v, 100 mL) and stirring for 30 min at rt, then the solvent was removed by vacuum filtration and the solid dried under a stream of nitrogen. After suspension in the suitable eluent, the obtained silica gel was used for packing chromatographic column. 4.2. CBS-catalyzed reduction of (±)-1 At first, (R)-CBS (0.20 mmol, 0.20 mL of 1 M solution in toluene) was dissolved in THF (10 mL) under argon and cooled to 0 °C. From a syringe charged with BH3Me2S (0.66 mmol, 0.33 mL of 2 M solution in THF) dissolved in 10 mL of THF, 30% of the final amount was added to the catalyst solution. After 10 min. of stirring, the remaining BH3Me2S and the solution of (±)-1 (180 mg, 0.66 mmol in 10 mL of THF) were simultaneously added by a syringe pump within 20 min, while maintaining the reaction mixture at 0–5 °C in an ice-bath. As soon as the quantitative conversion of the substrate was observed, the reaction was quenched by the careful dropwise addition of MeOH (2 mL), diluted with satd NH4Cl and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and taken to dryness under vacuum to give a residue that was charged on a short plug of silica gel to remove the catalyst. After elution with n-hexane/AcOEt 1:1 the eluate was taken to dryness, the residue dissolved in CH2Cl2 (5 mL) and Ac2O/Py mixture (1 mL, 1:1 v/v) was added. After stirring overnight at room temperature the reaction mixture was taken to dryness under vacuum and the residue applied to a deactivated silica gel column. Elution with n-hexane/Et2O 8:2 gave a first band of (1Rp,S)-1-acetoxyethyl-2methoxymethylferrocene, (+)-(1Rp,S)-4b (0.31 mol, 98 mg, 47% yield, 93.8% ee) as a yellow oil. 1H NMR: d 1.40 (d, 3H, J = 6.4 Hz, CH3), 2.18 (s, 3H, –OCOCH3), 3.32 (s, 3H, –OCH3), 4.09 (s, 5H, Cp0 H), 4.13 (m, 2H, Cp-H and CH2a), 4.20 (br s, 1H, Cp-H), 4.25 (br s, 1H, Cp-H), 4.43 (d, 1H, J = 11.2 Hz, CH2b), 5.89 (q, 1H, J = 6.4 Hz, CH). 13C NMR: d 21.3 (–OCOCH3), 23.3 (CH3), 57.8 (–OCH3), 66.5 (CH-OAc), 66.9 (Cp-H), 67.8 (Cp-H), 69.00 (Cp0 -H), 69.4 (Cp-H), 70.0 (CH2), 80.9 (Cp–Cq), 89.9 (Cp–Cq), 170.1 (OCOCH3). ½a25 D = +21.8 (c 0.52, CHCl3). HPLC: n-hexane/2-PrOH 90:10, tR/ min 9.7 (1Rp,S) and 16.3 (1Sp,R). Anal. Calcd for C16H20FeO3: C, 60.78; H, 6.38. Found: C, 60.35; H, 6.32. A second band was collected to afford (1Sp,S)-1-acetoxyethyl-2methoxymethylferrocene, (+)-(1Sp,S)-4a (0.30 mol, 95 mg, 45% yield, 90.4% ee determined on the corresponding alcohol) as a yellow oil. 1H NMR: d 1.61 (d, 3H, J = 6.4 Hz, CH3), 2.00 (s, 3H, –OCOCH3), 3.30 (s, 3H, –OCH3), 4.13 (br s, 6H, Cp0 -H and CH2a), 4.19 (t, 1H, J = 2.4 Hz, Cp-H), 4.30 (m, 2H, Cp-H), 4.25 (br s, 1H, Cp-H), 4.33 (d, 1H, J = 10.8 Hz, CH2b), 6.07 (q, 1H, J = 6.4 Hz, CH). 13C NMR: d 19.0 (CH3), 21.2 (–OCOCH3), 57.9 (OCH3), 67.1 (CH-OAc), 67.2 (Cp-H), 67.4 (Cp-H), 69.0 (Cp-H), 69.1 (Cp0 -H), 71.0 (CH2), 82.7 (Cp–Cq), 86.5 (Cp–Cq), 170.3 (–OCOCH3). ½a25 D = +77.3 (c 0.60, CHCl3). HPLC: n-hexane/2-PrOH 9:1, tR/min 12.4, unresolved peak. Anal. Calcd for C16H20FeO3: C, 60.78; H, 6.38. Found: C, 60.27; H, 6.30. 4.3. (1Sp,S)-1-Hydroxyethyl-2-methoxymethylferrocene ()(1Sp,S)-3a A solution of (+)-4a (95 mg, 0.30 mmol, 90.4% ee) in acetone/ H2O (1:1, 10 mL) was maintained at room temperature under stirring until HPLC analysis showed the complete conversion of substrate. The solvent was then removed under vacuum and the

2635

residue purified by column chromatography (Si gel, n-hexane/ AcOEt 8:2) to give ()-3a (0.29 mmol, 80 mg, 97% yield) as a yellow oil, whose NMR spectra were in agreement with reported data for the racemic compound.15 ½a25 D = 58.3 (c 0.18, CHCl3). HPLC: nhexane/2-PrOH 90:10, tR/min 13.7, unresolved peak. Anal. Calcd for C14H18FeO2: C, 61.34; H, 6.62. Found: C, 61.12; H, 6.56. 4.4. (1Rp,S)-1-Hydroxyethyl-2-methoxymethylferrocene (+)(1Rp,S)-3b A solution of (+)-4b (98 mg, 0.31 mmol, 93.8% ee) in acetone/ H2O (1:1, 10 mL) was maintained at room temperature under stirring until HPLC analysis showed the complete conversion of substrate. The solvent was then removed under vacuum and the residue purified by column chromatography (Si gel, n-hexane/ AcOEt 8:2) to give (+)-3b (0.30 mmol, 82 mg, 97% yield) as a yellow oil. Spectroscopic data were in agreement with those reported.15 ½a25 D = +62.3 (c 0.49, CHCl3). HPLC: n-hexane/2-PrOH 90:10, tR/ min 15.5 (1Rp,S) and 24.5 (1Sp,R). Anal. Calcd for C14H18FeO2: C, 61.34; H, 6.62. Found: C, 61.39; H, 6.65. 4.5. (1Sp)-1-Acetyl-2-methoxymethylferrocene (+)-(1Sp)-1 To a solution of ()-3a (30 mg, 0.11 mmol, 90.4% ee) in CH2Cl2 (5 mL) activated MnO2 (100 mg) was added and the suspension maintained under stirring at 40 °C overnight. The mixture was filtered on a Celite pad and the solution taken to dryness. The residue was purified by column chromatography (Si gel, n-hexane/Et2O 1:1) to afford (+)-1 (27 mg, 0.10 mmol, 92% yield) as a dark orange oil whose characterization data were identical to those reported for the racemic compound.15 ½a25 D = +387.1 (c 0.41, CHCl3). HPLC: nhexane/2-PrOH 90:10, tR/min 14.5 (1Sp) and 30.3 (1Rp). 4.6. (1Rp)-1-Acetyl-2-methoxymethylferrocene ()-(1Rp)-1 To a solution of (+)-3b (30 mg, 0.11 mmol, 93.8% ee) in CH2Cl2 (5 mL) activated MnO2 (100 mg) was added and the suspension maintained at 40 °C with stirring overnight. The mixture was filtered on a Celite pad and the solution taken to dryness. The residue was purified by column chromatography (Si gel, n-hexane/Et2O 1:1) to afford ()-1 (28 mg, 0.10 mmol, 94% yield). ½a25 D = 402.1 (c 0.37, CHCl3). 4.7. (1Rp,S)-N,N-Dimethyl-1-[2(hydroxymethyl)ferrocenyl]ethylamine, ()-(1Rp,S)-5 To a solution of (+)-4b (45 mg, 0.14 mmol, 93.8% ee) in CH3CN (3 mL), 40% aqueous NH(CH3)2 (0.25 mL, 2.22 mmol) was added and the mixture left to react overnight at room temperature. The reaction mixture was then diluted with 10% citric acid solution (5 mL) and extracted with AcOEt, discarding the organic phase. The aqueous layer was alkalinized with NaOH, extracted with AcOEt (3  5 mL) and the organic layer washed with brine and dried over Na2SO4. After removal of the solvent under vacuum, the residue was dissolved in acetone/H2O (1:2, 4 mL) and montmorillonite K-10 (100 mg) was added. The suspension was stirred in an open vessel at 45 °C for 6 h, then filtered on a short plug of Celite and washing the solid with AcOEt/TEA 95:5. The solution was taken to dryness and the residue purified by chromatography (Si gel, AcOEt/TEA 98:2) to give pure (1Rp,S)-5 as a yellow oil (27 mg, 0.094 mmol, 67% yield). 1H NMR: d 1.83 (d, 3H, J = 6.7 Hz, CH3), 2.12 (s, 6H, –NCH3), 2.77 (q, 1H, J = 6.7 Hz), 4.00 (br s, 1H, Cp-H), 4.03 (t, 1H, J = 2.4 Hz, Cp-H), 4.10 (d, 1H, J = 11.8 Hz, CH2a), 4.16 (s, 6H, Cp-H and Cp0 -H), 4.84 (d, 1H, J = 11.8 Hz, CH2b). 13CNMR: d 21.2 (CH3), 43.9 (–NCH3), 60.4 (CH2), 61.2 (–CH), 64.4 (Cp-H), 68.9 (Cp0 -H), 69.9 (Cp-H), 70.8 (Cp-H), 84.8 (Cp–Cq), 94.1

2636

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 21 (2010) 2631–2637

(Cp–Cq). ½a25 D = 20.6 (c 0.25, EtOH). Anal. Calcd for C15H21FeNO: C, 62.73; H, 7.37; N, 4.88. Found: C, 62.80; H, 7.34; N, 4.83. 4.8. (1Sp,S)-1-Methoxyethyl-2-methoxymethylferrocene (+)(1Sp,S)-6a In a sealed tube, a solution of ()-3a (30 mg, 0.11 mmol, 90.4% ee) in MeOH (1.5 mL) and AcOH (0.5 mL) was reacted at 80 °C for 3 h. The reaction mixture was taken to dryness under vacuum and the residue purified by column chromatography (Si gel, n-hexane/Et2O 85:15) to afford (+)-(1Sp,S)-6a (31 mg, 0.10 mmol, 98% yield) as a pale yellow oil. 1H NMR: d 1.59 (d, 3H, J = 6.4 Hz, CH3), 3.21 (s, 3H, –OCH3), 3. 37 (s, 3H, –OCH3), 4.10 (s, 5H, Cp0 -H), 4.17 (t, 1H, J = 2.4 Hz, Cp-H), 4.22 (d, 1H, J = 11.6 Hz, CH2a), 4.25 (br s, 1H, Cp-H), 4.29 (br s, 1H, Cp-H), 4.35 (d, 1H, J = 11.6 Hz, CH2b), 4.38 (q, 1H, J = 6.4 Hz, CH). 13C NMR: d 19.8 (CH3), 55.14 (–OCH3), 57.9 (–OCH3), 66.9 (Cp-H), 67.2 (Cp-H), 68.2 (CH2), 69.1 (Cp0 -H), 69.9 (Cp-H), 72.7 (CH–OCH3), 82.7 (Cp–Cq), 88.5 (Cp–Cq). ½a25 D = +27.6 (c 0.21, CHCl3) HPLC: n-hexane/2-PrOH 98:2, tR/min 16.0 (1Sp,S) and 17.3 (1Rp,R). Anal. Calcd for C15H20FeO2: C, 62.52; H, 7.00. Found: C, 62.24; H, 6.96. 4.9. (1Rp,S)-1-Methoxyethyl-2-methoxymethylferrocene, ()(1Rp,S)-6b In a sealed tube, a solution of (+)-3b (30 mg, 0.11 mmol, 93.8% ee) in MeOH (1.5 mL) and AcOH (0.5 mL) was reacted at 80 °C for 3 h. The reaction mixture was taken to dryness under vacuum and the residue purified by column chromatography (Si gel, n-hexane/Et2O 85:15) to afford ()-(1Rp,S)-6b (31 mg, 0.10 mmol, 98% yield) as a pale yellow oil. 1H NMR: d 1.38 (d, 3H, J = 6.4 Hz, CH3), 3.32 (s, 3H, –OCH3), 3. 50 (s, 3H, –OCH3), 4.10 (m, 2H, Cp-H), 4.14 (s, 5H, Cp0 H), 4.17 (m, 3H, Cp-H, CH and CH2a), 4.47 (d, 1H, J = 11.2 Hz, CH2b). 13 C NMR: d 21.5 (CH3), 56.8 (–OCH3), 57.7 (–OCH3), 66.3 (Cp-H), 67.1 (Cp-H), 69.0 (Cp0 -H and CH2), 69.7 (Cp-H), 70.0 (CH–OCH3), 80.2 (Cp–Cq), 91.8 (Cp–Cq). ½a25 D = 12.3 (c 0.32, CHCl3). HPLC: nhexane/2-PrOH 98:2, tR/min 11.4, unresolved peak. Anal. Calcd for C15H20FeO2: C, 62.52; H, 7.00. Found: C, 62.38; H, 7.02. 4.10. Transfer hydrogenation of (±)-1 with 2-PrOH A mixture of [RuCl2(p-cymene)]2 (5.4 mg, 0.009 mmol) and (1R,2R)-TsDPEN (6.6 mg, 0.018 mmol) in dry 2-PrOH (0.5 mL) was heated at 80 °C for 20 min under argon. The light brown solution was then cooled to rt and diluted with 2-PrOH (6.4 mL). Ketone (±)-1 (100 mg, 0.37 mmol) dissolved in 0.5 mL of 2-PrOH and KOH (0.23 mL of a 0.2 M solution in 2-PrOH, 0.046 mmol) were sequentially added and the mixture was stirred at room temperature, monitoring the reaction progress by HPLC. After 4 days, the reaction mixture was concentrated under vacuum, diluted with water (10 mL) and extracted with ethyl acetate (3  10 mL). The organic layer was washed with brine, dried over Na2SO4 and taken to dryness under vacuum. In order to remove the catalyst, the residue was applied on a short plug of Si gel eluting with AcOEt and the eluate taken to dryness. The residue was dissolved in CH2Cl2 (5 mL) and Ac2O/Py mixture (1 mL, 1:1 v/v) was added. After stirring overnight at room temperature, the reaction mixture was taken to dryness under vacuum and the residue purified on a deactivated silica gel column. Elution with n-hexane/Et2O 8:2 gave (1Sp,R)-4b (27 mg, 0.085 mmol, 23% yield, 91.3% ee) and (1Rp)-1 (72 mg, 0.26 mmol, 72% yield, 30.5% ee). 4.11. Transfer hydrogenation of (±)-1 with HCOOH/TEA A solution of [RuCl2(p-cymene)]2 (9.9 mg, 0.0165 mmol) and (1R,2R)-TsDPEN (12.1 mg, 0.033 mmol) in dry 2-PrOH (0.5 mL)

was heated at 80 °C for 20 min under argon, after which the solvent was removed under vacuum. Triethylamine–formic acid solution (2:5 mol/mol, 1.5 mL) and (±)-1 (180 mg, 0.66 mmol) were added to the Ru-complex and the mixture was stirred at 50 °C, monitoring the reaction progress by HPLC. After a suitable time, the reaction was quenched by the addition of water and workedup as above to afford (1Sp,R)-4b and (1Rp)-1. References 1. (a) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res. 2003, 36, 659–667; (b) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem. Soc. Rev. 2004, 33, 313–328; (c) Arrayás, R. G.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674–7715. 2. (a) Marquading, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389–5393; (b) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995, 60, 10–11; (c) Riant, O.; Samuel, O.; Flessener, T.; Taudien, S.; Kagan, H. B. J. Org. Chem. 1997, 62, 6733–6745; (d) Riant, O.; Argouarch, G.; Guillaneux, D.; Samuel, O.; Kagan, H. B. J. Org. Chem. 1998, 63, 3511–3514; (e) Enders, D.; Peters, R.; Lochtman, R.; Raabe, G. Angew. Chem., Int. Ed. 1999, 38, 2421–2423. 3. (a) Bolm, C.; Muñiz-Fernández, K.; Seger, A.; Raabe, G.; Günther, K. J. Org. Chem. 1998, 63, 7860–7867; (b) Hu, X.; Chen, H.; Dai, H.; Hu, X.; Zheng, Z. Tetrahedron: Asymmetry 2003, 14, 2073–2080; (c) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. Tetrahedron: Asymmetry 2006, 17, 1161–1164; (d) Grach, G.; Lohier, J.-F.; Sopkova-de Oliveira Santos, J.; Reboul, V.; Metzner, P. Chem. Commun. 2007, 4875–4877. 4. (a) Izumi, T.; Hino, T. J. Chem. Technol. Biotechnol. 1992, 55, 325–331; (b) Patti, A.; Lambusta, D.; Piattelli, M.; Nicolosi, G.; McArdle, P.; Cunningham, D.; Walsh, M. Tetrahedron 1997, 53, 1361–1368; (c) Patti, A.; Lambusta, D.; Piattelli, M.; Nicolosi, G. Tetrahedron: Asymmetry 1998, 9, 3073–3080; (d) D’Antona, N.; Lambusta, D.; Morrone, R.; Nicolosi, G.; Secundo, F. Tetrahedron: Asymmetry 2004, 15, 3835–3840. 5. Bueno, A.; Rosol, M.; García, J.; Moyano, A. Adv. Synth. Catal. 2006, 348, 2590– 2596. 6. Alba, A.-N.; Gómez-Sal, P.; Rios, R.; Moyano, A. Tetrahedron: Asymmetry 2009, 20, 1314–1318. 7. Ogasawara, M.; Watanabe, S.; Nakajima, K.; Takahashi, T. Pure Appl. Chem. 2008, 80, 1109–1113. 8. (a) Wright, J.; Frambes, R.; Reeves, P. J. Organomet. Chem. 1994, 476, 215–217; (b) Schwink, L.; Knochel, P. Chem. Eur. J. 1998, 4, 950–966; (c) Sato, H.; Watanabe, H.; Ohtsuka, Y.; Ikeno, Y.; Fukuzawa, S.-I.; Yamada, Y. Org. Lett. 2002, 4, 3313–3316; (d) Lam, W. S.; Kok, S. H. L.; Au-Yeung, T. T. L.; Wu, J.; Cheung, H. Y.; Lam, F. L.; Yeung, C. H.; Chan, A. C. S. Adv. Synth. Catal. 2006, 348, 370–374; (e) Ursini, C. V.; Mazzeo, F.; Rodrigues, J. A. R. Tetrahedron: Asymmetry 2006, 17, 3335–3340; (f) Šebesta, R.; Mecˇiarová, M.; Molnár, È.; Csizmadiová, J.; Fodran, P.; Onomura, O.; Toma, Š. J. Organomet. Chem. 2008, 693, 3131–3134. 9. (a) Gokel, G. W.; Marquading, D.; Ugi, I. J. Org. Chem. 1972, 37, 3052–3057; (b) Vicennati, P.; Cozzi, P. G. Eur. J. Org. Chem. 2007, 2248–2253; (c) Xu, X.; Jiang, R.; Zhou, X.; Liu, Y.; Ji, S.; Zhang, Y. Tetrahedron 2009, 65, 877–882. 10. (a) Patti, A.; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry 2001, 12, 3375– 3380; (b) Patti, A.; Pedotti, S.; Forni, A.; Casalone, G. Tetrahedron: Asymmetry 2005, 16, 3049–3058; (c) Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2006, 17, 1824–1830; (d) Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2008, 19, 1891–1897. 11. (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012; (b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045–2061; (c) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40–73; (d) Riant, O.; Mostefai, N.; Courmarcel, J. Synthesis 2004, 18, 2943–2958; (e) Matsumura, Y.; Ogura, K.; Kouchi, Y.; Iwasaki, F.; Onomura, O. Org. Lett. 2006, 8, 3789–3792. 12. (a) Kagan, H. B. Tetrahedron 2001, 57, 2449–2468; (b) Dorizon, P.; Martin, C.; Daran, J.-C.; Fiaud, J.-C.; Kagan, H. B. Tetrahedron: Asymmetry 2001, 12, 2625– 2630; (c) Delogu, G.; Fabbri, D.; de Candia, C.; Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2002, 13, 891–898. 13. (a) Walbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475–1504; (b) Hoogenraad, M.; Klaus, G. M.; Elders, N.; Hooijschur, S. M.; McKay, B.; Smith, A.; Damen, E. W. P. Tetrahedron: Asymmetry 2004, 15, 519–523; (c) Cho, B. T. Tetrahedron 2006, 62, 7621–7643. 14. Corey, E. J.; Bakhshi, K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553. 15. Delacroix, O.; Andriamihaja, B.; Picart-Goetheluck, S.; Brocard, J. Tetrahedron 2004, 60, 1549–1556. 16. At complete conversion of (±)-1 the exact value of the diastereoisomeric ratio 3a/3b can be calculated from the relationship ee3a[x3a] = ee3b[x3b]. 17. (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584–2585; (b) Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885–888; (c) Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365–370. 18. (a) Pedersen, T. C.; Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.; Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535–538; (b) Abraham, E.; Davies, S. G.; Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 1356–1362; (c) Chavda, S.; Coulbeck, E.; Dingjan, M.; Eames, J.; Flinn, A.; Northen, J. Tetrahedron: Asymmetry 2008, 19, 1536–1548; (d) Al Shayle, N.; Boa, A. N.; Coulbeck, E.; Eames, J. Tetrahedron Lett. 2008, 49, 4661–4665.

A. Patti, S. Pedotti / Tetrahedron: Asymmetry 21 (2010) 2631–2637 19. (a) Bianchi, P.; Roda, G.; Riva, S.; Danieli, B.; Zabelinskaja-Mackova, A.; Griengl, H. Tetrahedron 2001, 57, 2213–2220; (b) Dehli, J. R.; Gotor, V. J. Org. Chem. 2002, 67, 1716–1718. 20. (a) Kato, K.; Motodate, S.; Takaishi, S.; Kusakabe, T.; Akita, H. Tetrahedron 2008, 64, 4627–4636; (b) Miller, L. C.; Ndungu, J. M.; Sarpong, R. Angew. Chem., Int. Ed. 2009, 48, 2398–2402. 21. (a) Kurosu, M.; Kishi, Y. J. Org. Chem. 1998, 63, 6100–6101; (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5–26. 22. Dehli, J. R.; Gotor, V. ARKIVOC 2002, 196–202. 23. (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562–7563; (b) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–2522. 24. (a) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119–1121; (b) Cossy, J.; Eustache, F.; Dalko, P. Tetrahedron Lett. 2001,

2637

42, 5005–5007; (c) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem. 2002, 67, 1712–1715; (d) Wu, X.; Li, X.; King, F.; Xiao, J. Angew. Chem., Int. Ed. 2005, 44, 3407–3411; (e) Nonaka, H.; Maeda, N.; Kobayashi, Y. Tetrahedron Lett. 2007, 48, 5601–5604. 25. The conversion was accurately determined according to Ref. 12a from the relationship C = [(1 + dr)ee1]/[dr (ee1  ee3b) + ee1  ee3a] where all the required dr and ee data were measured by chiral HPLC analyses. 26. (a) Alcock, N. J.; Mann, I.; Peach, P.; Wills, M. Tetrahedron: Asymmetry 2002, 13, 2485–2490; (b) Ros, A.; Magriz, A.; Dietrich, H.; Fernández, R.; Alvarez, E.; Lassaletta, J. M. Org. Lett. 2006, 8, 127–130; (c) Ros, A.; Magriz, A.; Dietrich, H.; Lassaletta, J. M.; Fernández, R. Tetrahedron 2007, 63, 7532–7537; (d) Ding, Z.; Yang, J.; Wang, T.; Shen, Z.; Zhang, Y. Chem. Commun. 2009, 571–573. 27. García, J.; Moyano, A.; Rosol, M. Tetrahedron 2007, 63, 1907–1912.