Single-Step Preparation of a 4-(Dimethylamino)pyridine Analogue Bearing a Sulfoxide as New Chiral Inducer. Preliminary Evaluation as Nucleophilic Catalyst

Abstract

A one-step synthesis of a new chiral DMAP-1a equivalent is reported by bromine-magnesium exchange reaction of the 3-bromo-4-(dimethylamino)pyridine (2). The chiral sulfoxide appendage is introduced by trapping the resulting Grignard intermediate with (1R,2S,5R)-(-)-(S)-menthyl p-toluenesulfinate affording (S)-1a in 60% yield and high optical purity. A preliminary evaluation of 1a as nucleophilic catalyst has demonstrated promising selectivity (s = 4.5) during acylative kinetic resolution of various alcohols.

chiral DMAP - sulfoxide - kinetic resolution - alcohol

References

For leading references of chiral DMAP analogues, see:

1a Fu GC. Acc. Chem. Res.  2004,  37:  542 

1b Kawabata T. Nagato M. Takasu K. Fuji K. J. Am. Chem. Soc.  1997,  119:  3169 

1c Kawabata T. Yamamoto K. Momose Y. Yoshida H. Nagaoka Y. Kaoru F. Chem. Commun.  2001,  2700 

1d Shaw SA. Aleman P. Vedejs E. J. Am. Chem. Soc.  2003,  125:  13368 

1e Spivey AC. Zhu F. Mitchell MB. Davey SG. Jarvest RL. J. Org. Chem.  2003,  68:  7379 

1f Yamada S. Misono T. Iwai Y. Tetrahedron Lett.  2005,  46:  2239 

1g Dalaigh CO. Hynes SJ. Maher DJ. Connon SJ. Org. Biomol. Chem.  2005,  3:  981 

2 Groziak MP. Melcher LM. Heterocycles  1987,  26:  2905 

3

Geometry optimization was performed with the MS modeling (Accelrys) implementation of the CNFF force field.

4 For recent development of bromine-magnesium exchange reaction, see: Knochel P. Dohle W. Gommermann N. Kneisel FF. Kopp F. Korn T. Sapountzis I. Vu VA. Angew. Chem. Int. Ed.  2003,  42:  4302 

5

Preparation of DMAP 1b by Bromine-Magnesium Exchange.
To a solution of 3-bromo-4-(dimethylamino)pyridine (2, 898 mg, 4.47 mmol) in THF (30 mL) is added a solution of i-PrMgCl in THF (2.68 mL, 2 M, 5.36 mmol) at r.t. The resultant solution was stirred at this temperature for 3 h under a nitrogen atmosphere. The reaction mixture was quenched with EtOD and the solution stirred for a further 1 h. After adding H₂O (40 mL), the resulting aqueous layer was extracted twice with CH₂Cl₂ (2 × 10 mL), dried (MgSO₄) and evaporated under vacuum to give 1b in high deuterium incorporation (>95%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 8.22 (app t, 2 H, J = 6 Hz), 6.48 (d, 1 H, J = 6 Hz), 3.00 (3 H, s). HRMS (FAB+): m/z calcd for C₇H₉DN₂: 123.0907; found: 123.0910.

6

Preparation of DMAP ( S )-1a by Bromine-Magnesium Exchange.
DMAP 1a is prepared according to the procedure reported in ref. 5 by means of (1R,2S,5R)-(-)-(S)-menthyl p-toluene-sulfinate (1.45 g, 4.91 mmol) as electrophile in the quench-ing step of the procedure. The residue was chromato-graphed on silica gel using EtOAc as eluent to afford 1a in 60% yield. ¹H NMR (300 MHz, CDCl₃): δ = 8.74 (s, 1 H), 8.27 (d, 1 H, J = 6 Hz), 7.37 (d, 2 H, J = 8 Hz), 7.17 (d, 2 H, J = 8 Hz), 6.56 (d, 1 H, J = 6 Hz), 2.95 (s, 6 H), 2.30 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.3, 42.2, 109.7, 124.4, 127.3, 128.9, 140.2, 140.5, 148.4, 150.8, 154.2. IR (KBr): 1580, 1407, 1096, 1073, 1044, 957, 813 cm^-1. HRMS (FAB+): m/z calcd for C₁₄H₁₆N₂OS: 260.0903; found: 260.0907. [α]_D ²⁰ -323 (c 0.011, CH₂Cl₂). Following the same procedure, the chiral DMAP (R)-1a was prepared using (1R,2S,5R)-(-)-(R)-menthyl p-toluenesulfinate. The optical purity of the DMAP 1a was established by chiral HPLC analysis using a Chiralcelpak AD (250 × 4.6 mm; 10 µm). Chromatographic conditions: injection: 20 µL (0.5 mg of a racemic mixture of 1a in 10 mL of heptane). Eluent: heptane-2-PrOH, 80:20. Flow rate: 1 mL/min. Pressure:
300 psi. Temperature: 22 °C. UV detection: λ = 254 nm. Retention time: 16.9 min (R-enantiomer) and 20.9 min
(S-enantiomer).

7

Typical Procedure for Catalytic Kinetic Resolution of Secondary Alcohols. To a solution of catalyst 1a (13 mg, 0.05 mmol), 1-(2-methoxyphenyl)ethanol (3c, 152 mg, 1 mmol), Et₃N (86 µL, 0.6 mmol) in CH₂Cl₂ (5 mL) was added Ac₂O (57 µL, 0.6 mmol) at -78 °C. The reaction mixture was stirred at this temperature for 18 h after which time 100 µL was removed from the reaction mixture via a syringe and poured immediately in MeOH (2 mL). The conversion and the ee of both the alcohol and the acetate were determined by analytical chiral GC (Chiraldex CB 25 m × 0.25) of the resulting methanolic solution.

8 Kagan HB. Fiaud JC. Top. Stereochem.  1998,  249