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

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.

aldehydes - aldol reactions - ketones - proline catalysis - water

References

1a Sakthivel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 

1b List B. Lerner RA. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 

1c List B. Pojarliev P. Castello C. Org. Lett.  2001,  3:  573 

1d Notz W. List B. J. Am. Chem. Soc.  2000,  122:  7386 

1e Córdova A. Notz W. Barbas CF. Chem. Commun.  2002,  3024 

1f For a review of proline-catalyzed asymmetric reactions, see: List B. Tetrahedron  2002,  58:  5573 

Only one proline molecule is involved in the transition state:

2a Hoang L. Bahmanyar S. Houk KN. List B. J. Am. Chem. Soc.  2003,  125:  16 

2b For density functional studies of the mechanism and quantum mechanical predictions of the stereoselectivities, see: Arnó M. Domingo LR. Theor. Chem. Acc.  2002,  108:  232 

2c Rankin KN. Gauld JW. Boyd RJ. J. Phys. Chem.  2002,  106:  5155 

2d Bahmanyar S. Houk KN. Martin HJ. List B. J. Am. Chem. Soc.  2003,  125:  2479 

3 See for example: Zhong G. Lerner RA. Barbas CF. Angew. Chem. Int. Ed.  1999,  38:  3738 ; and references therein

4a Guthrie JP. Cossar J. Taylor KF. Can. J. Chem.  1984,  62:  1958 

4b Guthrie JP. Wang X.-P. Can. J. Chem.  1992,  70:  1055 

5a Seebach D. Boes M. Naef R. Schweizer B. J. Am. Chem. Soc.  1983,  105:  5390 

5b Orsini F. Pelizzoni F. Forte M. Sisti M. Bombieri G. Benetollo F. J. Heterocycl. Chem.  1989,  26:  837 

5c Rizzi GP. J. Org. Chem.  1970,  35:  2069 

5d Orsini F. Pelizzoni F. Forte M. Destro R. Gariboldi P. Tetrahedron  1988,  44:  519 

6a Hayashi T. Tetrahedron Lett.  1991,  32:  5369 

6b Ward DE. Sales M. Sasmal PK. Org. Lett.  2001,  3:  3671 

6c Ward DE. Sales M. Man CC. Shen J. Sasmal PK. Guo C. J. Org. Chem.  2002,  67:  1618 

6d Karisalmi K. Rissanen K. Koskinen AMP. Org. Biomol. Chem.  2003,  1:  3193 

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).

12a The assignment of the stereochemistry of 5a and 5b is based on the ¹H NMR coupling constants of the COCHCH(OH)Ph proton of the product (400 MHz, CDCl₃), characteristic shifts of 5a: δ = 4.90 [d, J = 9.9 Hz, 1 H, COCHCH(OH)Ph], 2.61 [br ddd, J = 9.9, 6.0, 4.9 Hz, 1 H, COCHCH(OH)Ph]; shifts of 5b: δ = 5.19 [d, J = 4.9 Hz, 1 H, COCHCH(OH)Ph], 2.68 [br q, J = 5 Hz, 1 H, COCHCH(OH)Ph)], indicating that the cyclohexanone ring does not adopt the chair conformation, as would be expected for the equatorial products. The major products also do not match the data reported for the corresponding equatorial product, see: Busch-Petersen J. Corey EJ. Tetrahedron Lett.  2000,  41:  6941 

12b

In addition, the stereochemical model presented in ref. [2d] clearly predicts an axial attack of the carbonyl electrophile to the enamine intermediate. Only minor amounts (<5% each) of the corresponding equatorial isomers were formed.

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; τ_minor = 26.1 min; τ_major = 20.7 min, λ = 254 nm). R_f (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; τ_minor = 40.8 min; τ_major = 31.0 min, λ = 254 nm). R_f (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.

14a A slight erosion in the diastereopurity of the product (12:1 to 8:1 anti:syn) was observed during the purification of the product by preparative TLC. The spectroscopic data of 8 match those reported earlier by Paterson and co-workers. See: Paterson I. Wallace DJ. Cowden CJ. Synthesis  1998,  639 

14b

[α]_D ²³ +29 (c 1.0, CHCl₃, 96% ee, 8:1 anti:syn), lit.: [α]_D ²³ +12.3 (c 0.6, CHCl₃).

15a

l-Proline is not racemized in this process (see ref. [5a] ). Very recently, List and co-workers [15b] have reported that ketones may also condense with proline to form the oxazolidinones. Our inability to detect these ketone-derived oxazolidinones may simply reflect the fact that the equilibrium constants for oxazolidinone formation are higher with aldehydes than with ketones. The observation by List et al. that cyclohexanone forms the oxazolidinone with an equilibrium constant ca. five times that of acetone (0.68 vs. 0.12) fits very nicely with our observations that the effect of added water is more dramatic with cyclic ketones such as 4-thianone.

15b List B. Hoang L. Martin HJ. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5839 

16

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

17a Itoh T. Yokoya M. Miyauchi K. Nagata K. Ohsawa A. Org. Lett.  2003,  5:  4301 

17b In contrast with these results, related proline-catalyzed Mannich reactions with glyoxylate-derived imine electrophiles were not improved by the addition of water. See: Notz W. Tanaka F. Watanabe S.-i. Chowdari NS. Turner JM. Thayumanavan R. Barbas CF. J. Org. Chem.  2003,  68:  9624 

18 Brown SP. Goodwin NC. MacMillan DWC. J. Am. Chem. Soc.  2003,  125:  1192 

19 Torii H. Nakadai M. Ishihara K. Saito S. Yamamoto H. Angew. Chem. Int. Ed.  2004,  43:  1983 

20 4-Thianone is an excellent surrogate for 3-pentanone, which is unreactive under proline catalysis (see ref.). For an earlier example of the 4-thianone strategy in polypropionate synthesis, see: Woodward RB. Logusch E. Nambiar KP. Sakan K. Ward DE. Au-Yeung B.-W. Balaram P. Browne LJ. Card PJ. Chen CH. Chênevert RB. Fliri A. Frobel K. Gais H.-J. Garrat DG. Hayakawa K. Heggie W. Hesson DP. Hoppe D. Hoppe I. Hyatt JA. Ikeda D. Jacobi PA. Kim KS. Kobuke Y. Kojima K. Krowicki K. Lee VJ. Leutert T. Malchenko S. Martens J. Matthews RS. Ong BS. Press JB. Rajan Babu TV. Rousseau G. Sauter HM. Suzuki M. Tatsuta K. Tolbert LM. Truesdale EA. Uchida I. Ueda Y. Uyehara T. Vasella AT. Vladuchick WC. Wade PA. Williams RM. Wong HN.-C. J. Am. Chem. Soc.  1981,  103:  3210