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).

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:

2a Togni A. Angew. Chem., Int. Ed. Engl.  1996,  35:  1475 

2b Richards CJ. Locke AJ. Tetrahedron: Asymmetry  1998,  9:  2377 

2c Colacot TJ. Chem. Rev.  2003,  103:  3101 

3 Togni A. Breutel C. Schnyder A. Spindler F. Landert H. Tijani A. J. Am. Chem. Soc.  1994,  116:  4062 

4 Pickett TE. Roca FX. Richards CJ. J. Org. Chem.  2003,  68:  2592 

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.

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 

9 Marr G. J. Organomet. Chem.  1967,  9:  147 

10 Riant O. Samuel O. Kagan HB. J. Am. Chem. Soc.  1993,  115:  5835 

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.

12 Davies SG. Goodfellow CL. J. Chem. Soc., Perkin Trans. 1  1990,  393 

13 Fukuzawa S. Tsuchiya D. Sasamoto K. Hirana K. Ohtaguchi M. Eur. J. Org. Chem.  2000,  2877 

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:

14a Fukuzawa S. Fujimoto K. Synlett  2001,  1275 

14b Fukuzawa S. Fujimoto K. Komuro Y. Matsuzawa H. Org. Lett.  2002,  4:  707 

15a Hill EA. Richards JH. J. Am. Chem. Soc.  1961,  83:  4216 

15b Gokel GW. Marquarding D. Ugi IK. J. Org. Chem.  1972,  37:  3052 

15c Locke AJ. Richards CJ. Tetrahedron Lett.  1996,  37:  7861 

16a Hayashi T. Mise T. Fukushima M. Kagotani M. Nagashima N. Hamada Y. Matsumoto A. Kawakami S. Konishi M. Yamamoto K. Kumada M. Bull. Chem. Soc. Jpn.  1980,  53:  1138 

16b Richards CJ. Mulvaney AW. Tetrahedron: Asymmetry  1996,  7:  1419 

16c Bolm C. Muñiz-Fernández K. Seger A. Raabe G. Günther K. J. Org. Chem.  1998,  63:  7860