Enantioselective Organocatalytic Diels Aminations: α-Aminations of Cyclic β-Keto Esters and β-Keto Lactones with Cinchonidine and Cinchonine

Abstract

Catalytic enantioselective α-amination reactions of β-keto esters and β-keto lactones with dibenzyl azodicarboxylate are catalyzed by cinchona alkaloids, affording the products in up to 99% yield and 90% ee.

aminations - β-keto esters - organocatalysis - cinchona alkaloids - enantioselectivity

References

1a Diels O. Liebigs Ann. Chem.  1922,  429:  1 

1b Diels O. Behncke H. Chem. Ber.  1924,  57:  653 

1c See also: Huisgen R. Jakob F. Liebigs Ann. Chem.  1954,  590 

1d For a recent review of asymmetric electrophilic α-aminations of carbonyl compounds, see: Greck C. Drouillat B. Thomassigny C. Eur. J. Org. Chem.  2004,  1377 

2a Marigo M. Juhl K. Jørgensen KA. Angew. Chem. Int. Ed.  2003,  42:  1367 

2b For a related auxiliary-controlled α-amination reaction using a Ru catalyst, see: Lumbierres M. Marchi C. Moreno-Mañas M. Sebastián RM. Vallribera A. Lago E. Molins E. Eur. J. Org. Chem.  2001,  2321 

3a List B. J. Am. Chem. Soc.  2002,  124:  5656 

3b Bøgevig A. Juhl K. Kumaragurubaran N. Zhuang W. Jørgensen KA. Angew. Chem. Int. Ed.  2002,  41:  1790 

3c Vogt H. Vanderheiden S. Bräse S. Chem. Commun.  2003,  2448 

4 Kumaragurubaran N. Juhl K. Zhuang W. Bøgevig A. Jørgensen KA. J. Am. Chem. Soc.  2002,  124:  6254 

5a During the preparation of this manuscript, Jørgensen and co-workers reported a similar approach to α-aminations of β-keto esters using a quinidine-derived β-isocupreidine catalyst: Saaby S. Bella M. Jørgensen KA. J. Am. Chem. Soc.  2004,  126:  8120 

5b

With substrates 1 and 5, the enantioselectivities obtained with cinchonine were similar to those obtained by Jørgensen with di-tert-butyl azodicarboxylate for similar substrates; however, the reaction rates were much faster in the present study.

6

General Experimental Procedure. To a solution of the azodicarboxylate (32.0 mg, 0.105 mmol, 105 mol%) in CH₂Cl₂ (1 mL) at -25 °C was added the β-keto ester or β-keto lactone substrate (0.1 mmol, 100 mol%) and the catalyst (0.02 mmol, 20 mol%). The resulting yellow solution was stirred at this temperature until the yellow color of the azodicarboxylate faded and the reaction was judged complete by TLC. The reaction mixture was partitioned between CH₂Cl₂ (3-5 mL) and 0.5 M HCl (2 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 1 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated to give the crude product which was typically >90-95% pure by ¹H NMR but could be purified further by flash chromatography.
Basification of the aqueous layer (1 M NaOH) and extraction with CH₂Cl₂ afforded the recovered catalyst in quantitative yield and >90% purity.

7

The racemic samples were prepared either with KOAc catalyst or by a mixing the cinchonine- and cinchonidine-derived products.

8

All new compounds gave satisfactory analytical and spectral data. Selected characterization data:
N , N ′-Bis(benzyloxycarbonyl)-1-hydrazino-2-oxocyclo-pentanecarboxylic acid, ethyl ester (Table [2] , entry 3): Colorless glass, R _f = 0.46 (1:1 MTBE-hexanes); [α]_D +2.0 (c = 1.1, CH₂Cl₂, 88% ee); lit.^2a [α]_D +3.7 (c 1.1, CH₂Cl₂, 99% ee). IR (thin film): 3307, 3034, 2962, 1728, 1498, 1455, 1399, 1343, 1224, 1118, 1027, 742, 697 cm^-1. ¹H NMR (400 MHz, d ₂-tetrachloroethane, 80 °C): δ = 7.35-7.29 (m, 10 H), 6.80 (s, 1 H), 5.14 (d, 4 H, J = 7.7 Hz), 4.18 (q, 2 H, J = 7.1 Hz), 2.68 (m, 2 H), 2.46 (m, 1 H), 2.34 (m, 1 H), 2.16 (m, 1 H), 1.95 (m, 1 H), 1.22 (t, 3 H, J = 7.1 Hz). ¹³C NMR (100 MHz, d ₂-tetrachloroethane, 80 °C): δ = 205.6 (br), 167.4, 155.5, 155.2, 135.3, 135.1, 128.3, 128.26, 128.1, 128.06, 127.7, 127.6, 76.3, 68.5, 67.6, 62.1, 36.4, 33.1, 18.2, 13.7. The enantioselectivity was determined by HPLC (Daicel Chiralcel AS, 20% i-PrOH in hexanes, 1 mL/min, λ = 254 nm, τ_major = 17.2 min, τ_minor = 36.1 min.
N , N ′-bis(benzyloxycarbonyl)-2-hydrazino-2-acetyl-γ-butyrolactone (Table [2] , entry 10): Colorless glass, R _f = 0.46 (1:1 MTBE-hexanes); [α]₅₄₆ -0.3 (c = 3.0, CHCl₃, 42% ee). IR (thin film): 3307, 3034, 1726, 1498, 1456, 1399, 1342, 1220, 1184, 1027, 744, 697 cm^-1. ¹H NMR (400 MHz, d ₂-tetrachloroethane, 90 °C): δ = 7.40-7.29 (m, 10 H), 6.93 (s, 1 H), 5.22-5.11 (m, 4 H), 4.36 (dt, 1 H, J = 3.8, 8.9 Hz), 4.27 (q, 1 H, J = 8.1 Hz), 3.19 (ddd, 1 H, J = 3.8, 7.6, 13.3 Hz), 2.77 (m, 1 H), 2.30 (s, 3 H). ¹³C NMR (100 MHz, d ₂-tetrachloroethane, 90 °C): δ = 196.7, 168.7, 155.5, 154.9, 135.0, 134.6, 128.3, 127.8, 127.7, 77.8, 69.1, 68.2, 66.4, 29.1, 24.1. HRMS (ESI+): m/z calcd for C₂₂H₂₂N₂O₇Na [M + Na]⁺: 449.1325; found: 449.1321, Δ = 0.8 ppm. The enantioselectivity was determined by HPLC (Chiralcel OD, 3% i-PrOH in hexanes, 1 mL/min, λ = 254 nm, τ_major = 106 min, τ_minor = 124 min.

9

In addition to 3, α-methyl, α-benzyl and α-allyl-substituted ethyl acetoacetates were also screened as substrates, all affording the products in good yields (70-85%) but poor enantioselectivity (<35% ee).

10 Compound 4 was readily prepared by transesterification from 1 (BnOH, 175 °C). See: Taniguchi M. Koga K. Yamada S. Chem. Pharm. Bull.  1972,  20:  1438 

11

Compounds 7 and 8 were obtained by acylation of γ-buty-rolactone [LDA, THF, -78 °C, then isobutyroyl chloride (7) or pivaloyl chloride (8)].

12 Brown HC. Brewster JH. Shechter H. J. Am. Chem. Soc.  1954,  76:  467 

13 Hoffmann RW. Chem. Rev.  1989,  89:  1841 

14

Control experiments with 20 mol% 6-methoxyquinoline and quinoline showed that these alone are poor catalysts for the reaction. Presumably, both the basic amine moiety and the free OH group are required for effective catalysis. Studies are in progress to determine the full mechanistic picture of these reactions.