Synthesis of 1,2-Disubstituted Aminoarylferrocene As Direct Way to Enantioenriched

Mounia Merabet-Khelassi,*a Louisa Aribi-Zouiouechea and Olivier Riant b

Synthesis of 1,2-Disubstituted Aminoarylferrocene as direct way to enantioenriched 2-Hydroxymethyl-1-phenylferrocene via enzymatic kinetic resolution a Ecocompatible Asymmetric Catalysis Laboratory.(LCAE) Badji Mokhtar Annaba- University. B.P 12, 23000 Annaba, Algeria. b Institute of Condensed Matter and Nanosciences Molecules, Solids and reactiviTy (IMCN/MOST. Université Catholique de Louvain. Bâtiment Lavoisier. Pl. Louis Pasteur, 1, bte 3. 1348 Louvain La Neuve, Belgium.

* E-mail: [email protected] ; [email protected] (M. Merabet-Khelassi).

*For correspondance

Supporting information

Table of Contents: General information 2 General procedure for the synthesis of 2-Dimethylaminomethyl-1-aryl- 2 ferrocene (2a-2c) General procedure for synthesis of 2-Hydroxymethyl-1-aryllferrocene (+/-)-4a-4c 4 General procedure for enzymatic acetylation of 2-Hydroxymethyl-1-aryllferrocene 6 (+/-)-4 NMR spectra of all compounds 7 Chiral HPLC analyses 12

GENERAL INFORMATION

1 All starting materials and reagents used in this study were obtained commercially from Aldrich and Acros and were used without purification. The lipases: Pseudomonas cepacia lipase (PCL, Specific activity >30000 U/ mg) from Amano, and the Candida antarctica lipase immobilized on acrylic resin (CAL-B, Specific activity >10000U/g) are used as purchased without any pre-treatment. All solvents are distillated under argon atmosphere and using freshly. All reaction were monitored by thin-layer chromatography (TLC) carried out on 0.25-mm Merck silica-gel plates (60F-254) using ultraviolet light (254 nm) as the visualizing agent. 1H NMR and 13C NMR spectra were recorded on Brüker spectrometers (300MHz for 1H,

13 75MHz for C). Chemical shifts were reported downfield from CDCl3 ( δ =7.26 ppm).

13 For C NMR, chemical shifts were reported in the scale relative to the solvent of CDCl3 (δ=77 ppm) used as internal reference. Coupling constants (J) are given in hertz. Following abbreviations classify the multiplicity: s = singulet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal. Melting points were measured using BÜCHI MELTING POINT B-545. The mass spectra were obtained from the mass-service at Université catholique de Louvain (FINNIGAN-MAT TSQ 7000 and FINNIGAN-MAT LQC spectrometers). IR spectra were recorded on Shimadzu FTIR-8400S spectrometer. The enantiomeric excesses were measured by a chiral stationary phase HPLC on Chiralpak® AD column. Retention times are reported in minutes.

GENERAL PROCEDURE FOR THE SYNTHESIS OF 2-DIMETHYLAMINOMETHYL-1- ARYLLFERROCENE (2a-2c)

A dry Schlenck tube was loaded under argon with 1equivalent of DMAF 1 and diluted with (5 mL) of freshly distilled diethyl ether. 1.15 equivalent of a tert-butyl lithium solution (1.5 M) were added dropwise via syringe under -78°C. After 15 min of stirring, a solution of 1.4 equivalents of zinc chloride in 2 mL of freshly distilled THF were added dropwise, and the stirring at this temperature was maintained for further 45 minutes. In parallel, and in other a dry Schlenk tube was loaded under argon, 0.12 equivalent of diisobutylaluminium hydride were added dropwise to a solution of 0.05 equivalent of bis

2 (triphenylphosphine) palladium(II) chloride diluted in 2mL de THF. Once a red colour was developed, this solution was then transferred via transfer cannula to the first schlenk where the zincic intermediate was already formed. At the same time of the formation of palladium (0), a solution of 1.5 equivalents the appropriate bromoaryl was added. The finally reaction mixture was remaining to 50°C under magnetic stirring until total consumption of the DMAF the outcome of the reaction was monitored by TLC. The crude reaction mixture was carefully quenched with brine. The aqueous phase was extracted with ether and the organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo.

2-Dimethylaminomethyl-1-phenylferrocene (+/-)-2a The general procedure was applied with the use of 2.3 g of DMAF (1 eq. ; 8.015 mmoles), 5.45 mL of t-BuLi (1.7 M), and 2.56 g (2 eq.; 16.03mmoles) of bromobenzene. The aminoferrocene (2a) is isolated as brown crystals after flash chromatography on silica gel (8:2:1; cyclohexane :ethyl acetate : triethylamine), with 90 % yield (2.31 g; 7.26 mmoles).

1 C19H21FeN (319.22). Rf = 0.71 (5 :5 :1; cyclohexane :ethyl acetate : triethylamine). H

NMR (300MHz, CDCl3): δ (ppm) = 2.11 (s, 6H, N(CH3)2) ; 3.17-3.21 & 3.66-3,7 AB

(2d, J=12.75Hz, 1H for each one, CH2N(CH3)2) ; 4.09 (s, 5H, CP) ; 4.27 & 4.28 (d,

J=12.75Hz, 1H, CP); 4.34 (s, 1H, CP); 4.5 (s, 1H, CP); 7.26-7.38 (ma , 3H, aromatics);

13 7.74-7.57 (ma , 2H, aromatics). C NMR (75MHz, CDCl3): δ (ppm) = 45; 57; 69; 70; 72;

+ + 83; 88; 125; 127; 130; 139. MS (D-APCI ; m/z): 275 ([FcPhCH2] ,100%); 318.9 ([M] , 95%). Chiral HPLC: Chiralpak AD Column. Eluent : hexane / EtOH (97/3). Flow :

1ml /min. Retention times: tR1 = 4.06 minutes and tR2 = 4.47 minutes.

2-Dimethylaminomethyl-1-naphtylferrocene (+/-)-2b The general procedure was applied with the use of 2.5 g of DMAF (1 eq. ; 8.71 mmoles), 6.67 mL of t-BuLi (1.7 M), and 2.92 g (1.4 eq.; 13.8 mmoles) of 2- bromonaphthalene. The aminoferrocene (2c) is isolated as brown crystals after flash chromatography on silica gel (8:2:1; cyclohexane :ethyl acetate : triethylamine), with 80 % yield (2.58 g; 7mmoles).

3 C23H23FeN (369.12). Rf = 0.71 (5:5:1; Cyclohexane : Ethyl acetate : Triethylamine).

1 RMN H (300MHz, CDCl3): δ (ppm) = 2.34 (s, 6H, N(CH3)2) ; 3.2-3,24 & 3.81-3,86 AB

(2d, J=12.9Hz, 1H for each one, CH2N(CH3)2) ; 4.17 (s, 5H, CP) ; 4.35-4.36 (d, J=2.4Hz,

1H, CP); 4.41 (s, 1H, CP); 4.67 (s, 1H, CP); 7.5-7.57 (ma , 2H, aromatics); 7,86-8,37 (ma ,

13 4H, aromatics); 8.48 (s , 1H, aromatic). RMN C (75MHz, CDCl3): δ (ppm) = 12.5; 27.5; 45; 58; 67; 69; 70; 72; 82 ; 89; 125 ; 126 ; 127 ; 128 ; 129 ; 132; 134 ; 137. MS (D- APCI; m/z): 369.3 ([M] +, 100%).

2-Dimethylaminomethyl-1-biphenylferrocene (+/-)-2c The general procedure was applied with the use of 2.5 g of DMAF (1 eq. ; 8.71 mmoles), 6.67 mL of t-BuLi (1.7 M), and 3.52 g (1.5 eq.; 14.8 mmoles) of 4- bromobiphenyle. The aminoferrocene (2b) is isolated as brown crystals after flash chromatography on silica gel (8:2:1; cyclohexane :ethyl acetate : triethylamine), with 84 % yield (2.88 g; 7.3 mmoles).

C25H25FeN (395.13). Rf = 0.91 (5:5:1; Cyclohexane : Ethyl acetate : Triethylamine).

1 RMN H (300MHz, CDCl3): δ (ppm) = 2.28 (s, 6H, N(CH3)2) ; 3.19-3.24 & 3.75-3.79 AB

(2d, J=12.6Hz, 1H for each one, CH2N(CH3)2) ; 4.14 (s, 5H, CP) ; 4.32-4,33 (d, J=2.4Hz,

1H, CP); 4.39 (s, 1H, CP); 4.58 (s, 1H, CP); 7.41-7.43 (ma , 1H, aromatics); 7.49-7.54 (t , J=7.8Hz, 2H, aromatics); 7.62-7.65 (d , J=8.4Hz, 2H, aromatics) ; 7.7-7.73 (d , J=7.5Hz,

13 2H, aromatics) ; 7.87-7.9 (d , J=8.1Hz, 2H, aromatics). RMN C (75MHz, CDCl3): δ (ppm) = 45; 59; 65; 67; 69 ; 70; 72; 82 ; 87; 126 ; 127 ; 129 ; 130 ; 138; 139 ; 141. MS (D-APCI; m/z): 395.1 ([M] +, 100%).

General procedure for synthesis of 2-Hydroxymethyl-1-aryllferrocene (+/-)-4a-4c

4 mL of acetic anhydride are added to 2 mmol of 2-dimethylaminomethyl-1- arylferrocene (+/-)-2, previously obtained. The solution was refluxed over night. After filtration on celite and concentration in vacuo, the crude reaction mixture was engaged directly, for a methanolysis, with 5 equivalents de K2CO3 in 5 mL of methanol, the reaction was stirred overnight. After filtration on celite and concentration, the residue is taken up in dichloromethane and washed with water. After standard work up, the crude

4 reaction mixture was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate (80/20) as eluent.

2-Acetoxymethyl-1-phenylferrocene (+/-)-3a

1 Brown oil. C19H18FeO2 (334.07). Rf = 0.54 (8:2; Cyclohexane : Ethyl acetate). NMR H

(300MHz, CDCl3): δ (ppm) = 2.12 (s, 3H, OC-CH3) ; 4.15 (s, 5H, CP) ; 4.34 (s, 1H, CP);

4.49 (s, 1H, CP); 4.58 (s, 1H, CP); 4.94-4.98 (d, J=12 Hz, 1H) & 5.30-5.35 (d, J=12 Hz,

1H) CH2OAc; 7.28-7.4 (ma , 3H, aromatics); 7.60-7.64 (ma , 2H, aromatics). Chiral HPLC Chiralpak AS Column. Eluent : hexane / EtOH (97/3). Flow : 1ml / min. Retention times: tR1 = 6.54 minutes and tR2 = 7.16 minutes.

2-hydroxymethyl-1-phenylferrocene (+/-)-4a After the both successively steps, the alcohol was yielded as brown oil (73%).

1 C17H16FeO (292.06). Rf = 0.2 (8:2; Cyclohexane : Ethyl acetate). NMR H (300MHz,

CDCl3): δ (ppm) = 1.83 (bs, 1H, OH) ; 4.16 (s, 5H, CP) ; 4.33 (s, 1H, CP); 4.44 (s, 1H,

CP); 4.45 (q, J=9.6 Hz, 3H, CH2+ 1H CP); 7.28-7.39 (ma , 3H, aromatics); 7.61-7.63 (d , J=9.6 Hz, 2H, aromatics). Chiral HPLC: Chiralpak AD Column. Eluent : hexane / EtOH

(97/3). Flow: 1ml /min. Retention times: tR1 = 22.21 minutes and tR2 = 24.02 minutes.

2-Hydroxymethyl-1-naphtylferrocene (+/-)-4b After the both successively steps, the alcohol was yielded as brown oil (68%).

CDCl3): δ (ppm) =1.83 (bs, 1H, OH) ; 4.11 (s, 5H, CP) ; 4.31 (t, J=2.4 Hz, 1H, CP); 4.41

(q, J=2.4 Hz, 1H, CP); 4.58-4.66 (ma,1H, CP); 7.42-7.49 (ma , 2H, aromatics); 7.73-7.84

(ma , 4H, aromatics); 8.06 (s ,1H, aromatic).

2-Hydroxymethyl-1-biphenylferrocene (+/-)-4c After the both successively steps, the alcohol was yielded as brown oil (70%).

CDCl3): δ (ppm) =1.74 (bs, 1H, OH) ; 4.16 (s, 5H, CP) ; 4.34 (s, 1H, CP); 4.44 (s, 1H,

CP); 4.45 (q, J=12.3 Hz, 3H, CH2+ 1H CP); 7.26-7.39 (ma , 2H, aromatics); 7.44-7.49 (t ,

5 J=7.8 Hz, 2H, aromatics); 7.56 & 7.59 (d , J=8.1 Hz, 2H, aromatics) ; 7,63 (q , J=7.2 Hz, 3H, aromatics).

GENERAL PROCEDURE FOR ENZYMATIC ACETYLATION OF 2- HYDROXYMETHYL-1-ARYLLFERROCENE (+/-)-4

A round bottomed flask was loaded with 1 equivalent of the racemic alcohol 4 and 3 equivalent of enol acetate in DIPE. The appropriate amount of lipase was added in one portion and the reaction mixture was stirred at room temperature for three days. At the end of the reaction, the mixture was filtered over celite and concentrated in vacuo. The enantioselectivities were measured by HPLC.

NMR spectra of all compounds

6 7 8 9 10 11 Chiral HPLC Analyses

Chiral HPLC: Chiralpak AD Column. Eluent : hexane / EtOH (97/3). Flow :

Chiral HPLC Chiralpak AS Column. Eluent : hexane / EtOH (97/3). Flow :

1ml / min. Retention times: tR1 = 6.54 minutes and tR2 = 7.16 minutes.

Chiral HPLC Chiracel ODH Column. Eluent : hexane / EtOH (97/3). Flow :

1ml / min. Retention times: tR1 = 13.25 minutes and tR2 = 14.33 minutes.

12 Chiral HPLC: Chiralpak AD Column. Eluent : hexane / EtOH (97/3). Flow:

Table 2- Entry 3

(+/-)-4a + AI+ CAL-B (Before derivatization)

13 Table 2- Entry 4 (+/-)-4a + AI+ CAL-B (After derivatisation)