Synlett 2005(14): 2159-2162  
DOI: 10.1055/s-2005-872240
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Caroline J. Taylor, Francesc X. Roca, Christopher J. Richards*
Department of Chemistry, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK
Fax: +44(20)78827794; e-Mail: c.j.richards@qmul.ac.uk;
Further Information

Publication History

Received 7 April 2005
Publication Date:
22 July 2005 (eFirst)

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).

    References

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  • For reviews, see:
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  • 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 
  • 8b For p-TolMgBr see: Taudien S. Riant O. Kagan HB. Tetrahedron Lett.  1995,  36:  3513 
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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): νmax = 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): νmax = 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. NaHCO3 ( 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.