Chiral ferrocene-based ligands have been extensively studied in asymmetric catalytic reactions and widely used in the industrial production of chiral compounds ^[1]. Some of the most efficient chiral ferrocene ligands,including BoPhoz ^[2],Josiphos ^[3], Taniaphos ^[4],Walphos ^[5],PPFA ^[6],Ferriphos ^[7],Pigiphos ^[8], Trap ^[9],etc.,share a common intermediate (R)-N,N-dimethyl-1-ferrocenylethyl-amine,namely (R)-Ugi’s amine ((R)-1) (Fig. 1),a compound first prepared in 1970 ^[10a]. Presently,a large amount of (R)-Ugi’s amine is required as an important intermediate.

Fig. 1

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Fig. 1.Structure of Ugi’s amine (1).

The classic method to produce optically pure (R)-1 is through resolution of its racemic mixture (Scheme 1) ^[10]. Alternatively, chiral auxiliaries have also been reported to generate a (R)-Ugi’s amine analog by Togni’s group ^[11] and Hayashi’s group ^[12]. Chan’s group reported an efficient approach for chiral ferrocenebased secondary alcohols via asymmetric hydrogenation of ferrocenyl ketones,and Ugi’s amine analog could be synthesized via acylation and amination of chiral ferrocene-based secondary alcohols ^[13a]. Li’s group reported a probable approach for asymmetric transfer hydrogenation of ferrocenyl ketones ^[13b]. However,very expensive metal catalysts or organic ligands were used in asymmetric reduction,asymmetric acylation,or stereoselective enzymatic acylation to synthesize the precursors of Ugi’s amine of (R)-2 and (R)-3 ^{[13a, 14]}. Compared with these methods mentioned above,resolution of its racemic mixture is a better one. To decrease the cost of materials,the most economical and ecobenign synthetic pathway to chiral Ugi’s amine is to transform another configuration. It was surprising,however,that few laboratory methods were known for transformation of the (S)-Ugi’s amine to (R)-Ugi’s amine and its precursor. A major progress has been made by Ugi’s group ^[10],transformation from Ugi’s amine (1) to 1-ferrocenylethanol (3) viatwo or three steps including methylation and hydrolysis,or including methylation,esterification,and hydrolysis. In other words,the efficient transformation of (S)-Ugi’s amine had not been achieved by Ugi’s group. Additionally, the yield of the process was not very high,and expensive CH3I was used in the methylation. This method,to some extent,could give us some inspiration in our laboratory study.

Scheme 1

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Scheme 1.Ugi’s method to prepare (R)-Ugi’s amine ((R)-1).

Chen ^[15] reported that the Ugi’s amine derivatives could be transformed to related substituted ferrocenylethyl acetates in the solution of anhydride at ambient temperature with high yield. Nicolosi ^[16] gave an example of alkaline hydrolysis of substituted ferrocenylethyl acetates to related ferrocenyl alcohols,and followed by manganese dioxide oxidation in aprotic solvent to give related ketones. But in the transformation,a large amount of anhydride would be used,and the reaction time was very long.

This paper describes our attempt to report the first example of the transformation of (S)-Ugi’s amine via esterification using anhydride,alkaline hydrolysis,and oxidation (Scheme 2). Acetylferrocene (4) was obtained which could be changed to (R)-Ugi’s amineviaUgi’s method (Scheme 1).

Scheme 2

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Scheme 2.Synthesis of acetyl ferrocene (4) from (S)-Ugi’s amine ((S)-1).

All reactions were carried out in reaction tubes with magnetic stirring and no special precautions were taken to exclude air from the reaction vessels. NMR spectra were recorded with a Bruker Avance HD III 500 NMR spectrometer. Chemical shifts were reported in parts per million (ppm) downfield from TMS with the solvent resonance as the internal standard. Coupling constants (J) are reported in Hz. ESI-MS was recorded on a Thermo-LTQ XL mass spectrometer. Optical rotation data was obtained at 25 ℃. Melting points were determined on a WRS-2A (Shanghai Jingke) instrument and uncorrected. All other reagents were purchased from commercial sources and used without further purification.

General procedure of esterification of (S)-Ugi’s amine ((S)-1): A solution of (S)-1(2.57 g,10 mmol) in acetic anhydride (1.88 mL, 20 mmol) and dichloromethane (5 mL) were stirred for 1 h at room temperature. The reaction mixture was then stirred until TLC (petroleum ether:ethyl acetate,10:1) analysis indicated the complete disappearance of the starting material. The solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL),washed with the solution of 10% NaHCO₃, washed with water,and dried over anhydrous Na₂SO₄. Thereafter, the solvents were removedin vacuoto offer a crude product,which was recrystallized fromn-hexane (3 mL),affording (S)-2 2.58 g (95% yield) as an orange solid,mp 66-68 ℃,[α]_D²⁰ +28.5 (c 1.5,ethanol). ¹H NMR (500 MHz,CDCl₃):δ 5.85 (q,1H,J= 6.5 Hz),4.28 (s,1H),4.23 (s,1H),4.21 (s,7H),2.06 (s,3H),1.58 (d,3H,J= 6.5 Hz). ₁₃C NMR (126 MHz,CDCl₃):δ 170.46,88.03,68.82,68.35,67.98, 66.02,21.39,20.04. MS (ESI): m/z 273.1 (M+1),213.76 (M-CH₃CO₂H+1),295.86 (M+Na); IR (KBr,cm^-1 ):v 1723,1235.

General procedure of hydrolysis of (S)-1-ferrocenylethyl acetate ((S)-2): A solution of (S)-2(1.36 g,5 mmol) in ethanol (10 mL) and 2 mol/L NaOH (7 mL) were allowed to stand for 5 min at ambient temperature,the reaction mixture was then stirred until TLC (petroleum ether:ethyl acetate,10:1) analysis indicated the complete disappearance of (S)-2. The solution was diluted with water (20 mL),extracted with ethyl acetate (3 × 20 mL) and dried over anhydrous Na₂SO₄,and the solvent was removed in vacuo. The resulting product was recrystallized fromn-hexane (2 mL), affording 1.05 g (92% yield) (S)-3 as a yellow powder,mp 75-76 ℃, [α]_D²⁰ +30.0 (c1.2,benzene),>99% ee. ₁H NMR (500 MHz,CDCl₃):δ 4.56 (m,1H,J= 4.2,6.3 Hz),4.35-4.10 (m,9H),1.85 (d,1H, J= 4.2 Hz),1.46 (d,3H,J= 6.3 Hz). ₁₃C NMR (126 MHz,CDCl₃): δ 94.81,68.63,68.36,67.93,66.18,65.59,23.73. MS (ESI):m/z 214.50 (M-OH+1),231.04 (M+1). IR (KBr,cm^-1 ): n3220,1411,1308,1237,1069,1001,869,806.

General procedure of oxidation of (S)-1-Ferrocenylethanol ((S)-3): (S)-1-Ferrocenylethanol (S)-3) (575 mg,2.5 mmol) was stirred at room temperature for 4 h with a suspension of active manganese dioxide (2.17 g,25 mmol) in toluene (10 mL),The reaction mixture was then stirred until TLC (petroleum ether:ethyl acetate,10:1) analysis indicated the complete disappearance of (S)-3. The mixture was filtered and the filtrate evaporated. The residue was dissolved in dichloromethane and washed with water. The dichloromethane fractions were dried over anhydrous Na2SO4,and concentrated under reduced pressure. The resulting products were purified by silica gel flash column chromatography (PE:EtOAc,10:1) to afford acetylferrocene (4) (542 mg,95% yield) as a yellow solid,mp 86-87 ℃. ¹H NMR (500 MHz,CDCl₃):δ 4.82- 4.76 (t,2H,J= 1.9 Hz,H₂ and H₅ of subst. Cp ring),4.55-4.50 (t,2H, J= 1.9 Hz,H₃ and H₄ of subst. Cp ring),4.22 (s,5H,unsubst. Cp ring),2.42 (s,3H,CH₃). ¹³C NMR (126 MHz,CDCl₃):δ 202.03 (C=O), 79.32 (C₁ of subst. Cp ring),72.33 (C₃ and C₄ of subst. Cp ring), 69.87 (C of unsubst. Cp ring),69.62 (C₂ and C₅ of subst. Cp ring), 27.42(CH₃). MS (ESI): m/z 229.58 (M+1),251.41 (M+Na). IR (KBr,cm^-1 ):n3116,3096,3075,1660,1457,1281.

The spectra of ¹H NMR,¹³C NMR,MS,IR of (S)-2,(S)-3 and 4 are available in Supporting information. 3. Results and discussion

As described above,the nucleophilic displacement of (S)-1 with acetic anhydride took a very long time and required a large amount of anhydride,therefore,improvements that cut down the amount of acetic anhydride and avoid the long reaction time should be investigated. We tried to add solvents into the reaction system to form a dilute solution. A solvent study showed that dichloromethane as solvent provided the best result (Table 1,entry 3). Further studies showed that there was no increase in yield when increasing the quantity of acetic anhydride. The best result was obtained when a solution of (S)-1 (10 mmol) in acetic anhydride (20 mmol) and dichloromethane (5 mL) reacted at room temperature for 1 h. Determination of rotation value showed that no racemization occurred during the process of esterification of (S)-1.

Table 1

Table 1 Esterification of (S)-Ugi’s amine ((S)-1) under various conditions.a

Table 1 Esterification of (S)-Ugi’s amine ((S)-1) under various conditions.a

With (S)-1-ferrocenylethyl acetate ((S)-2) in hand,we further studied the chemical hydrolysis of (S)-2. It was found that solvent was important to the hydrolysis yield,and ethanol was the best solvent. Temperature could influence the speed of reaction but had no obvious influence on the yield (Table 2). The rational condition was a solution of (S)-2(5 mmol) in ethanol (10 mL) and 2 mol/L aqueous sodium hydroxide solution (7 mL). The reaction was allowed to stand for 5 min at ambient temperature. Determination ofee value showed that no racemization occurred during the process of alkaline hydrolysis of (S)-2(see HPLC of Supporting information).

Table 2

Table 2 Hydrolysis of (S)-1-ferrocenylethyl acetate ((S)-2) under various conditions.a

Table 2 Hydrolysis of (S)-1-ferrocenylethyl acetate ((S)-2) under various conditions.a

To accomplish the transformation of (S)-Ugi’s amine ((S)-1), oxidation of (S)-1-ferrocenethanol ((S)-3)isthekeystep.We have tested several oxidants to achieve this transformation (Table 3,entries 1-7). It was found that active manganese dioxide was the best oxidant. After optimizing the reaction conditions,a nearly complete oxidation within 4 h at room temperature was achieved with an activated form of manganese dioxide. Normal commercial precipitated manganese dioxide commonly has a much lower activity and is often inactive. In the preparation of the active material ^[17],it has been found essential to precipitate it in the presence of alkali or to treat it with alkali after precipitation and before drying. The latter process is also critical,and both under- and over-drying can profoundly reduce the activity of manganese dioxide. The active material is a hydrated oxide and a chocolate-brown color. The solvent effect was also investigated. Different polar solvents such as toluene,benzene,dichloromethane,and ether,were suitable for this oxidation.

Table 3

Table 3 Oxidation of (S)-1-ferrocenyl alcohols ((S)-3) under various conditions.a

Table 3 Oxidation of (S)-1-ferrocenyl alcohols ((S)-3) under various conditions.a

In summary,we successfully developed a simple synthetic approach for the transformation ofS-Ugi’ s amineviaesterification using anhydride,alkaline hydrolysis,and oxidation using active manganese dioxide. It compares favorably with and represents a valid alternative to the existing methods. The important features of our method are: mild reaction conditions,simple work-up, inexpensive reaction agents,and high total yield (up to 83%). Additionally,this research can also provide a method for the transformation of other representative amines. Further efforts will be directed at synthesizing large amounts of bisphosphine ligands based on ferrocenyl used in the asymmetric catalytic reaction.

We are grateful for financial support from the National Natural Science Foundation of China (No. 20972123) and Wuhan Science and Technology Bureau.

Supplementary data associated with this article can be found, in the online version,at http://dx.doi.org/10.1016/j.cclet.2014. 06.009.