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

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.

imines - lactams - silicon - phenols - tandem reactions

References and Notes

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<A NAME="RG18909ST-5">5</A> Poisson T. Gembus V. Oudeyer S. Marsais F. Levacher V. J. Org. Chem.  2009,  74:  3516 

For examples of the beneficial effect of the 2-aminophenol-derived imines in nucleophilic addition reactions, see:

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<A NAME="RG18909ST-7">7</A>

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.

<A NAME="RG18909ST-8">8</A>

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.

<A NAME="RG18909ST-9">9</A>

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.

<A NAME="RG18909ST-10">10</A> 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.

<A NAME="RG18909ST-11">11</A>

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.

<A NAME="RG18909ST-12">12</A> cis- and trans-β-Lactam 4ab resulting from the reaction with 2b can be easily identified by comparison with literature data: Jiao L. Liang Y. Xu J. J. Am. Chem. Soc.  2006,  128:  6060 

For examples of such hexavalent silicon species, see:

<A NAME="RG18909ST-13A">13a</A> Fujisawa H. Nakagawa T. Mukaiyama T. Adv. Synth. Catal.  2004,  346:  1241 

<A NAME="RG18909ST-13B">13b</A> Kawano Y. Fujisawa H. Mukaiyama T. Chem. Lett.  2005,  34:  422 

<A NAME="RG18909ST-14">14</A> Fujita M. Kitagawa O. Yamada Y. Izawa H. Hasegawa H. Tagushi T. J. Org. Chem.  2000,  65:  1108