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Synlett 2005(17): 2635-2638  
DOI: 10.1055/s-2005-917098
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Brønsted Acid Catalyzed Addition Reactions of ­Methyleneaminopyrrolidine to Imines

Darren J. Dixon*a, A. Louise Tillmanb
a School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Fax: +44(161)2754939; e-Mail: Darren.Dixon@manchester.ac.uk;
b University of Cambridge, University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK
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Publication History

Received 12 July 2005
Publication Date:
05 October 2005 (online)

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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.

Key words

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

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.

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.

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.