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Synlett 2010(8): 1227-1230  
DOI: 10.1055/s-0029-1219830
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Acyl Radicals from Nitriles Promoted by Cp2TiCl in β-Lactam Chemistry

Laura M. Monleón, Manuel Grande*, Josefa Anaya
Departamento de Química Orgánica, Universidad de Salamanca, 37008 Salamanca, Spain
e-Mail: mgrande@usal.es;
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Publication History

Received 16 February 2010
Publication Date:
15 April 2010 (online)

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Abstract

In order to synthesize new tricyclic β-lactams we have studied the reactivity of 4-alkenylepoxy-N-(1-cyano-1-dimethylethyl)-2-azetidinones with Cp2TiCl. The desired trilactams were not formed at all but an unsaturated nitrile and an aldehyde were obtained instead. Under similar reaction conditions, the treatment of styrylnitrile with Cp2TiCl afforded the styrylaldehyde. The formation of aldehydes in these reactions suggest the generation of acyl radicals from nitriles mediated by Cp2TiCl.

Key words

acyl radical - radical reduction of nitriles - titanocene monochloride - epoxynitrile-2-azetidinones

    References and Notes

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6

Epoxynitriles (Z/E)-1 were prepared by Staudinger reaction between methoxyacetyl chloride in the presence of Et3N and the imine prepared from 2,2-demethylaminoethanol and citral, followed by several functional-group conversion reactions and finally, selective epoxidation of the C9-C10 double bond with MCPBA at -25 ˚C. The C-9 stereochemistry in the epoxynitriles (Z/E)-1 could not be determined by ¹H NMR data.

8

Typical Procedure for the Reactions with Titanocene Monochloride
Method A (Inverse Addition)
A 0.058 M solution of the specific epoxide (1.0 mmol) in anhyd THF (17.0 mL) was added dropwise to a 0.176 M green suspension of Cp2TiCl, generated from titanocene dichloride (548 mg, 2.2 mmol) and activated zinc granules (262 mg, 4.0 mmol), in anhyd and strictly deoxygenated THF (12.5 mL). The reaction mixture was stirred at r.t. until a color change from green to orange was observed, and then the reaction was quenched with 10% v/v aq KH2PO4 (30.0 mL). The aqueous phase was extracted with EtOAc, and the organic combined extracts were filtered through Celite®, dried (over anhyd Na2SO4), and concentrated in vacuo. The crude material obtained was purified by column chromatography on silica gel. Method B (Direct Addition)
The green suspension of Cp2TiCl in THF, prepared as in method A, was added to the solution of the epoxide in THF, and the reaction mixture was then treated as in method A.
Selected Data for Compounds ( E )-2, ( E )-3, and 5
Compound (E)-2: R f = 0.30 (hexanes-EtOAc, 1:1). IR: ν = 3479, 3080, 2238, 1766 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.48 (3 H, s), 1.51 (3 H, s), 1.60-1.85 (2 H, m), 1.69 (3 H, s), 1.77 (3 H, s), 2.10-2.35 (2 H, m), 3.38 (3 H, s), 4.03 (1 H, dd, J = 6.8, 13.6 Hz), 4.46 (1 H, d, J = 4.9 Hz), 4.59 (1 H, dd, J = 4.9, 9.5 Hz), 4.80 (1 H, s), 4.90 (1 H, s), 5.34 (1 H, d, J = 9.5 Hz) ppm. ¹³C NMR (50 MHz, CDCl3): δ = 16.4, 16.6, 25.9, 26.5, 28.5, 36.4, 49.6, 56.2, 58.4, 77.3, 83.8, 111.0, 118.9, 119.7, 143.5, 147.2, 165.8 ppm. HRMS (Q-TOF): m/z calcd for C17H26N2O3Na [M+ + 23]: 329.1836; found: 329.1871.
Compound ( E )-3: R f = 0.22 (hexanes-EtOAc, 1:1). IR: ν = 3447, 3080, 1750, 1730 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.34 (3 H, s), 1.36 (3 H, s), 1.55-1.80 (2 H, m), 1.70
(6 H, s), 2.00-2.20 (2 H, m), 3.39 (3 H, s), 4.00 (1 H, dd, J = 5.8, 11.5 Hz), 4.49 (1 H, d, J = 4.5 Hz), 4.52 (1 H, dd, J = 4.5, 11.7 Hz), 4.82 (1 H, s), 4.92 (1 H, s), 5.29 (1 H, d, J = 11.7 Hz), 9.50 (1 H, s) ppm. ¹³C NMR (50 MHz, CDCl3): δ = 16.6, 17.6, 20.4, 20.7, 32.7, 35.7, 55.3, 58.3, 62.9, 75.1, 83.6, 111.0, 119.8, 142.9, 147.2, 167.1, 198.7 ppm. HRMS (Q-TOF): m/z calcd for C17H27NO4Na [M+ + 23]: 332.1970; found: 332.1975.
Compound 5: The physical data of aldehyde 5 were in agreement with those previously reported for this compound.²c