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Synlett 2006(18): 3100-3104  
DOI: 10.1055/s-2006-949624
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Functionalized Δ3-Pyrrolines via a Ag(I)-Catalyzed Cyclization of Amino Acid Derived Allenes

Branko Mitasev, Kay M. Brummond*
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Fax: +1(412)6248611; e-Mail: kbrummon@pitt.edu;
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Publication History

Received 19 April 2006
Publication Date:
04 August 2006 (online)

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Abstract

Diversity-oriented synthesis (DOS) of a collection of novel, highly functionalized Δ3-pyrrolines has been accomplished by a AgNO3-catalyzed cyclization reaction of allenic amino acids that proceeds with transfer of chiral information. A new mode of cyclization of allenic benzoyl-protected amines in the Ag(I)-catalyzed reaction leading to oxazines was observed.

Key words

pyrrolines - allene - cyclization - silver catalysis - amino acid - oxazine

    References and Notes

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  • 16a

    Sample Procedure for Benzamide Deprotection.
    Et3OBF4 (Meerwein’s reagent) was prepared as described previously [16b] and stored as a 1.0 M solution in CH2Cl2. Benzamide 1a (6.32g, 25.8 mmol) was dissolved in CH2Cl2 (250 mL) and Et3OBF4 (129 mL, 129.0 mmol of a 1.0 M solution in CH2Cl2) was added via cannula under N2 atmosphere. The reaction mixture was heated to reflux for 2 h when the formation of ethyl imidate was complete. The solvent was then removed under vacuum, and the resulting brown residue was dissolved in THF (100 mL) and H2O (100 mL) and glacial AcOH (5 mL) was added. The reaction mixture was stirred at r.t. for 12 h. Upon completion of the hydrolysis, HCl (300 mL of a 1.0 M solution) was added and the aqueous layer was extracted with Et2O (3 × 100 mL) to remove all non-amine organic impurities. The aqueous layer was then carefully basified using NaHCO3 to prevent foaming and extracted with Et2O (3 × 150 mL). The organic layer was dried over MgSO4, and concentrated under vacuum to afford a colorless oil which was purified by column chromatography (gradient elution, 5:1 to 1:1 hexanes-EtOAc, v/v) to afford 12a (2.81 g, 77%).

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13

Isolated yields were ca. 60-70%. The NMR yield was determined by performing the reaction in acetone-d 6 with mesitylene as an internal standard.

14

A mechanistic depiction of the chirality transfer in this reaction has been presented in ref. 9b.

15

The crystallographic data (cif file) were submitted to the Cambridge Crystallographic Data Centre (CCDC 607952).

17

Sample Procedure for AgNO 3 -Catalyzed Cyclization. In a 100-mL round-bottomed flask equipped with a stirring bar, the allenic amine 12d (1.86 mmol, 1 equiv) was added, followed by acetone (36 mL). The flask was then wrapped in aluminum foil to limit exposure to light, sealed with a rubber septum and N2 was bubbled through the stirred solution for 5 min. Then, AgNO3 (0.37 mmol, 0.2 equiv) was weighed in the dark and added to the solution and the reaction mixture was stirred for 1 h at r.t. Upon completion, the acetone was removed under vacuum, and the crude residue was redissolved in CH2Cl2 (100 mL). The light brown solution was washed with sat. aq NaHCO3 (2 × 50 mL), then dried over MgSO4 and concentrated under vacuum to afford the 3-pyrroline 13d in quantitative yield.
Compound 13d: 1H NMR (300 MHz, CDCl3): δ = 7.45-7.20 (m, 5 H), 5.92 (dd, J = 5.8, 1.5 Hz, 1 H), 5.86 (dd, J = 5.7, 1.4 Hz, 1 H), 4.08-4.01 (m, 1 H), 3.79 (s, 3 H), 3.35 (d, J = 14.0 Hz, 1 H), 3.09 (d, J = 14.0 Hz, 1 H), 1.11 (d, J = 6.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 175.1, 136.7, 136.0, 130.0, 129.8, 127.7, 126.3, 77.0, 60.6, 52.0, 45.4, 22.0. IR (thin film): 3350, 2957, 1734, 1455, 1257 cm-1. MS: m/z (%) = 232 (25), 172 (80), 141 (75), 108 (57), 51 (100). HRMS (EI): m/z calcd for C12H14N [M - 59+]: 172.1126; found: 172.1133.

18

Sample Procedure for N-Acylation. To a solution of the amine 13d (1.03 mmol, 1 equiv) in CHCl3 (20 mL) was added Et3N (3.09 mmol, 3 equiv) and acetyl chloride (2.06 mmol, 2 equiv) at r.t., under N2 atmosphere. The reaction mixture was stirred for 2 h. The solution was then diluted with CHCl3 (100 mL), and washed with sat. aq NaHCO3 (50 mL), sat. aq NH4Cl (50 mL), dried over MgSO4 and concentrated under vacuum. Purification by flash chromatography (gradient elution, 4:1 to 1:1 hexane-EtOAc, v/v) afforded the N-acylated 3-pyrroline 14a in 61% yield.
Compound 14a: 1H NMR (300 MHz, CDCl3): δ = 7.20-7.15 (m, 3 H), 7.01-6.98 (m, 2 H), 5.59 (0.5 ABq, J = 8.0 Hz, 1 H), 5.56 (0.5 ABq, J = 8.0 Hz, 1 H), 3.95 (d, J = 13.8 Hz, 1 H), 3.89 (q, J = 6.3 Hz, 1 H), 3.74 (s, 3 H), 3.11 (d, J = 13.8 Hz, 1 H), 2.01 (s, 3 H), 1.29 (d, J = 6.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 171.6, 168.8, 136.3, 133.6, 130.5, 127.7, 127.4, 126.2, 77.3, 61.6, 52.5, 37.1, 22.4, 21.0. IR (thin film): 3067, 1732, 1643, 1409 cm-1. MS: m/z (%) = 273 (8), 214 (10), 172 (29), 140 (100), 91 (70). HRMS (EI): m/z calcd for C14H16NO: [M - 59+]: 214.1232; found: 214.1231.

19

Sample Procedure for Methyl Ester Hydrolysis. To a solution of the methyl ester 14a (0.24 mmol, 1 equiv) in THF (3 mL) was added H2O (3 mL), followed by LiOH·H2O (10 equiv) at r.t., and the homogeneous reaction mixture was stirred for 8 h. Upon completion, the reaction mixture was acidified with 1 M HCl and extracted with EtOAc (2 × 50 mL). Upon removal of solvent under vacuum the desired acid was obtained in quantitative yield and sufficient purity to be used in the next step.

20

Sample Procedure for the Preparation of Amides 15a-f. To a solution of the carboxylic acid (0.077 mmol, 1 equiv) in CH2Cl2 (2 mL) at r.t., under N2 atmosphere, were added the amine (0.16 mmol, 2.1 equiv), 4-(dimethylamino)pyridine (0.084 mmol, 1.1 equiv), 1-hydroxybenzothiazole (0.084 mmol, 1.1 equiv) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide HCl (0.16 mmol, 2.1 equiv) in this order. The reaction was stirred at r.t. for 2 h, and then diluted with EtOAc (75 mL). The solution was washed with sat. aq NH4Cl, 1 M HCl and brine, then dried over MgSO4 and concentrated under vacuum. Purification by flash chroma-tography (gradient elution, 3:1 to 1:1 hexane-EtOAc, v/v) afforded 15a in 95% yield.
Compound 15a 1H NMR (300 MHz, CDCl3): δ = 8.12 (br s, 1 H), 7.27-7.05 (m, 5 H), 5.91 (dd, J = 6.3, 1.8 Hz, 1 H), 5.59 (dd, J = 6.3, 2.0 Hz, 1 H), 4.15 (dd, J = 18.2, 5.9 Hz, 1 H), 4.00 (d, J = 13.8 Hz, 1 H), 4.03-3.98 (m, 1 H), 3.98 (dd, J = 18.2, 4.9 Hz, 1 H), 3.75 (s, 3 H), 3.18 (d, J = 13.8 Hz, 1 H), 2.11 (s, 3 H), 1.30 (d, J = 6.3 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 173.1, 171.3, 170.3, 135.9, 130.6, 130.3, 130.2, 127.6, 126.5, 79.9, 62.9, 52.2, 41.4, 37.5, 23.2, 22.0. IR (thin film): 3428, 2952, 1752, 1654, 1396 cm-1. MS: m/z (%) = 330 (25), 299 (15), 214 (91), 172 (75), 91 (100). HRMS (EI): m/z calcd for C18H22N2O4 [M+]: 330.1580; found: 330.1584.