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.

Key words

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

3

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

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.