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Synlett 2009(15): 2437-2440  
DOI: 10.1055/s-0029-1217729
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Preparation of β-Lactams by Mannich-Type Addition of Ethyl(trimethyl­silyl)acetate (ETSA) to N-(2-Hydroxyphenyl)aldimine Sodium Salts

Vincent Gembus, Thomas Poisson, Sylvain Oudeyer*, Francis Marsais, Vincent Levacher*
COBRA (UMR6014) IRCOF, CNRS, Université et INSA de Rouen, BP08, 76131 Mont-Saint-Aignan Cedex, France
Fax: +33(235)522962; e-Mail: sylvain.oudeyer@insa-rouen.fr;
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Publication History

Received 12 June 2009
Publication Date:
27 August 2009 (online)

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Abstract

The synthesis of highly substituted β-lactams was achieved by addition of air-stable ethyl(trimethylsilyl)acetate derivatives to N-(2-hydroxyphenyl)aldimine sodium salts in a THF-EtCN mixture. This reaction proceeds with moderate to good yields and diastereomeric ratio of up to 78:22. The reactivity of the N-(2-hydroxyphenyl)aldimine can be modified by simply changing the co-solvent from EtCN to MeCN to afford the cyanomethylated addition product.

Key words

imines - lactams - silicon - phenols - tandem reactions

    References and Notes

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  • 10 Typical Procedure for the Preparation of 2b and 2c: To a solution of diisopropylamine (1.1 equiv) in anhyd THF was added n-BuLi (2.5 M in hexane, 1.1 equiv) dropwise at -78 ˚C under nitrogen. The solution was warmed to r.t. for 10 min, then cooled to -78 ˚C prior to addition of ETSA (1 equiv) dropwise over 5 min. The solution was maintained at -78 ˚C for further 1 h before addition of the electrophile (1.1 equiv for BnBr or 2 equiv for MeI). The resulting solution was warmed to r.t. and stirred until complete disappearance of the starting materials. Saturated aq NH4Cl solution was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine and then dried over anhyd MgSO4. The residue was purified by flash chromatography to afford the alkylated product.Spectral data of 2b were in agreement with those described in the literature: Kuwajima I. Matsumoto K. Inoue T. Chem. Lett.  1979,  8:  41.  Ethyl 2-Methyl-3-phenyl-2-(trimethylsilyl)propanoate (2c): colorless oil. Purification: SiO2; 0-2% EtOAc in PE; R f 0.73 (10% EtOAc in PE). ¹H NMR (300 MHz, CDCl3): δ = 0.00 (s, 9 H), 0.91 (s, 3 H), 1.09 (t, J = 7.2 Hz, 3 H), 2.33 (d, J = 13.4 Hz, 1 H), 3.40 (d, J = 13.4 Hz, 1 H), 3.96 (q, J = 7.0 Hz, 2 H), 6.97-7.10 (m, 5 H). ¹³C NMR (75 MHz, CDCl3): δ = -4.1, 14.2, 15.9, 20.6, 37.9, 38.9, 59.6, 125.9, 127.8, 129.5, 176.0. FTIR (KBr): 844, 1180, 1199, 1252, 1262, 1454, 1715, 2963, 3030 cm-¹. HRMS: m/z [M + H]+ calcd for C15H24O2Si: 265.1624; found: 265.1631.
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7

Typical Procedure for the Preparation of 3a: To a suspension of NaH (0.5 mmol, 0.013 g) in THF (0.4 mL) was added imine (0.5 mmol) as a solution in THF (0.4 mL). Then MeCN (1.2 mL) was added. After 5 min, TMSCH2CO2Et (0.092 mL, 0.5 mmol) was added and the resulting mixture was stirred until complete disappearance of the starting materials. The solution was poured into brine and extracted with Et2O (2 × 10 mL). The combined organic layers were dried over MgSO4, and concentrated. The residue was purified by flash chromatography to afford the corresponding cyanomethylated product.
3-Phenyl-3-(2-hydroxyphenylamino)propanenitrile (3a): orange solid; mp 119-120 ˚C. Purification: SiO2; 30% Et2O in PE. ¹H NMR (300 MHz, CDCl3): δ = 2.86 (d, J = 6.2 Hz, 2 H), 4.72 (t, J = 6.4 Hz, 1 H), 6.52 (d, J = 7.9 Hz, 1 H), 6.62-6.68 (m, 1 H), 6.73-6.78 (m, 2 H), 7.31-7.43 (m, 5 H). ¹³C NMR (75 MHz, CDCl3): δ = 26.4, 54.9, 113.8, 114.8, 117.5, 119.3, 121.4, 126.3, 128.5, 129.2, 134.5, 140.0, 144.3. FTIR (KBr): 610, 703, 734, 1128, 1199, 1244, 1445, 1510, 1522, 1613, 2264, 3380 cm-¹. HRMS (EI): m/z calcd for C15H14N2O: 238.1106; found: 238.1111.

8

Spectral Data for 2-Methyl-3-phenyl-3-(3-hydroxy-phenylamino)propanenitrile (3b): pale yellow solid; mp <50 ˚C (syn/anti = 1:1 mixture). Purification: SiO2; 30-50% Et2O in PE. ¹H NMR (300 MHz, CDCl3; syn/anti = 1:1 mixture): δ = 1.12 (d, J = 7.2 Hz, 3 H), 1.27 (d, J = 7.2 Hz, 3 H), 2.29-2.95 (m, 1 H), 3.11-3.17 (m, 1 H), 4.32-4.37 (m, 1 H + 1 H), 5.98-6.00 (m, 2 H), 6.07-6.12 (m, 4 H), 6.83-6.90 (m, 2 H), 7.16-7.23 (m, 10 H). ¹³C NMR (75 MHz, CDCl3; syn/anti = 1:1 mixture): δ = 14.9, 16.0, 59.4, 59.9, 101.1, 105.8, 105.9, 106.8, 120.9, 126.0, 126.6, 127.3, 128.4, 128.6, 129.0, 130.3, 130.4, 130.5, 137.9, 139.6, 147.6, 147.9, 156.8, 156.9. FTIR (KBr): 772, 1161, 1219, 1338, 1599, 1732, 2921, 3378 cm-¹. HRMS (EI): m/z calcd for C16H16N2O: 252.1263; found: 252.1272.

9

Typical Procedure for the Preparation of 4: To a suspension of NaH (0.5 mmol, 0.013 g) in THF (0.5 mL) was added imine (0.5 mmol) as a solution in THF (1 mL). Then EtCN (0.5 mL) was added. After 5 min, TMSCH2CO2Et (0.138 mL, 0.75 mmol) was added and the resulting mixture was stirred until complete disappearance of the starting materials. The solution was poured into brine and extracted with Et2O (2 × 10 mL). The combined organic layers were dried over MgSO4, and concentrated. The residue was purified by flash chromatography to afford the corresponding β-lactam.
1-(2-Hydroxyphenyl)-4-(2-naphthyl)azetidin-2-one (4ca): pale yellow solid; mp 136-138 ˚C. Purification: SiO2; 20-30% Et2O in PE; R f 0.56 (33% EtOAc in PE). ¹H NMR (300 MHz, CDCl3): δ = 2.99 (dd, J = 15.6, 2.4 Hz, 1 H), 3.58 (dd, J = 15.4, 5.4 Hz, 1 H), 5.22 (dd, J = 2.3, 1.8 Hz, 1 H), 6.54-6.62 (m, 2 H), 6.99-7.04 (m, 2 H), 7.43-7.55 (m, 3 H), 7.83-7.89 (m, 4 H), 9.92 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 43.9, 54.3, 117.6, 119.0, 119.8, 122.7, 125.6, 125.9, 126.7, 126.9, 127.9, 128.0, 129.6, 133.3, 133.5, 134.4, 147.7, 166.2. FTIR (KBr): 742, 1377, 1495, 1707, 2967, 3016 cm-¹. HRMS (EI): m/z calcd for C19H15NO2: 289.1103; found: 289.1106.
3-Benzyl-1-(2-hydroxyphenyl)-3-methyl-4-[4-(trifluoromethyl)phenyl]azetidin-2-one (4kc): purification: SiO2; 10-15% Et2O in PE.
trans Isomer: white solid; mp 154-156 ˚C; R f 0.47 (30% Et2O in PE). ¹H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3 H), 3.09 (d, J = 14.0 Hz, 1 H), 3.26 (d, J = 13.9 Hz, 1 H), 5.17 (s, 1 H), 6.32 (dd, J = 0.8, 7.7 Hz, 1 H), 6.61-6.67 (m, 1 H), 7.04-7.07 (m, 4 H), 7.30-7.42 (m, 5 H), 7.54 (d, J = 8.8 Hz, 2 H), 9.79 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 16.8, 41.8, 57.0, 62.2, 117.9, 119.3, 119.9, 124.8, 125.7, 125.8, 125.9, 125.95, 126.0, 127.0, 127.1, 127.6, 128.9, 130.2, 130.3, 130.7, 135.8, 138.5, 147.8, 171.9.
cis Isomer (trans/cis mixture = 63:36): pale yellow oil;
R f 0.28 (30% Et2O in PE). ¹H NMR (300 MHz, CDCl3): δ = 1.50 (s, 3 H), 2.26 (d, J = 14.1 Hz, 1 H), 2.74 (d, J = 14.1 Hz, 1 H), 5.04 (s, 1 H), 6.43 (app. d, J = 7.6 Hz, 1 H), 6.60-6.67 (m, 1 H), 6.90-6.94 (m, 2 H), 7.03-7.08 (m, 3 H), 7.09-7.13 (m, 3 H), 7.30-7.41 (m, 1 H), 7.57 (app. d, J = 8.1 Hz, 2 H), 9.85 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 21.0, 38.6, 56.1, 66.3, 118.1, 119.6, 120.1, 125.2, 126.15, 126.2, 126.25, 126.3, 127.0, 127.2, 127.8, 129.2, 130.2, 130.4, 135.6, 138.4, 148.1, 172.0. FTIR (KBr): 748, 1068, 1125, 1168, 1326, 1498, 1714, 2929, 3067 cm-¹. HRMS (EI): m/z calcd for C24H20NO2F3: 411.1446; found: 411.1450.

11

A NOESY experiment was conducted on trans-4kc. Strong NOE correlation was observed between CH 2Ph and H(4) indicating a cis relationship between these substituents. The stereochemistry of the other β-lactams 4 was assigned by extrapolation of these findings along with the fact that H(4) of the major isomer always exhibit a higher chemical shift than that observed in the minor isomer.