Exploiting Planar Chirality for the Generation of α-Ferrocenyl Stereogenic Centres

Abstract

Addition of Grignard reagents R¹MgBr (R¹ = Me, Et, i-Pr, t-Bu, Ph) to 2-bromo- and 2-trimethylsilylferrocenecarboxaldehyde proceeded, in most cases, with high diastereoselectivity to generate α-ferrocenyl alcohols of S*,_p S* configuration. Following conversion into their corresponding acetates, reaction with dimethylamine provided α-ferrocenyl amines with retention of configuration (R¹ = Me, Et, Ph).

Key words

asymmetric synthesis - Grignard reactions - ligands - metallocenes - stereoselectivity

References

• 1a Marquarding D. Klusacek H. Gokel G. Hoffmann P. Ugi I. J. Am. Chem. Soc.  1970,  92:  5389 
• 1b Hayashi T. Yamamoto K. Kumada M. Tetrahedron Lett.  1974,  4405 
• For reviews, see:
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• 4 Pickett TE. Roca FX. Richards CJ. J. Org. Chem.  2003,  68:  2592 
• We are aware of only two brief reports on the addition of Grignard reagents to this aldehyde. For MeMgI see:
• 8a Gokel G. Hoffmann P. Kleimann H. Klusacek H. Marquarding D. Ugi I. Tetrahedron Lett.  1970,  1771 
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• The stereochemical outcome of addition to (R,_p S)-1-(α-dimethylamino)phenylmethyl-2-formylferrocene is dependent upon the organometallic employed. Grignard reagents give predominantly a new R stereogenic centre (dr up to 9:1), dialkylzinc reagents give exclusively a new S centre. See:
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5

Other oxidants such as MnO₂ failed to give the required aldehyde even though this reagent cleanly oxidised ferrocenemethanol to ferrocenecarboxaldehyde.

6

Synthesis of _p S-4.
To a solution of _p S-6 (0.295 g, 1.0 mmol) in CH₂Cl₂ (12 mL) was added N-methylmorpholine N-oxide (NMO, 0.300 g, 2.6 mmol) and TPAP (0.018 g, 0.05 mmol). The resulting solution was stirred at r.t. for 80 min, the completion of the reaction being confirmed by TLC (10% EtOAc, 40-60 °C petroleum ether). The reaction mixture was washed with H₂O (20 mL), sat. NaCl solution (20 mL), dried (MgSO₄), filtered and evaporated to give _p S-4 as an orange/red crystalline solid (0.270 g, 92%). The compound is fairly stable in the solid state if stored under nitrogen; solutions exposed to the air decompose quite rapidly. IR (thin film): ν_max = 1676 (C=O) cm^-1. ¹H NMR (CDCl₃): δ = 4.33 (5 H, s, C₅ H ₅), 4.55 (1 H, br s, FcH), 4.82 (1 H, br s, FcH), 4.85 (1 H, br s, FcH), 10.17 (1 H, s, CHO). ¹³C{¹H} NMR (CDCl₃): δ = 66.78 (Fc-CH), 71.42 (Fc-CH), 72.34 (C ₅H₅), 75.19 (Fc-CH), 193.09 (CHO). HRMS (ES): m/z calcd for C₁₁H₁₀ ⁷⁹BrFeO: 292.9259; found for MH⁺: 292.9258.

7

Grignard Addition - Representative Procedure.
To a solution of _p S-4 (0.106 g, 0.36 mmol) in dry Et₂O (3.6 mL) under nitrogen cooled to -80 °C, was added dropwise a solution of 3.0 M MeMgBr in Et₂O (0.15 mL, 0.45 mmol). The resulting bright red solution was allowed to warm slowly to r.t. over a period of 2 h to give a dark yellow solution. This was quenched with H₂O (5 mL), and the organic layer was separated and washed with additional H₂O (5 mL) and sat. NaCl solution (5 mL). Subsequent drying (MgSO₄) and removal of the solvent in vacuo gave 8a as a yellow solid (0.093 g, 83%). Examination by ¹H NMR (270 MHz, CDCl₃) revealed the presence of only a single diastereoisomer. IR (thin film): ν_max = 3422 (OH) cm^-1. ¹H NMR (CDCl₃): δ = 1.37 (3 H, d, J = 6 Hz, CHCH ₃), 4.11 (1 H, br s, FcH), 4.26 (6 H, s, C₅ H ₅ + FcH), 4.46 (1 H, br s, FcH), 4.75 (1 H, q, J = 6 Hz, CHCH₃). ¹³C{¹H} NMR (CDCl₃): δ = 24.26 (CHCH₃), 63.54, 65.33, 66.08, 70.40 (3 × Fc-CH + CHCH₃), 71.13 (C ₅H₅). HRMS (EI): m/z calcd for C₁₂H₁₃ ⁷⁹BrFeO: 307.9494; found for M⁺: 307.9494.

11

Amination - Representative Procedure.
To a solution of 10a (0.100 g, 0.28 mmol) in MeOH (1 mL) was added a 40 wt% aqueous solution of NHMe₂ (0.33 mL) and the reaction mixture stirred at r.t. for 48 h. Addition of phosphoric acid (1M, 10 mL) and extraction with Et₂O (2 × 10 mL), was followed by neutralisation of the aqueous phase [sat. NaHCO_{3 ( aq)}] and extraction with CH₂Cl₂ (2 × 10 mL). The combined CH₂Cl₂ layers were dried (MgSO₄), filtered and evaporated to give 12a as a brown viscous oil (0.095 g, 99% yield). ¹H NMR (CDCl₃): δ = 1.68 (3 H, d, J = 7 Hz, CHCH ₃), 2.22 [6 H, s, N(CH ₃)₂], 3.59 (1 H, q, J = 7 Hz, CHCH₃), 4.04 (1 H, br s, FcH), 4.09 (1 H, br s, FcH), 4.20 (5 H, s, C₅ H ₅), 4.39 (1 H, br s, FcH). ¹³C{¹H} NMR (CDCl₃): δ = 16.65 (CHCH₃), 41.60 [N(CH₃)₂], 60.35, 66.25, 69.12, 71.70 (3 × Fc-CH + CHCH₃), 71.37 (C ₅H₅). HRMS (ES): m/z calcd for C₁₄H₁₉ ⁷⁹BrFeN: 336.0045; found for M⁺: 336.0043.