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Synlett 2004(11): 1891-1896  
DOI: 10.1055/s-2004-831296
LETTER
© Georg Thieme Verlag Stuttgart · New York

Proline-Catalyzed Ketone-Aldehyde Aldol Reactions are Accelerated by Water

Annika I. Nyberg, Annina Usano, Petri M. Pihko*
Laboratory of Organic Chemistry, Helsinki University of Technology, P.O.Box. 6100, FI-02015 HUT, Finland
Fax: +358(9)4512538; e-Mail: Petri.Pihko@hut.fi;
Further Information

Publication History

Received 8 April 2004
Publication Date:
06 August 2004 (online)

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Abstract

Proline-catalyzed aldol reactions between acetone or 4-thianone and different aldehydes are accelerated by addition of 1-10 equivalents of water to the reaction medium, allowing stoichiometric aldol reactions to proceed at acceptable rates.

Key words

aldehydes - aldol reactions - ketones - proline catalysis - water

    References

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7

General Experimental Procedure. To ensure that all reactions were performed under otherwise identical conditions, all reactions were conducted in flame-dried glassware under an argon atmosphere. DMF and DMSO were dried by distillation over 4 Å molecular sieves, and acetone was dried over anhyd CaSO4. To a mixture of 1 mL anhyd DMF or DMSO, ketone donor (1 mmol) and l-proline (10 mol% or 30 mol%) was added aldehyde (1 mmol) and H2O (0-1500 mol%). The flask was capped and the reaction mixture was stirred at r.t. under argon for 3-13 d. The reaction was then quenched with H2O (10 mL, Table [3] ) or with a sat. NH4Cl solution (10 mL, Table [1] and Table [2] ) and then extracted with Et2O (3 × 10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The pure aldol products were obtained by flash column chromatography [silica gel, pentane-Et2O (Table [1] ), hexane-EtOAc (Table [2] ) or hexane-MTBE (Table [3] )].

8

The racemic samples for the reactions with acetone, 4-tert-butylcyclohexanone and 4-thianone (entries 13-15, Table [3] ) as the donor were prepared by using racemic proline as catalyst. For other reactions with 4-thianone, the racemic samples were obtained using the procedure of Hayashi. [6a]

9

Reaction conditions: 14.0 mmol acetone, 0.5 mmol isobutyraldehyde, 30 mol% l-proline, 1 mL DMSO, r.t.,
50 h; 0 mol% H2O gave a conversion of 59% (ee 95%), 300 mol% H2O a conversion of 68% (ee 95%).

10

Reaction conditions: 27 mmol acetone, 1 mmol p-nitro-benzaldehyde, 20 mol% l-proline, 1 mL DMF, r.t., 24 h, 555 mol% (3 vol%) H2O; yield 90% (100% conversion), ee 76%. Previously, List and Barbas had obtained this aldol product in 68% yield and 76% ee in dry DMSO (see ref. [1a] [b] ).

11

As an example, under the List-Barbas conditions, the reactions with cyclohexanone and isobutyraldehyde require five days for reasonable yields (ref. [2d] ). It should be noted that the stoichiometric reactions with cyclohexanone and isobutyraldehyde were also accelerated (0% water: <30% conversion after 4 d; 300 mol% water: ca. 60% conversion).

13

All new compounds gave satisfactory analytical and spectral data. Selected characterization data: (3 S ,1′ S )-3-[(1′-hydroxy-2′-methyl)propyl]-tetrahydrothiopyran-4-one (Table 3, Entry 4): The ee was determined by HPLC (Chiralpak OD column, hexane-i-PrOH, 98:2, flow rate 0.7 mL/min; τminor = 26.1 min; τmajor = 20.7 min, λ = 254 nm). Rf (1:1, hexane-MTBE) = 0.27. [α]D 23 -72 (c 1.0, MeOH, 95% ee). 1H NMR: δ = 3.50 (t, J = 5.1 Hz, 1 H), 2.93-2.77 (m, 5 H), 2.70-2.65 (m, 2 H), 1.83-1.70 (m, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H). 13C NMR: δ = 212.4, 76.1, 55.7, 44.9, 33.5, 30.9, 29.9, 19.9, 16.0. IR (film): 3488, 2960, 2874, 1704, 1426, 1274, 990 cm-1. HRMS (ESI): m/z calcd for C9H16O2NaS: 211.0769. Found: 211.0762.
(3 S ,1′ R )-3-[(1′-hydroxy-1′-phenyl)methyl]-tetrahydrothiopyran-4-one (Table 3, Entry 10): The ee was determined by HPLC (Chiralpak OD column, hexane-i-PrOH, 90:10, flow rate 0.5 mL/min; τminor = 40.8 min; τmajor = 31.0 min, λ = 254 nm). Rf (1:1, hexane-MTBE) = 0.19. Mp 126-127 °C. [α]D 23 -73 (c 1.1, MeOH, 98% ee). 1H NMR: δ = 7.32-7.22 (m, 5 H), 4.90 (dd, J = 8.9, 3.0 Hz, 1 H), 3.34 (s, 1 H), 2.96-2.86 (m, 3 H), 2.78 (m, 1 H), 2.70 (m, 1 H), 2.49 (dd, J = 13.8, 9.9 Hz, 1 H), 2.44 (ddd, J = 13.8, 5.2, 1.8 Hz, 1 H). 13C NMR: δ = 211.8, 140.2, 128.7, 128.3, 126.9, 73.8, 59.7, 44.5, 32.9, 30.9. IR (KBr pellet): ν = 3421, 2914, 1690, 1426, 1275, 1051, 706 cm-1. Anal. calcd for C12H14O2S: C, 64.8%; H, 6.4%. Found: C, 64.4%; H, 6.3%. HRMS (ESI): m/z calcd for C12H14O2NaS: 245.0612. Found: 245.0605.

16

Reaction conditions: 1 mmol 4-thianone, 1 mmol iso-butyraldehyde, 1 mL DMF, r.t., 10 d.