Enantioselective Brønsted Acid Catalyzed Addition Reactions of ­Methyleneaminopyrrolidine to Imines

Abstract

A new series of BINOL-derived multidentate Brønsted acid catalysts has been developed for the enantioselective addition of the d¹-synthon, methyleneaminopyrrolidine, to N-Boc imines, yielding the versatile, protected α-aminohydrazone intermediates in moderate to good ee.

organocatalysis - hydrogen bond donor - imines - hydrazone - asymmetric synthesis

References

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4a Sigman MS. Vachal P. Jacobsen EN. Angew. Chem. Int. Ed.  2000,  39:  1279 

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11

The formation of undesired hydrazono transfer products has previously been reported by Fernandez and Lassaletta. [10] Their formation is thought to occur via a [2+2], retro-[2+2] cycloaddition sequence (Scheme [3] ).

12

Catalysts 17a, 18a and 18b were kindly donated by Isabel Villaneuva Margalef.

13 Taft RW. Kamlet MJ. J. Am. Chem. Soc.  1976,  2886 

14

Reactions were carried out in CDCl₃ to allow us to monitor the progress of the reactions. Reactions with imines 11 and 20c have also been carried out in CHCl₃, with no observable deleterious effect on yield or ee.

15 All imine substrates were made using the procedure reported by Jacobsen: Wenzel AG. Jacobsen EN. J. Am. Chem. Soc.  2002,  124:  12964 

16

Absolute stereochemistry of adduct 16 was determined by the synthesis of a matched compound from (S)-N-Boc-phenylglycine and comparing retention times on chiral stationary phase HPLC. The absolute stereochemistry of all other adducts was assigned by analogy.

17

General Procedure for the Addition of 1-Methylene-aminopyrrolidine ( 2) to N -Boc Imines Catalyzed by 19a.
To a solution of N-Boc imine (0.25 mmol, 2 equiv) and catalyst 19a (16 mg, 0.025 mmol, 0.2 equiv) in CDCl₃ (0.5 mL) at r.t. was added 2 (12 mg, 0.125 mmol, 1 equiv). After the reaction was observed to have gone to completion by NMR, volatiles were removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with hexane-acetone (100:1 to 3:1). This method was used to prepare compound 16.
( R )-1-Phenyl-2-(pyrrolidin-1-ylimino)ethylcarbamic Acid tert -Butyl Ester ( 16).
Yield 33 mg, 0.11 mmol, 87% from benzaldehyde N-(tert-butoxycarbonyl)imine (11) as a white solid; [α]_D ²⁵ -20.0
(c 0.13, CHCl₃). Analytical Chiral HPLC (Daicel CHIRALCEL OD, 25 cm ¥ 0.46 cm dia., 254 nm), hexane-i-PrOH (98:2, 1.0 mL/min); t _R = 7.08 min (591.2 mAu s), 7.76 min (142.7 mAu s) gives 63% ee. ¹H NMR (400 MHz, CDCl₃): δ = 7.33 (2 H, m), 7.32 (2 H, m), 7.25 (1 H, td, J = 8.0, 4.6 Hz), 6.47 (1 H, br s), 6.04 (1 H, br s), 5.25 (1 H, br s), 3.14 (4 H, t, J = 6.6 Hz), 1.88 (4 H, m), 1.41 (9 H, br s). ¹³C NMR (100 MHz, CDCl₃): δ = 155.1, 141.4, 132.9, 128.6, 127.3, 127.0, 79.3, 56.5, 51.3, 28.4, 23.2. IR (film): 3347 (br, N-H), 1701 (C=O), 1602 (Ar) cm^-1. MS (ESI-H⁺): m/z calcd for C₁₇H₂₆N₃O₂ ⁺: 304.2025. Found: 304.2025. Mp 72 °C. General Procedure for the Synthesis of the BIMBOL Catalyst 19a,c,d.
To a solution of (S)-MOM-BINOL (0.5 g, 1.34 mmol), in THF (4 mL) under argon at -78 °C, was added dropwise n-BuLi (2 mL, 1.6 M in hexane, 3.21 mmol, 2.4 equiv). The reaction mixture was allowed to warm to 0 °C over 2 h and a solution of the appropriate benzophenone (2.94 mmol, 2.2 equiv) in THF (6 mL) was added dropwise. The reaction mixture was stirred at r.t. for 2 h then quenched with sat. aq NH₄Cl (10 mL). The reaction mixture was washed with H₂O (10 mL) and the organic layer was extracted with Et₂O (2 ¥ 10 mL). The combined organic layers where washed with brine (20 mL) and dried over MgSO₄. The solvent was removed in vacuo. The resulting solid was washed with petroleum ether (bp 40-60 °C)-Et₂O (9:1) to yield a white solid. Without further purification, this was dissolved in dioxane (15 mL), and heated at 55 °C under N₂. Then, concd aq HCl (2.7 mL) was added dropwise and the reaction mixture was stirred for 3 h and then quenched with H₂O (10 mL), extracted with Et₂O (20 mL), washed with brine (15 mL) and dried over MgSO₄. The solvent was removed in vacuo, and the resulting solid was purified by flash column chromatography on silica gel eluting with hexane-EtOAc (20:1 to neat EtOAc). This method was used to prepare the following: ( S )-3,3′-Bis(hydroxydiphenylmethyl)-[1,1′]-binaphthalenyl-2,2′-diol ( 19a).
Yield 71% over two steps from benzophenone as a white solid; [α]_D ²⁵ -89.0 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (2 H, dd, J = 9.2, 1.9 Hz), 7.36-7.24 (24 H, m), 7.14 (2 H, s), 7.09 (2 H, dd, J = 9.0, 1.8 Hz), 6.61 (2 H, s), 4.59 (2 H, s). Mp 156-158 °C.
( S )-3,3′-Bis[bis-(2-chlorophenyl)hydroxymethyl]-[1,1′]-binaphthalenyl-2,2′-diol ( 19c). Yield 36% over two steps from 2,2′-dichlorobenzophenone as a white solid; [α]_D ²⁵ -156.0 (c 0.05, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.70-7.61 (10 H, m), 7.50-7.42 (8 H, m), 7.40-7.35 (4 H, m), 7.33-7.17 (4 H, m), 6.67 (2 H, br s), 4.76 (2 H, br s). ¹³C NMR (100 MHz, CDCl₃): δ = 152.1, 140.4, 139.9, 134.2, 133.4, 132.5, 132.0, 131.7, 131.6, 131.1, 130.9, 129.9, 129.8, 128.9, 128.7, 127.9, 127.2, 126.9, 126.4, 124.6, 123.6, 117.7, 85.4. IR (film): 3497 (br, O-H), 3056 (s, O-H), 1622 (Ar), 1598 (Ar) cm^-1. MS (ESI): m/z calcd for C₄₆H₃₀O₄Cl₄Na: 809.0771. Found: 809.0790. Mp 160-162 °C. ( S )-3,3′-Bis[bis-(3-methoxyphenyl)hydroxymethyl]-[1,1′]binaphthalenyl-2,2′-diol ( 19d).
Yield 56% over two steps from 3,3′-bismethoxybenzo-phenone as a white solid; [α]_D ²⁵ -104.0 (c 0.93, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (2 H, d, J = 7.6 Hz), 7.29-7.20 (8 H, m), 7.19 (2 H, s), 7.11 (2 H, d, J = 8.1 Hz), 6.95 (2 H, s), 6.94 (2 H, s), 6.87-6.80 (8 H, m), 6.62 (2 H, s), 4.77 (2 H, s), 3.74 (6 H, s), 3.71 (6 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 159.4, 151.1, 147.1, 146.8, 133.7, 133.2, 130.9, 128.9, 128.8, 128.3, 127.4, 124.2, 124.1, 120.5, 120.2, 114.1, 113.6, 113.5, 113.2, 113.0, 82.9, 55.2. IR (film): 3493 (br, O-H), 3311 (br, O-H), 1597 (Ar), 1583 (Ar) cm^-1. MS (ESI-NH₄ ⁺): m/z calcd for C₄₈H₄₂NO₄: 788.3218. Found: 788.3218. Mp 145-147 °C.